animal models of COVID-19 [SEP] what drugs have been active against SARS-CoV or SARS-CoV-2 in animal studies? [SEP] Papers that describe the results  of testing drugs that bind to spike proteins of the virus or any other drugs in any animal models. Papers about SARS-CoV-2 infection in cell culture assays are also relevant.
An outbreak of COVID‐19 caused by a new coronavirus: what we know so far
02f0opkr
02f0opkr
2020-03-08
10.5694/mja2.50530
0.5
Screening of an FDA-approved compound library identifies four small-molecule inhibitors of Middle East respiratory syndrome coronavirus replication in cell culture.
Coronaviruses can cause respiratory and enteric disease in a wide variety of human and animal hosts. The 2003 outbreak of severe acute respiratory syndrome (SARS) first demonstrated the potentially lethal consequences of zoonotic coronavirus infections in humans. In 2012, a similar previously unknown coronavirus emerged, Middle East respiratory syndrome coronavirus (MERS-CoV), thus far causing over 650 laboratory-confirmed infections, with an unexplained steep rise in the number of cases being recorded over recent months. The human MERS fatality rate of ∼ 30% is alarmingly high, even though many deaths were associated with underlying medical conditions. Registered therapeutics for the treatment of coronavirus infections are not available. Moreover, the pace of drug development and registration for human use is generally incompatible with strategies to combat emerging infectious diseases. Therefore, we have screened a library of 348 FDA-approved drugs for anti-MERS-CoV activity in cell culture. If such compounds proved sufficiently potent, their efficacy might be directly assessed in MERS patients. We identified four compounds (chloroquine, chlorpromazine, loperamide, and lopinavir) inhibiting MERS-CoV replication in the low-micromolar range (50% effective concentrations [EC(50)s], 3 to 8 μM). Moreover, these compounds also inhibit the replication of SARS coronavirus and human coronavirus 229E. Although their protective activity (alone or in combination) remains to be assessed in animal models, our findings may offer a starting point for treatment of patients infected with zoonotic coronaviruses like MERS-CoV. Although they may not necessarily reduce viral replication to very low levels, a moderate viral load reduction may create a window during which to mount a protective immune response.
02n30zc5
02n30zc5
2014
10.1128/aac.03011-14
2
Molecular Basis for ADP-ribose Binding to the Macro-X Domain of SARS-CoV-2 Nsp3
The virus that causes COVID-19, SARS-CoV-2, has a large RNA genome that encodes numerous proteins that might be targets for antiviral drugs. Some of these proteins, such as the RNA-dependent RNA polymers, helicase and main protease, are well conserved between SARS-CoV-2 and the original SARS virus, but several others are not. This study examines one of the proteins encoded by SARS-CoV-2 that is most different, a macrodomain of nonstructural protein 3 (nsp3). Although 26% of the amino acids in this SARS-CoV-2 macrodomain differ from those seen in other coronaviruses, biochemical and structural data reveal that the protein retains the ability to bind ADP-ribose, which is an important characteristic of beta coronaviruses, and potential therapeutic target.
02q9y011
02q9y011
2020-04-29
10.1101/2020.03.31.014639
1
Boceprevir, GC-376, and calpain inhibitors II, XII inhibit SARS-CoV-2 viral replication by targeting the viral main protease
A novel coronavirus SARS-CoV-2, also called novel coronavirus 2019 (nCoV-19), started to circulate among humans around December 2019, and it is now widespread as a global pandemic. The disease caused by SARS-CoV-2 virus is called COVID-19, which is highly contagious and has an overall mortality rate of 6.96% as of May 4, 2020. There is no vaccine or antiviral available for SARS-CoV-2. In this study, we report our discovery of inhibitors targeting the SARS-CoV-2 main protease (M(pro)). Using the FRET-based enzymatic assay, several inhibitors including boceprevir, GC-376, and calpain inhibitors II, and XII were identified to have potent activity with single-digit to submicromolar IC(50) values in the enzymatic assay. The mechanism of action of the hits was further characterized using enzyme kinetic studies, thermal shift binding assays, and native mass spectrometry. Significantly, four compounds (boceprevir, GC-376, calpain inhibitors II and XII) inhibit SARS-CoV-2 viral replication in cell culture with EC(50) values ranging from 0.49 to 3.37 μM. Notably, boceprevir, calpain inhibitors II and XII represent novel chemotypes that are distinct from known M(pro) inhibitors. A complex crystal structure of SARS-CoV-2 M(pro) with GC-376, determined at 2.15 Å resolution with three monomers per asymmetric unit, revealed two unique binding configurations, shedding light on the molecular interactions and protein conformational flexibility underlying substrate and inhibitor binding by M(pro). Overall, the compounds identified herein provide promising starting points for the further development of SARS-CoV-2 therapeutics.
047xpt2c
047xpt2c
2020-01-06
10.1101/2020.04.20.051581
2
Full spectrum of COVID-19 severity still being depicted
05qglt1f
05qglt1f
2020-03-27
10.1016/s0140-6736(20)30308-1
1.5
The anti‐HIV drug nelfinavir mesylate (Viracept) is a potent inhibitor of cell fusion caused by the SARSCoV‐2 spike (S) glycoprotein warranting further evaluation as an antiviral against COVID‐19 infections
Severe acute respiratory syndrome coronavirus‐2 (SARS CoV‐2) is the causative agent of the coronavirus disease‐2019 (COVID‐19) pandemic. Coronaviruses enter cells via fusion of the viral envelope with the plasma membrane and/or via fusion of the viral envelope with endosomal membranes after virion endocytosis. The spike (S) glycoprotein is a major determinant of virus infectivity. Herein, we show that the transient expression of the SARS CoV‐2 S glycoprotein in Vero cells caused extensive cell fusion (formation of syncytia) in comparison to limited cell fusion caused by the SARS S glycoprotein. Both S glycoproteins were detected intracellularly and on transfected Vero cell surfaces. These results are in agreement with published pathology observations of extensive syncytia formation in lung tissues of patients with COVID‐19. These results suggest that SARS CoV‐2 is able to spread from cell‐to‐cell much more efficiently than SARS effectively avoiding extracellular neutralizing antibodies. A systematic screening of several drugs including cardiac glycosides and kinase inhibitors and inhibitors of human immunodeficiency virus (HIV) entry revealed that only the FDA‐approved HIV protease inhibitor, nelfinavir mesylate (Viracept) drastically inhibited S‐n‐ and S‐o‐mediated cell fusion with complete inhibition at a 10‐μM concentration. In‐silico docking experiments suggested the possibility that nelfinavir may bind inside the S trimer structure, proximal to the S2 amino terminus directly inhibiting S‐n‐ and S‐o‐mediated membrane fusion. Also, it is possible that nelfinavir may act to inhibit S proteolytic processing within cells. These results warrant further investigations of the potential of nelfinavir mesylate to inhibit virus spread at early times after SARS CoV‐2 symptoms appear.
06lddk87
06lddk87
2020-05-17
10.1002/jmv.25985
3
Complete protection against severe acute respiratory syndrome coronavirus-mediated lethal respiratory disease in aged mice by immunization with a mouse-adapted virus lacking E protein.
Zoonotic coronaviruses, including the one that caused severe acute respiratory syndrome (SARS), cause significant morbidity and mortality in humans. No specific therapy for any human coronavirus is available, making vaccine development critical for protection against these viruses. We previously showed that recombinant SARS coronavirus (SARS-CoV) (Urbani strain based) lacking envelope (E) protein expression (rU-ΔE) provided good but not perfect protection in young mice against challenge with virulent mouse-adapted SARS-CoV (MA15). To improve vaccine efficacy, we developed a second set of E-deleted vaccine candidates on an MA15 background (rMA15-ΔE). rMA15-ΔE is safe, causing no disease in 6-week-, 12-month-, or 18-month-old BALB/c mice. Immunization with this virus completely protected mice of three ages from lethal disease and effected more-rapid virus clearance. Compared to rU-ΔE, rMA15-ΔE immunization resulted in significantly greater neutralizing antibody and SARS-CoV-specific CD4 and CD8 T cell responses. After challenge, inflammatory cell infiltration, edema, and lung destruction were decreased in the lungs of rMA15-ΔE-immunized mice compared to those in rU-ΔE-immunized 12-month-old mice. Collectively, these results show that immunization with a species-adapted attenuated coronavirus lacking E protein expression is safe and provides optimal immunogenicity and long-term protection against challenge with lethal virus. This approach will be generally useful for development of vaccines protective against human coronaviruses as well as against coronaviruses that cause disease in domestic and companion animals.
076qek8o
076qek8o
2013
10.1128/jvi.00087-13
4
Extensive Literature Search on the ‘Effects of Copper intake levels in the gut microbiota profile of target animals, in particular piglets’
08ugoxns
08ugoxns
2016-05-02
10.2903/sp.efsa.2016.en-1024
5
Dose-dependent response to infection with SARS-CoV-2 in the ferret model: evidence of protection to re-challenge
In December 2019 an outbreak of coronavirus disease (COVID-19) emerged in Wuhan, China. The causative agent was subsequently identified and named severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) which rapidly spread worldwide causing a pandemic. Currently there are no licensed vaccines or therapeutics available against SARS-CoV-2 but numerous candidate vaccines are in development and repurposed drugs are being tested in the clinic. There is a vital need for authentic COVID-19 animal models to further our understanding of pathogenesis and viral spread in addition to pre-clinical evaluation of candidate interventions. Here we report a dose titration study of SARS-CoV-2 to determine the most suitable infectious dose to use in the ferret model. We show that a high (5×106 pfu) and medium (5×104 pfu) dose of SARS-CoV-2 induces consistent upper respiratory tract (URT) viral RNA shedding in both groups of six challenged animals, whilst a low dose (5×102 pfu) resulted in only one of six displaying signs of URT viral RNA replication. The URT shedding lasted up to 21 days in the high dose animals with intermittent positive signal from day 14. Sequential culls revealed distinct pathological signs of mild multifocal bronchopneumonia in approximately 5-15% of the lung, observed on day 3 in high and medium dosed animals, with presence of mild broncho-interstitial pneumonia on day 7 onwards. No obvious elevated temperature or signs of coughing or dyspnoea were observed although animals did present with a consistent post-viral fatigue lasting from day 9-14 in the medium and high dose groups. After virus shedding ceased, re-challenged ferrets were shown to be fully protected from acute lung pathology. The endpoints of URT viral RNA replication in addition to distinct lung pathology and post viral fatigue were observed most consistently in the high dose group. This ferret model of SARS-CoV-2 infection presents a mild clinical disease (as displayed by 80% of patients infected with SARS-CoV-2). In addition, intermittent viral shedding on days 14-21 parallel observations reported in a minority of clinical cases.
08zf7161
08zf7161
2020-05-29
10.1101/2020.05.29.123810
4
Modelling SARS-CoV-2 Dynamics: Implications for Therapy
The scientific community is focussed on developing antiviral therapies to mitigate the impacts of the ongoing novel coronavirus disease (COVID-19) outbreak. This will be facilitated by improved understanding of viral dynamics within infected hosts. Here, using a mathematical model in combination with published viral load data collected from the same specimen (throat / nasal swabs or nasopharyngeal / sputum / tracheal aspirate), we compare within-host dynamics for patients infected in the current outbreak with analogous dynamics for MERS-CoV and SARS-CoV infections. Our quantitative analyses revealed that SARS-CoV-2 infection dynamics are more severe than those for mild cases of MERS-CoV, but are similar to severe cases, and that the viral dynamics of SARS-CoV infection are similar to those of MERS-CoV in mild cases but not in severe case. Consequently, SARS-CoV-2 generates infection dynamics that are more severe than SARS-CoV. Furthermore, we used our viral dynamics model to predict the effectiveness of unlicensed drugs that have different methods of action. The effectiveness was measured by AUC of viral load. Our results indicated that therapies that block de novo infections or virus production are most likely to be effective if initiated before the peak viral load (which occurs around three days after symptom onset on average), but therapies that promote cytotoxicity are likely to have only limited effects. Our unique mathematical approach provides insights into the pathogenesis of SARS-CoV-2 in humans, which are useful for development of antiviral therapies.
09r4d3nu
09r4d3nu
2020-03-27
10.1101/2020.03.23.20040493
1.5
Repurposing antimalarials and other drugs for COVID-19
0aj2zwx8
0aj2zwx8
2020-04-02
10.1016/j.tmaid.2020.101658
3
A Review of SARS-CoV-2 and the Ongoing Clinical Trials
The sudden outbreak of 2019 novel coronavirus (2019-nCoV, later named SARS-CoV-2) in Wuhan, China, which rapidly grew into a global pandemic, marked the third introduction of a virulent coronavirus into the human society, affecting not only the healthcare system, but also the global economy. Although our understanding of coronaviruses has undergone a huge leap after two precedents, the effective approaches to treatment and epidemiological control are still lacking. In this article, we present a succinct overview of the epidemiology, clinical features, and molecular characteristics of SARS-CoV-2. We summarize the current epidemiological and clinical data from the initial Wuhan studies, and emphasize several features of SARS-CoV-2, which differentiate it from SARS-CoV and Middle East respiratory syndrome coronavirus (MERS-CoV), such as high variability of disease presentation. We systematize the current clinical trials that have been rapidly initiated after the outbreak of COVID-19 pandemic. Whereas the trials on SARS-CoV-2 genome-based specific vaccines and therapeutic antibodies are currently being tested, this solution is more long-term, as they require thorough testing of their safety. On the other hand, the repurposing of the existing therapeutic agents previously designed for other virus infections and pathologies happens to be the only practical approach as a rapid response measure to the emergent pandemic, as most of these agents have already been tested for their safety. These agents can be divided into two broad categories, those that can directly target the virus replication cycle, and those based on immunotherapy approaches either aimed to boost innate antiviral immune responses or alleviate damage induced by dysregulated inflammatory responses. The initial clinical studies revealed the promising therapeutic potential of several of such drugs, including favipiravir, a broad-spectrum antiviral drug that interferes with the viral replication, and hydroxychloroquine, the repurposed antimalarial drug that interferes with the virus endosomal entry pathway. We speculate that the current pandemic emergency will be a trigger for more systematic drug repurposing design approaches based on big data analysis.
0b0fvnhn
0b0fvnhn
2020-04-10
10.3390/ijms21072657
2
Big Data and Biodefense: Prospects and Pitfalls
This chapter will provide an overview of how “big data” and “big data” analytics can be brought to bear on the pressing biodefense challenges of: (1) threat awareness; and (2) surveillance and detection. The chapter will also discuss potential problems that can arise by relying exclusively on “big data” approaches, which have properties and limitations inherent in their composition that may not be initially recognized but which may lead to erroneous results. The chapter will conclude by discussing how multi-disciplinary teams of researchers using hybrid systems, involving “big data” and “small data,” could more effectively and accurately contribute to understanding biodefense problems.
0bhvljeh
0bhvljeh
2019-03-31
10.1007/978-3-030-03053-7_15
1
Antiviral Drugs Against Severe Fever With Thrombocytopenia Syndrome Virus Infection
Severe fever with thrombocytopenia syndrome (SFTS) is an emerging tick-borne infectious disease caused by SFTS virus (SFTSV), which is a novel bunyavirus. SFTSV was first isolated from patients who presented with fever, thrombocytopenia, leukocytopenia, and multiorgan dysfunction in China. Subsequently, it was found to be widely distributed in Southeast Asia (Korea, Japan, and Vietnam). SFTSV can be transmitted not only from ticks but also from domestic animals, companion animals, and humans. Because the case fatality rate of SFTS is high (6–30%), development of specific and effective treatment for SFTS is required. Studies of potential antiviral drugs for SFTS-specific therapy have been conducted on existing or newly discovered agents in vitro and in vivo, with ribavirin and favipiravir being the most promising candidates. While animal experiments and retrospective studies have demonstrated the limited efficacy of ribavirin, it was also speculated that ribavirin would be effective in patients with a viral load <1 × 10(6) copies/mL. Favipiravir showed higher efficacy than ribavirin against SFTSV in in vitro assays and greater efficacy in animal models, even administrated 3 days after the virus inoculation. Although clinical trials evaluating the efficacy of favipiravir in SFTS patients in Japan are underway, this has yet to be confirmed. Other drugs, including hexachlorophene, calcium channel blockers, 2′-fluoro-2′-deoxycytidine, caffeic acid, amodiaquine, and interferons, have also been evaluated for their inhibitory efficacy against SFTSV. Among them, calcium channel blockers are promising because in addition to their efficacy in vitro and in vivo, retrospective clinical data have indicated that nifedipine, one of the calcium channel blockers, reduced the case fatality rate by >5-fold. Although further research is necessary to develop SFTS-specific therapy, considerable progress has been achieved in this area. Here we summarize and discuss recent advances in antiviral drugs against SFTSV.
0czu600e
0czu600e
2020-02-11
10.3389/fmicb.2020.00150
2.5
COVID-19 Outbreak in Malaysia
In 2020 a significant threat to public health emerged. The novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) epidemic outbreak emerged in December 2019 from Wuhan City, Hubei Province, China and spread to the rest of the world. This disease was named COVID-19 by World Health Organization. To date (17(th) April 2020) a total of 2,230,439 cases of COVID-19; 150,810 cases of deaths and 564,210 recovered cases have been reported worldwide. In this review the SARS-CoV-2 morphology, pathogenic mechanism, similarities and differences between SARS-CoV and Middle East Respiratory Syndrome and severe acute respiratory syndrome, transmission mode, diagnosis, treatment, and preventive measures were investigated. The outbreak of COVID-19 from a Malaysian perspective was explored and mental health care during the COVID-19 outbreak was explored. To date, there is no vaccine or no specific treatment for COVID-19. Therefore, preventive measures are very important to prevent and control the rapid spread of the SARS-CoV-2 virus. Preparedness should be a priority for future pandemic outbreaks.
0d34abdo
0d34abdo
2020-06-16
10.24171/j.phrp.2020.11.3.08
4
Antigenicity and immunogenicity of SARS-CoV S protein receptor-binding domain stably expressed in CHO cells
The receptor-binding domain (RBD) of SARS coronavirus (SARS-CoV) spike (S) protein contains multiple conformation-dependent epitopes that induce neutralizing antibody responses. Here we used CHO-K1 cells to establish a cell line for stable expression of a 193-mer (residues 318–510) RBD (RBD193-CHO) and determined its antigenicity and immunogenicity. We found that RBD193-CHO reacted strongly with a panel of six monoclonal antibodies recognizing various conformational and linear epitopes in RBD, suggesting that this recombinant protein maintains intact conformation and good antigenicity. Immunization of mice with RBD193-CHO resulted in induction of high titers of RBD-specific neutralizing antibodies and potent IL-4-expressing T cell responses. RBD193-CHO induced immunity that protected a majority of the vaccinated mice from SARS-CoV challenge. These results suggest that the recombinant RBD produced in an established stable cell line maintains strong immunogenicity with high potential for use as an effective and economic subunit SARS vaccine.
0dbuo39v
0dbuo39v
2009-07-01
10.1016/j.bbrc.2009.05.003
3.5
Mechanistic modeling of the SARS-CoV-2 disease map
Here we present a web interface that implements a comprehensive mechanistic model of the SARS-CoV-2 disease map in which the detailed activity of the human signaling circuits related to the viral infection and the different antiviral responses, including immune and inflammatory activities, can be inferred from gene expression experiments. Moreover, given to the mechanistic properties of the model, the effect of potential interventions, such as knock-downs, over-expression or drug effects (currently the system models the effect of more than 8000 DrugBank drugs) can be studied in specific conditions. By providing a holistic, systems biology approach to the understanding of the complexities of the viral infection process, this tool will become an important asset in the search for efficient antiviral treatments. The tool is freely available at: http://hipathia.babelomics.org/covid19/
0dpzat5z
0dpzat5z
2020-04-12
10.1101/2020.04.12.025577
2.5
Targeting the SARS-CoV-2 spike
0e3pyxgb
0e3pyxgb
2020
10.1126/science.368.6491.616-b
5
Modeling SARS-CoV-2 infection in mice
0f7csvg7
0f7csvg7
2020
5
Molecular advances in the cell biology of SARS-CoV and current disease prevention strategies
In the aftermath of the SARS epidemic, there has been significant progress in understanding the molecular and cell biology of SARS-CoV. Some of the milestones are the availability of viral genome sequence, identification of the viral receptor, development of an infectious cDNA clone, and the identification of viral antigens that elicit neutralizing antibodies. However, there is still a large gap in our understanding of how SARS-CoV interacts with the host cell and the rapidly changing viral genome adds another variable to this equation. Now the SARS-CoV story has entered a new phase, a search for preventive strategies and a cure for the disease. This review highlights the progress made in identifying molecular aspects of SARS-CoV biology that is relevant in developing disease prevention strategies. Authors conclude that development of successful SARS-CoV vaccines and antivirals depends on the progress we make in these areas in the immediate future.
0fitbwuv
0fitbwuv
2005-04-15
10.1186/1743-422x-2-35
0.5
Mathematical modeling explains differential SARS CoV-2 kinetics in lung and nasal passages in remdesivir treated rhesus macaques
Remdesivir was recently demonstrated to decrease recovery time in hospitalized patients with SARS-CoV-2 infection. In rhesus macaques, early initiation of remdesivir therapy prevented pneumonia and lowered viral loads in the lung, but viral loads increased in the nasal passages five days after therapy. We developed mathematical models to explain these results. We identified that 1) drug potency is slightly higher in nasal passages than in lungs, 2) viral load decrease in lungs relative to nasal passages during therapy because of infection-dependent generation of refractory cells in the lung, 3) incomplete drug potency in the lung that decreases viral loads even slightly may allow substantially less lung damage, and 4) increases in nasal viral load may occur due to a slight blunting of peak viral load and subsequent decrease of the intensity of the innate immune response, as well as a lack of refractory cells. We also hypothesize that direct inoculation of the trachea in rhesus macaques may not recapitulate natural infection as lung damage occurs more abruptly in this model than in human infection. We demonstrate with sensitivity analysis that a drug with higher potency could completely suppress viral replication and lower viral loads abruptly in the nasal passages as well as the lung. One Sentence Summary We developed a mathematical model to explain why remdesivir has a greater antiviral effect on SARS CoV-2 in lung versus nasal passages in rhesus macaques.
0ipyt9xq
0ipyt9xq
2020-06-22
10.1101/2020.06.21.163550
5
Déjà vu: Stimulating open drug discovery for SARS-CoV-2
In the past decade we have seen two major Ebola virus outbreaks in Africa, the Zika virus in Brazil and the Americas and the current pandemic of coronavirus disease (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). There is a strong sense of déjà vu because there are still no effective treatments. In the COVID-19 pandemic, despite being a new virus, there are already drugs suggested as active in in vitro assays that are being repurposed in clinical trials. Promising SARS-CoV-2 viral targets and computational approaches are described and discussed. Here, we propose, based on open antiviral drug discovery approaches for previous outbreaks, that there could still be gaps in our approach to drug discovery.
0j69n035
0j69n035
2020
3
Antiviral Drugs Specific for Coronaviruses in Preclinical Development
Coronaviruses are positive stranded RNA viruses that cause respiratory, enteric and central nervous system diseases in many species, including humans. Until recently, the relatively low burden of disease in humans caused by few of these viruses impeded the development of coronavirus specific therapeutics. However, the emergence of severe acute respiratory syndrome coronavirus (SARS-CoV), and more recently, Middle East respiratory syndrome coronavirus (MERS-CoV), has impelled the development of such drugs. This review focuses on some newly identified SARS-CoV inhibitors, with known mechanisms of action and their potential to inhibit the novel MERS-CoV. The clinical development of optimized versions of such compounds could be beneficial for the treatment and control of SARS-CoV, the current MERS-CoV and other future SARS-like epidemics.
0j8rvapz
0j8rvapz
2014-10-01
10.1016/j.coviro.2014.06.002
3
An Update on Current Therapeutic Drugs Treating COVID-19
The current pandemic of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has presented unprecedented challenges to the healthcare systems in almost every country around the world. Currently, there are no proven effective vaccines or therapeutic agents against the virus. Current clinical management includes infection prevention and control measures and supportive care including supplemental oxygen and mechanical ventilatory support. Evolving research and clinical data regarding the virologic SARS-CoV-2 suggest a potential list of repurposed drugs with appropriate pharmacological effects and therapeutic efficacies in treating COVID-19 patients. In this review, we will update and summarize the most common and plausible drugs for the treatment of COVID-19 patients. These drugs and therapeutic agents include antiviral agents (remdesivir, hydroxychloroquine, chloroquine, lopinavir, umifenovir, favipiravir, and oseltamivir), and supporting agents (Ascorbic acid, Azithromycin, Corticosteroids, Nitric oxide, IL-6 antagonists), among others. We hope that this review will provide useful and most updated therapeutic drugs to prevent, control, and treat COVID-19 patients until the approval of vaccines and specific drugs targeting SARS-CoV-2.
0jr31q5g
0jr31q5g
2020
4
Power of Artificial Intelligence to Diagnose and Prevent Further COVID-19 Outbreak: A Short Communication
Novel coronavirus-19 (2019-nCoV or COVID-19) is by far the most dangerous coronavirus ever identified for the third time in the three decades capable of infecting not only the animals but also the humans across the globe. Nearly 6000 deaths have been recorded due mainly to COVID-19 outbreak worldwide and more than 50% of these deaths appeared to have evolved from China where the virus was thought to originate. The endemicity of COVID-19 dramatically surpassed severe acute respiratory syndrome coronavirus (SARS-CoV) and Middle East respiratory syndrome coronavirus (MERS-CoV) that were so far discovered in 2003 and 2012 respectively. Thus, the World Health Organization (WHO) has declared the 2019-nCoV outbreak not only a public health emergency but also pandemic in nature. Currently, over 120 countries including Nigeria were reported to have more than 157,844 confirmed cases and 5,846 deaths due mainly to COVID-19 outbreak as of March 15, 2020, 10:55 GMT. Artificial Intelligence (AI) is widely used to aid in the prediction, detection, response, recovery of disease and making clinical diagnosis. In this study, we highlighted the power of AI in the containment and mitigation of the spread of COVID-19 outbreak in African countries such as Nigeria where human to human contact is apparently inevitable.
0khg28ex
0khg28ex
2020-04-26
2.5
Role of Chloroquine and Hydroxychloroquine in the Treatment of COVID-19 Infection- A Systematic Literature Review
Background: Coronavirus pandemic is currently a global public health emergency. At present, no pharmacological treatment is known to treat this condition, and there is a need to review the available treatments. Objective: While there have been studies to describe the role of chloroquine and hydroxychloroquine in various viral conditions, there is limited information about the use of them in COVID-19. This systematic review aims to summarize the available evidence regarding the role of chloroquine in treating coronavirus infection. Methods: The preferred reporting items for systematic reviews and meta-analyses (PRISMA) guidelines were used for this review. A literature search was performed using PUBMED & Google Scholar to find articles about the role of CQ in COVID-19 patients. Results: We included 19 publications (Five published articles, three letters/correspondence, one commentary, five pre-proofs of accepted articles, one abstract of yet to be published article, and four were pre-prints (not yet peer-reviewed) articles) in this systematic review. All the articles mentioned about the role of chloroquine and /or hydroxychloroquine in limiting the infection with SARS-CoV-2 (the virus causing COVID-19). Conclusions: There is theoretical, experimental, preclinical and clinical evidence of the effectiveness of chloroquine in patients affected with COVID-19. There is adequate evidence of drug safety from the long-time clinical use of chloroquine and hydroxychloroquine in other indications. More data from ongoing and future trials will add more insight into the role of chloroquine and hydroxychloroquine in COVID-19 infection.
0lk8eujq
0lk8eujq
2020-03-30
10.1101/2020.03.24.20042366
0.5
Insights from the Association of SARS-CoV S-Protein with its Receptor, ACE2
0m5umout
0m5umout
2006
10.1007/978-0-387-33012-9_36
1
Mapping the Global Research and Clinical Trials in COVID-19
COVID-19 has created an unprecedented level of research and innovation activity globally to bring out drug to control or cure the disease, and develop vaccine for long time prevention. A 'new/better normal' is emerging that is trying to push this time period for drug development and vaccine within a year and earlier than that from typical 8 to 10 years for drugs and 10 to 15 years for vaccine. This is happening due to multiple factors: strong policy push by different government that includes dedicated investment, speeding up regulation process, multiple agencies involvement, and multilateral bodies led by WHO trying to create a global platform, huge grants from private funding bodies, strategic linkages across the whole research and innovation value chain between firms, academic, research organisations and start-ups. The paper maps the research papers and ongoing clinical trials to provide an informed view of the current status of the research and drug development activity as seen through the lens of research papers and clinical trials. The intended goal of this study is to help the research community and policy makers to keep track of highly relevant research and drug development in COVID-19.
0mn4jua2
0mn4jua2
2020-06-29
10.1101/2020.06.27.20141788
5
Genetic diversity and evolution of SARS-CoV-2
Abstract COVID-19 is a viral respiratory illness caused by a new coronavirus called SARS-CoV-2. The World Health Organization declared the SARS-CoV-2 outbreak a global public health emergency. We performed genetic analyses of eighty-six complete or near-complete genomes of SARS-CoV-2 and revealed many mutations and deletions on coding and non-coding regions. These observations provided evidence of the genetic diversity and rapid evolution of this novel coronavirus.
0nh58odf
0nh58odf
2020-07-31
10.1016/j.meegid.2020.104260
1
Structural elucidation of SARS-CoV-2 vital proteins: Computational methods reveal potential drug candidates against main protease, Nsp12 polymerase and Nsp13 helicase
Abstract The recently emerged SARS-CoV-2 caused a major outbreak of coronavirus disease 2019 (COVID-19) and instigated a widespread fear, threatening global health security. To date, no licensed antiviral drugs or vaccines are available against COVID-19 although several clinical trials are underway to test possible therapies. During this urgency situation, computational drug discovery methods provide an alternative to tiresome high-throughput screening, particularly in the hit-to-lead-optimization stage. Identification of small molecules that specifically target viral replication apparatus has indicated highest potential towards antiviral drug discovery. In this work, we present potential compounds that specifically target SARS-CoV-2 vital proteins, including the main protease, Nsp12 RNA polymerase and Nsp13 helicase. An integrative virtual screening and molecular dynamics simulations approach led to the identification of potential binding modes and favourable molecular interaction profile of corresponding compounds. Moreover, the identification of structurally important binding site residues in conserved motifs located inside the active site highlights relative importance of ligand binding based on residual energy decomposition analysis. Although the current study lacks experimental validation, the structural information obtained from this computational study has paved way for the design of targeted inhibitors to combat COVID-19 outbreak.
0nqz5y20
0nqz5y20
2020-04-28
10.1016/j.jpha.2020.04.008
2
Activation and maturation of SARS-CoV main protease
The worldwide outbreak of the severe acute respiratory syndrome (SARS) in 2003 was due to the transmission of SARS coronavirus (SARS-CoV). The main protease (M(pro)) of SARS-CoV is essential for the viral life cycle, and is considered to be an attractive target of anti-SARS drug development. As a key enzyme for proteolytic processing of viral polyproteins to produce functional non-structure proteins, M(pro) is first auto-cleaved out of polyproteins. The monomeric form of M(pro) is enzymatically inactive, and it is activated through homo-dimerization which is strongly affected by extra residues to both ends of the mature enzyme. This review provides a summary of the related literatures on the study of the quaternary structure, activation, and self-maturation of M(pro) over the past years.
0oh701o3
0oh701o3
2011-04-01
10.1007/s13238-011-1034-1
3
Bridging protein local structures and protein functions
One of the major goals of molecular and evolutionary biology is to understand the functions of proteins by extracting functional information from protein sequences, structures and interactions. In this review, we summarize the repertoire of methods currently being applied and report recent progress in the field of in silico annotation of protein function based on the accumulation of vast amounts of sequence and structure data. In particular, we emphasize the newly developed structure-based methods, which are able to identify locally structural motifs and reveal their relationship with protein functions. These methods include computational tools to identify the structural motifs and reveal the strong relationship between these pre-computed local structures and protein functions. We also discuss remaining problems and possible directions for this exciting and challenging area.
0oq2n0af
0oq2n0af
2008-04-18
10.1007/s00726-008-0088-8
1
How the SARS vaccine effort can learn from HIV—speeding towards the future, learning from the past
A remarkable collaborative effort coordinated by the severe acute respiratory syndrome (SARS) team at WHO resulted in discovery of the etiologic agent of severe acute respiratory syndrome less than 2 months after the announcement of global alert. The development of a vaccine to prevent SARS should be pursued with the same urgency and cooperative spirit, as SARS is highly lethal and, if not controlled during the first few generations of transmission, is likely to become endemic in regions of the world where health-care infrastructure is underdeveloped and epidemiological control measures are weak. The scientific community already learned many important lessons from HIV vaccine development; these should be heeded. For example, consideration should be given to the development of a vaccine that will protect across regional strains of SARS, as the newly emergent coronavirus SARS-coronavirus (SARS-CoV) is proving to be variable and may be mutating in response to immune pressure. SARS-specific research reagents should also be collected and shared. These would include SARS peptides, adjuvants, DNA vaccine vectors and clinical grade viral vectors. Rapidly developing a collaborative approach to developing a SARS vaccine that will be both effective and safe is the only way to go. This article reviews parallels between HIV and SARS and proposes an approach that would accelerate the development of a SARS vaccine.
0plznmwi
0plznmwi
2003-10-01
10.1016/s0264-410x(03)00489-4
2.5
Structure-based drug designing for potential antiviral activity of selected natural products from Ayurveda against SARS-CoV-2 spike glycoprotein and its cellular receptor
The recent outbreak of COVID-19 caused by SARS-CoV-2 brought a great global public health and economic concern. SARS-CoV-2 is an enveloped RNA virus, from the genus Betacoronavirus. Although few molecules have been tested and shown some efficacy against SARS-CoV-2 in humans but a safe and cost-effective attachment inhibitors are still required for the treatment of COVID-19. Natural products are gaining attention because of the large therapeutic window and potent antiviral, immunomodulatory, anti-inflammatory, and antioxidant properties. Therefore, this study was planned to screen natural products from Ayurveda that have the potential to modulate host immune system as well as block the virus entry in host cells by interfering its interaction with cellular receptor and may be used to develop an effective and broad-spectrum strategy for the management of COVID-19 as well as other coronavirus infections in coming future. To decipher the antiviral activity of the selected natural products, molecular docking was performed. Further, the drug-likeness, pharmacokinetics and toxicity parameters of the selected natural products were determined. Docking results suggest that curcumin and nimbin exhibits highest interaction with spike glycoprotein (MolDock score − 141.36 and − 148.621 kcal/mole) and ACE2 receptor (MolDock score − 142.647 and − 140.108 kcal/mole) as compared with other selected natural products/drugs and controls. Also, the pharmacokinetics data illustrated that all selected natural products have better pharmacological properties (low molecular weight; no violation of Lipinski rule of five, good absorption profiles, oral bioavailability, good blood–brain barrier penetration, and low toxicity risk). Our study exhibited that curcumin, nimbin, withaferin A, piperine, mangiferin, thebaine, berberine, and andrographolide have significant binding affinity towards spike glycoprotein of SARS-CoV-2 and ACE2 receptor and may be useful as a therapeutic and/or prophylactic agent for restricting viral attachment to the host cells. However, few other natural products like resveratrol, quercetin, luteolin, naringenin, zingiberene, and gallic acid has the significant binding affinity towards ACE2 receptor only and therefore may be used for ACE2-mediated attachment inhibition of SARS-CoV-2.
0qwveb68
0qwveb68
2020-05-24
10.1007/s13337-020-00598-8
4.5
Predicting inhibitors for SARS-CoV-2 RNA-dependent RNA polymerase using machine learning and virtual screening
Global coronavirus disease pandemic (COVID-19) caused by newly identified SARS- CoV-2 coronavirus continues to claim the lives of thousands of people worldwide. The unavailability of specific medications to treat COVID-19 has led to drug repositioning efforts using various approaches, including computational analyses. Such analyses mostly rely on molecular docking and require the 3D structure of the target protein to be available. In this study, we utilized a set of machine learning algorithms and trained them on a dataset of RNA-dependent RNA polymerase (RdRp) inhibitors to run inference analyses on antiviral and anti-inflammatory drugs solely based on the ligand information. We also performed virtual screening analysis of the drug candidates predicted by machine learning models and docked them against the active site of SARS- CoV-2 RdRp, a key component of the virus replication machinery. Based on the ligand information of RdRp inhibitors, the machine learning models were able to identify candidates such as remdesivir and baloxavir marboxil, molecules with documented activity against RdRp of the novel coronavirus. Among the other identified drug candidates were beclabuvir, a non-nucleoside inhibitor of the hepatitis C virus (HCV) RdRp enzyme, and HCV protease inhibitors paritaprevir and faldaprevir. Further analysis of these candidates using molecular docking against the SARS-CoV-2 RdRp revealed low binding energies against the enzyme active site. Our approach also identified anti-inflammatory drugs lupeol, lifitegrast, antrafenine, betulinic acid, and ursolic acid to have potential activity against SARS-CoV-2 RdRp. We propose that the results of this study are considered for further validation as potential therapeutic options against COVID-19.
0s1vgu85
0s1vgu85
2020-06-09
4
A SARS-CoV-2 infection model in mice demonstrates protection by neutralizing antibodies
Abstract Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused a pandemic with millions of human infections. One limitation to the evaluation of potential therapies and vaccines to inhibit SARS-CoV-2 infection and ameliorate disease is the lack of susceptible small animals in large numbers. Commercially available laboratory strains of mice are not readily infected by SARS-CoV-2 because of species-specific differences in their angiotensin-converting enzyme 2 (ACE2) receptors. Here, we transduced replication-defective adenoviruses encoding human ACE2 via intranasal administration into BALB/c mice and established receptor expression in lung tissues. hACE2-transduced mice were productively infected with SARS-CoV-2, and this resulted in high viral titers in the lung, lung pathology, and weight loss. Passive transfer of a neutralizing monoclonal antibody reduced viral burden in the lung and mitigated inflammation and weight loss. The development of an accessible mouse model of SARS-CoV-2 infection and pathogenesis will expedite the testing and deployment of therapeutics and vaccines.
0slywdik
0slywdik
2020-06-10
10.1016/j.cell.2020.06.011
4
COVID-19 (Novel Coronavirus 2019) - recent trends
The World Health Organization (WHO) has issued a warning that, although the 2019 novel coronavirus (COVID-19) from Wuhan City (China), is not pandemic, it should be contained to prevent the global spread. The COVID-19 virus was known earlier as 2019-nCoV. As of 12 February 2020, WHO reported 45,171 cases and 1115 deaths related to COVID-19. COVID-19 is similar to Severe Acute Respiratory Syndrome coronavirus (SARS-CoV) virus in its pathogenicity, clinical spectrum, and epidemiology. Comparison of the genome sequences of COVID-19, SARS-CoV, and Middle East Respiratory Syndrome coronavirus (MERS-CoV) showed that COVID-19 has a better sequence identity with SARS-CoV compared to MERS CoV. However, the amino acid sequence of COVID-19 differs from other coronaviruses specifically in the regions of 1ab polyprotein and surface glycoprotein or S-protein. Although several animals have been speculated to be a reservoir for COVID-19, no animal reservoir has been already confirmed. COVID-19 causes COVID-19 disease that has similar symptoms as SARS-CoV. Studies suggest that the human receptor for COVID-19 may be angiotensin-converting enzyme 2 (ACE2) receptor similar to that of SARS-CoV. The nucleocapsid (N) protein of COVID-19 has nearly 90% amino acid sequence identity with SARS-CoV. The N protein antibodies of SARS-CoV may cross react with COVID-19 but may not provide cross-immunity. In a similar fashion to SARS-CoV, the N protein of COVID-19 may play an important role in suppressing the RNA interference (RNAi) to overcome the host defense. This mini-review aims at investigating the most recent trend of COVID-19.
0tpy95ki
0tpy95ki
2020
5
Hydroxychloroquine for the management of COVID-19: Hope or Hype? A Systematic review of the current evidence
Purpose: The COVID-19 Pandemic has literally left the world breathless in the chase for Pharmacotherapy. With the vaccine approval likely more than a year away and novel drugs in early clinical trials, repurposing of existing drugs takes the center stage. A potential drug discussed both in geopolitical and global scientific community is hydroxychloroquine (HCQ). We intend to systematically weigh and analyze the existing evidence of HCQ in the light of published and pre-print data available so far. Methods: PubMed Ovid MEDLINE, EMBASE, Google scholar databases and official clinical trial Registries of the United States, China, WHO ICTRP were electronically searched for studies for the use of HCQ in patients with COVID-19. Pre-proof article repositories like MedRxiv, BioRxiv, and ChemRxiv were also included in the search. The literature was critically appraised. Results: Total 71 articles were available as of 15 th April of which articles of relevance (three invitro studies, two open label non-randomized trials, two open label randomized control trials, one follow-up study, three reviews, ten short communications) and 88 clinical trials registered in three clinical trial registries were analyzed. HCQ seems to be efficient in inhibiting of SARS CoV-2 in in-vitro cell lines; there is lack of strong evidence from human studies. Conclusions: The in-vitro cell culture based data of viral inhibition does not suffice for the use of hydroxychloroquine in the patients with COVID-19. Currently literature shows inadequate, low level evidence in human studies. Scarcity of safety and efficacy data warrants medical communities, health care agencies and governments across the world against the widespread use of HCQ in COVID-19 prophylaxis and treatment, until robust evidence becomes available. Keywords: Hydroxychloroquine, SARS-CoV-2, COVID-19, Corona virus, nCov2, systematic review
0u4ar3b5
0u4ar3b5
2020-04-22
10.1101/2020.04.16.20068205
2
COVID-19 and treatment with NSAIDs and corticosteroids: should we be limiting their use in the clinical setting?
Given the current SARS-CoV-2 (COVID-19) pandemic, the availability of reliable information for clinicians and patients is paramount. There have been a number of reports stating that non-steroidal anti-inflammatory drugs (NSAIDs) and corticosteroids may exacerbate symptoms in COVID-19 patients. Therefore, this review aimed to collate information available in published articles to identify any evidence behind these claims with the aim of advising clinicians on how best to treat patients. This review found no published evidence for or against the use of NSAIDs in COVID-19 patients. Meanwhile, there appeared to be some evidence that corticosteroids may be beneficial if utilised in the early acute phase of infection, however, conflicting evidence from the World Health Organisation surrounding corticosteroid use in certain viral infections means this evidence is not conclusive. Given the current availability of literature, caution should be exercised until further evidence emerges surrounding the use of NSAIDs and corticosteroids in COVID-19 patients.
0uengr9t
0uengr9t
2020-03-30
10.3332/ecancer.2020.1023
1.5
Potential therapeutic targets for combating SARS-CoV-2: Drug repurposing, clinical trials and recent advancements
The present pandemic of SARS-CoV-2 has been a tough task for the whole world to deal with. With the absence of specific drugs or vaccines against SARS-CoV-2, the situation is very difficult to control. Apart from the absence of specific therapies, the lack of knowledge about potential therapeutic targets and individual perception is adding to the complications. The present review describes the novel SARS-CoV-2 structure, surface proteins, asymptomatic and symptomatic transmission in addition to the genotype and phenotype of SARS-CoV-2 along with genetic strains and similarity between SARS, MERS and SARS-CoV-2. Therapeutic strategies such as inhibition of the endocytic pathway and suppressing RNA polymerase activity by metal ions, which could be quite beneficial for controlling COVID-19, are outlined. The drug repurposing for SARS-CoV-2 is discussed in detail along with therapeutic classes such as antivirals, antibiotics, and amino quinolones and their probable role in suppressing SARS-CoV-2 with reference to case studies. The ongoing clinical trials both with respect to drug repurposing and vaccines are summarized along with a brief description. The recent advancements and future perspective of ongoing research for therapy and detection of SARS-CoV-2 are provided. The review, in brief, summarizes epidemiology, therapy and the current scenario for combating SARS-CoV-2.
0wh7x410
0wh7x410
2020
4.5
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and coronavirus disease-2019 (COVID-19): The epidemic and the challenges
The emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2; previously provisionally named 2019 novel coronavirus or 2019-nCoV) disease (COVID-19) in China at the end of 2019 has caused a large global outbreak and is a major public health issue. As of 11 February 2020, data from the World Health Organization (WHO) have shown that more than 43 000 confirmed cases have been identified in 28 countries/regions, with >99% of cases being detected in China. On 30 January 2020, the WHO declared COVID-19 as the sixth public health emergency of international concern. SARS-CoV-2 is closely related to two bat-derived severe acute respiratory syndrome-like coronaviruses, bat-SL-CoVZC45 and bat-SL-CoVZXC21. It is spread by human-to-human transmission via droplets or direct contact, and infection has been estimated to have mean incubation period of 6.4 days and a basic reproduction number of 2.24–3.58. Among patients with pneumonia caused by SARS-CoV-2 (novel coronavirus pneumonia or Wuhan pneumonia), fever was the most common symptom, followed by cough. Bilateral lung involvement with ground-glass opacity was the most common finding from computed tomography images of the chest. The one case of SARS-CoV-2 pneumonia in the USA is responding well to remdesivir, which is now undergoing a clinical trial in China. Currently, controlling infection to prevent the spread of SARS-CoV-2 is the primary intervention being used. However, public health authorities should keep monitoring the situation closely, as the more we can learn about this novel virus and its associated outbreak, the better we can respond.
0xhho1sh
0xhho1sh
2020-02-17
10.1016/j.ijantimicag.2020.105924
1
Prediction of the COVID-19 outbreak based on a realistic stochastic model
The current outbreak of coronavirus disease 2019 (COVID-19) has become a global crisis due to its quick and wide spread over the world. A good understanding of the dynamic of the disease would greatly enhance the control and prevention of COVID-19. However, to the best of our knowledge, the unique features of the outbreak have limited the applications of all existing models. In this paper, a novel stochastic model is proposed which aims to account for the unique transmission dynamics of COVID-19 and capture the effects of intervention measures implemented in Mainland China. We find that, (1) instead of aberration, there is a remarkable amount of asymptomatic individuals, (2) an individual with symptoms is approximately twice more likely to pass the disease to others than that of an asymptomatic patient, (3) the transmission rate has reduced significantly since the implementation of control measures in Mainland China, (4) it is expected that the epidemic outbreak would be contained by early March in the the selected provinces and cities.
0xzsa21a
0xzsa21a
2020-03-13
10.1101/2020.03.10.20033803
1
Types of Recombinant Vaccines
The original scientific strategy behind vaccinology has historically been to “isolate, inactivate, and inject,” first invoked by Louis Pasteur.
0zrnfaad
0zrnfaad
2015-09-24
10.1007/978-3-319-25832-4_9
1.5
Mapping the drivers of within-host pathogen evolution using massive data sets
Differences among hosts, resulting from genetic variation in the immune system or heterogeneity in drug treatment, can impact within-host pathogen evolution. Genetic association studies can potentially identify such interactions. However, extensive and correlated genetic population structure in hosts and pathogens presents a substantial risk of confounding analyses. Moreover, the multiple testing burden of interaction scanning can potentially limit power. We present a Bayesian approach for detecting host influences on pathogen evolution that exploits vast existing data sets of pathogen diversity to improve power and control for stratification. The approach models key processes, including recombination and selection, and identifies regions of the pathogen genome affected by host factors. Our simulations and empirical analysis of drug-induced selection on the HIV-1 genome show that the method recovers known associations and has superior precision-recall characteristics compared to other approaches. We build a high-resolution map of HLA-induced selection in the HIV-1 genome, identifying novel epitope-allele combinations.
100r7w2n
100r7w2n
2019-07-09
10.1038/s41467-019-10724-w
1.5
Comparison of SARS-CoV-2 spike protein binding to ACE2 receptors from human, pets, farm animals, and putative intermediate hosts
The emergence of a novel coronavirus, SARS-CoV-2, resulted in a pandemic. Here, we used X-ray structures of human ACE2 bound to the receptor-binding domain (RBD) of the spike protein (S) from SARS-CoV-2 to predict its binding to ACE2 proteins from different animals, including pets, farm animals, and putative intermediate hosts of SARS-CoV-2. Comparing the interaction sites of ACE2 proteins known to serve or not serve as receptor allows to define residues important for binding. From the 20 amino acids in ACE2 that contact S up to seven can be replaced and ACE2 can still function as the SARS-CoV-2 receptor. These variable amino acids are clustered at certain positions, mostly at the periphery of the binding site, while changes of the invariable residues prevent S-binding or infection of the respective animal. Some ACE2 proteins even tolerate the loss or the acquisition of N-glycosylation sites located near the S-interface. Of note, Pigs and dogs, which are not or not effectively infected and have only a few changes in the binding site, exhibit relatively low levels of ACE2 in the respiratory tract. Comparison of the RBD of S of SARS-CoV-2 with viruses from Bat-CoV-RaTG13 and Pangolin-CoV revealed that the latter contains only one substitution, whereas the Bat-CoV-RaTG13 exhibits five. However, ACE2 of pangolin exhibit seven changes relative to human ACE2, a similar number of substitutions is present in ACE2 of bats, raccoon, and civet suggesting that SARS-CoV-2 may not especially adapted to ACE2 of any of its putative intermediate hosts. These analyses provide new insight into the receptor usage and animal source/origin of SARS-CoV-2.IMPORTANCE SARS-CoV-2 is threatening people worldwide and there are no drugs or vaccines available to mitigate its spread. The origin of the virus is still unclear and whether pets and livestock can be infected and transmit SARS-CoV-2 are important and unknown scientific questions. Effective binding to the host receptor ACE2 is the first prerequisite for infection of cells and determines the host range. Our analysis provides a framework for the prediction of potential hosts of SARS-CoV-2. We found that ACE2 from species known to support SARS-CoV-2 infection tolerate many amino acid changes indicating that the species barrier might be low. An exception are dogs and especially pigs, which, however, revealed relatively low ACE2 expression levels in the respiratory tract. Monitoring of animals is necessary to prevent the generation of a new coronavirus reservoir. Finally, our analysis also showed that SARS-CoV-2 may not be specifically adapted to any of its putative intermediate hosts.
10ecm4wi
10ecm4wi
2020
4
Discovery and Development of Antiviral Drugs for Biodefense: Experience of a Small Biotechnology Company
The unmet need for effective antivirals against potential agents of bioterrorism and emerging infections is obvious; however, the challenges to developing such drugs are daunting. Even with the passage of Project BioShield and more recently the BARDA legislation, there is still not a clear market for these types of drugs and limited federal funding available to support expensive drug development studies. SIGA Technologies, Inc. is a small biotech company committed to developing novel products for the prevention and treatment of severe infectious diseases, with an emphasis on products for diseases that could result from bioterrorism. Through trials and error SIGA has developed an approach to this problem in order to establish the infrastructure necessary to successfully advance new antiviral drugs from the discovery stage on through to licensure. The approach that we have taken to drug development is biology driven and dependent on a dispersive development model utilizing essential collaborations with academic, federal, and private sector partners. This consortium approach requires success in acquiring grants and contracts as well as iterative communication with the government and regulatory agencies. However, it can work as evidenced by the rapid progress of our lead antiviral against smallpox, ST-246, and should serve as the template for development of new antivirals against important biological pathogens.
12kihnp7
12kihnp7
2008-01-01
10.1016/j.antiviral.2007.07.003
3.5
What happens next?
The novel coronavirus that emerged in Wuhan has exploded worldwide. What happens if it goes pandemic? Debora MacKenzie reports
12peh5yu
12peh5yu
2020-02-08
10.1016/s0262-4079(20)30235-9
2.5
nSynergistic antiviral effect of hydroxychloroquine and azithromycin in combination against SARS-CoV-2: what molecular dynamics studies of virus-host interactions reveal
The emergence of SARS-coronavirus-2 (SARS-CoV-2) is responsible for a global pandemic disease referred to as coronavirus disease 19 (Covid-19). Hydroxychloroquine/azithromycin combination therapy is currently tested for curing Covid-19, with promising results. However, the molecular mechanism of action of this combination is not established yet. Using molecular dynamics (MD) simulations we show that both drugs act in synergy to prevent any close contact between the virus and the plasma membrane of host cells. We reveal unexpected molecular similarity between azithromycin and the sugar moiety of GM1, a lipid raft ganglioside acting as a host attachment cofactor for respiratory viruses. Due to this mimicry, azithromycin interacts with the ganglioside-binding domain of SARS-CoV-2 spike protein. This binding site shared by azithromycin and GM1 displays a conserved amino acid triad Q-134/F-135/N-137 located at the tip of the spike protein. We also show that hydroxychloroquine molecules can saturate virus attachment sites on gangliosides in the vicinity of the primary coronavirus receptor ACE-2. Taken together, these data show that azithromycin is directed against the virus, whereas hydroxychloroquine is directed against cellular attachment cofactors. We conclude that both drugs act as competitive inhibitors of SARS-CoV-2 attachment to the host cell membrane. This is consistent with a synergistic antiviral mechanism at the plasma membrane level, where the most efficient therapeutic intervention probably stands. This molecular mechanism may explain the beneficial effects of hydroxychloroquine/azithromycin combination therapy in patients with Covid-19. Incidentally, our data suggest that the conserved Q-134/F-135/N-137 triad could be considered as a target for vaccine strategies.
12th7nja
12th7nja
2020-05-13
10.1016/j.ijantimicag.2020.106020
3
A close-up on COVID-19 and cardiovascular diseases
Abstract Aims To analyze the potential mechanism of cardiovascular dysfunctions induced by Coronavirus Disease 2019 (COVID-19) and to evaluate more effective therapeutic pathways for patients with cardiovascular diseases. Data Synthesis COVID-19 mainly invades the lungs, causing its serious damage. Studies found that COVID-19 induced the renin-angiotensin system imbalance, inflammatory storm, hypoxemia and stress response et al, all contributed to hypertension and serious myocardial damage in the process of virus pathogenesis, even increasing mortality in COVID-19 patients. Conclusions In the process of management of COVID-19 infections, close attention should be paid on both lung and cardiovascular damage, especially on those with only symptoms of cardiovascular diseases. Early identification, timely and effective treatments, maintenance of hemodynamics and electrophysiological stability are of great significance on effective treatment and long-term prognosis. The pandemic of COVID-19 has been taking lives worldwide. It caused by a novel coronavirus which human being are lack of defensive function in whole population. It targets human’s lung and causes serious damage of lungs. Based on early reports, for people with underlying heart issues, the concerns are serious. It appears people over 65 with coronary heart diseases or hypertension is more likely to be infected and to develop more severe symptoms. In addition, some of hospitalized COVID-19 patients had cardiovascular diseases in China. As characteristic analysis of COVID-19 patients, hypertension and severe myocardial damage contribute to severity [1] and mortality of COVID-19 patients [2]. Therefore, to better understand the development of COVID-19 and the impacts of cardiovascular diseases will add valuable measures to the management of COVID-19 patients.
13akn7dm
13akn7dm
2020-04-08
10.1016/j.numecd.2020.04.001
1
Computers and viral diseases. Preliminary bioinformatics studies on the design of a synthetic vaccine and a preventative peptidomimetic antagonist against the SARS-CoV-2 (2019-nCoV, COVID-19) coronavirus
Abstract This paper concerns study of the genome of the Wuhan Seafood Market isolate believed to represent the causative agent of the disease COVID-19. This is to find a short section or sections of viral protein sequence suitable for preliminary design proposal for a peptide synthetic vaccine and a peptidomimetic therapeutic, and to explore some design possibilities. The project was originally directed towards a use case for the Q-UEL language and its implementation in a knowledge management and automated inference system for medicine called the BioIngine, but focus here remains mostly on the virus itself. However, using Q-UEL systems to access relevant and emerging literature, and to interact with standard publically available bioinformatics tools on the Internet, did help quickly identify sequences of amino acids that are well conserved across many coronaviruses including 2019-nCoV. KRSFIEDLLFNKV was found to be particularly well conserved in this study and corresponds to the region around one of the known cleavage sites of the SARS virus that are believed to be required for virus activation for cell entry. This sequence motif and surrounding variations formed the basis for proposing a specific synthetic vaccine epitope and peptidomimetic agent. The work can, nonetheless, be described in traditional bioinformatics terms, and readily reproduced by others, albeit with the caveat that new data and research into 2019-nCoV is emerging and evolving at an explosive pace. Preliminary studies using molecular modeling and docking, and in that context the potential value of certain known herbal extracts, are also described.
13jupb26
13jupb26
2020-04-30
10.1016/j.compbiomed.2020.103670
0.5
Covid-19 treatment update: follow the scientific evidence
189vax2m
189vax2m
2020-04-27
10.1007/s11239-020-02120-9
3
Structural and molecular modelling studies reveal a new mechanism of action of chloroquine and hydroxychloroquine against SARS-CoV-2 infection
The recent emergence of the novel pathogenic SARS-coronavirus 2 (SARS-CoV-2) is responsible for a worldwide pandemic. Given the global health emergency, drug repositioning is the most reliable option to design an efficient therapy for infected patients without delay. The first step of the viral replication cycle [i.e. attachment to the surface of respiratory cells, mediated by the spike (S) viral protein] offers several potential therapeutic targets. The S protein uses the angiotension-converting enzyme-2 (ACE-2) receptor for entry, but also sialic acids linked to host cell surface gangliosides. Using a combination of structural and molecular modelling approaches, this study showed that chloroquine (CLQ), one of the drugs currently under investigation for SARS-CoV-2 treatment, binds sialic acids and gangliosides with high affinity. A new type of ganglioside-binding domain at the tip of the N-terminal domain of the SARS-CoV-2 S protein was identified. This domain (111-158), which is fully conserved among clinical isolates worldwide, may improve attachment of the virus to lipid rafts and facilitate contact with the ACE-2 receptor. This study showed that, in the presence of CLQ [or its more active derivative, hydroxychloroquine (CLQ-OH)], the viral S protein is no longer able to bind gangliosides. The identification of this new mechanism of action of CLQ and CLQ-OH supports the use of these repositioned drugs to cure patients infected with SARS-CoV-2. The in-silico approaches used in this study might also be used to assess the efficiency of a broad range of repositioned and/or innovative drug candidates before clinical evaluation.
18yzwa2g
18yzwa2g
2020
3.5
Pathology Elsewhere
19exzl3t
19exzl3t
2004-08-19
10.1038/labinvest.3700153
1
Issues Related to the Use of Animals in Biocontainment Research Facilities
The expansion and improvement of high-containment animal facilities has been driven by terrorism, economics, the emergence of new pathogens, and the re-emergence of other pathogens in new areas. Working with highly infectious viral agents requires a team of trained scientists, laboratory technicians, veterinarians, animal care staff, biological safety officers, engineers, and physical plant staff to ensure safety, biocontainment, and the animals' well being, while providing essential scientific data. The challenges of working with infectious disease agents in high levels of containment, and some solutions to these challenges, are described from an animal care point of view.
1a606yc2
1a606yc2
2005-01-01
10.1093/ilar.46.1.34
5
Protease Inhibitors: Candidate Drugs to Inhibit Severe Acute Respiratory Syndrome Coronavirus 2 Replication.
The number of patients infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has rapidly increased, although the WHO declared a pandemic. However, drugs that function against SARS-CoV-2 have not been established. SARS-CoV-2 has been suggested to bind angiotensin-converting enzyme 2, the receptor of the SARS coronavirus. SARS coronavirus and coronavirus 229E, the cause of the common cold, replicate through cell-surface and endosomal pathways using a protease, the type II transmembrane protease. To examine the effects of protease inhibitors on the replication of coronavirus 229E, we pretreated primary cultures of human nasal epithelial (HNE) cells with camostat or nafamostat, each of which has been used for the treatment of pancreatitis and/or disseminated intravascular coagulation. HNE cells were then infected with coronavirus 229E, and viral titers in the airway surface liquid of the cells were examined. Pretreatment with camostat (0.1-10 μg/mL) or nafamostat (0.01-1 μg/mL) reduced the titers of coronavirus 229E. Furthermore, a significant amount of type II transmembrane protease protein was detected in the airway surface liquid of HNE cells. Additionally, interferons have been reported to have antiviral effects against SARS coronavirus. The additive effects of interferons on the inhibitory effects of other candidate drugs to treat SARS-CoV-2 infection, such as lopinavir, ritonavir and favipiravir, have also been studied. These findings suggest that protease inhibitors of this type may inhibit coronavirus 229E replication in human airway epithelial cells at clinical concentrations. Protease inhibitors, interferons or the combination of these drugs may become candidate drugs to inhibit the replication of SARS-CoV-2.
1a6guo10
1a6guo10
2020
10.1620/tjem.251.27
4
Structures of two coronavirus main proteases: implications for substrate binding and antiviral drug design.
Coronaviruses (CoVs) can infect humans and multiple species of animals, causing a wide spectrum of diseases. The coronavirus main protease (M(pro)), which plays a pivotal role in viral gene expression and replication through the proteolytic processing of replicase polyproteins, is an attractive target for anti-CoV drug design. In this study, the crystal structures of infectious bronchitis virus (IBV) M(pro) and a severe acute respiratory syndrome CoV (SARS-CoV) M(pro) mutant (H41A), in complex with an N-terminal autocleavage substrate, were individually determined to elucidate the structural flexibility and substrate binding of M(pro). A monomeric form of IBV M(pro) was identified for the first time in CoV M(pro) structures. A comparison of these two structures to other available M(pro) structures provides new insights for the design of substrate-based inhibitors targeting CoV M(pro)s. Furthermore, a Michael acceptor inhibitor (named N3) was cocrystallized with IBV M(pro) and was found to demonstrate in vitro inactivation of IBV M(pro) and potent antiviral activity against IBV in chicken embryos. This provides a feasible animal model for designing wide-spectrum inhibitors against CoV-associated diseases. The structure-based optimization of N3 has yielded two more efficacious lead compounds, N27 and H16, with potent inhibition against SARS-CoV M(pro).
1a75s5l0
1a75s5l0
2008
0.5
Which animals are at risk? Predicting species susceptibility to Covid-19
In only a few months, the novel coronavirus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused a global pandemic, leaving physicians, scientists, and public health officials racing to understand, treat, and contain this zoonotic disease. SARS-CoV-2 has made the leap from animals to humans, but little is known about variations in species susceptibility that could identify potential reservoir species, animal models, and the risk to pets, wildlife, and livestock. While there is evidence that certain species, such as cats, are susceptible, the vast majority of animal species, including those in close contact with humans, have unknown susceptibility. Hence, methods to predict their infection risk are urgently needed. SARS-CoV-2 spike protein binding to angiotensin converting enzyme 2 (ACE2) is critical for viral cell entry and infection. Here we identified key ACE2 residues that distinguish susceptible from resistant species using in-depth sequence and structural analyses of ACE2 and its binding to SARS-CoV-2. Our findings have important implications for identification of ACE2 and SARS-CoV-2 residues for therapeutic targeting and identification of animal species with increased susceptibility for infection on which to focus research and protection measures for environmental and public health.
1bvw9f96
1bvw9f96
2020-07-10
10.1101/2020.07.09.194563
5
Self-amplifying RNA SARS-CoV-2 lipid nanoparticle vaccine candidate induces high neutralizing antibody titers in mice
The spread of the SARS-CoV-2 into a global pandemic within a few months of onset motivates the development of a rapidly scalable vaccine. Here, we present a self-amplifying RNA encoding the SARS-CoV-2 spike protein encapsulated within a lipid nanoparticle (LNP) as a vaccine. We observe remarkably high and dose-dependent SARS-CoV-2 specific antibody titers in mouse sera, as well as robust neutralization of both a pseudo-virus and wild-type virus. Upon further characterization we find that the neutralization is proportional to the quantity of specific IgG and of higher magnitude than recovered COVID-19 patients. saRNA LNP immunizations induce a Th1-biased response in mice, and there is no antibody-dependent enhancement (ADE) observed. Finally, we observe high cellular responses, as characterized by IFN-γ production, upon re-stimulation with SARS-CoV-2 peptides. These data provide insight into the vaccine design and evaluation of immunogenicity to enable rapid translation to the clinic.
1c15qxb8
1c15qxb8
2020-07-09
10.1038/s41467-020-17409-9
5
Replication of SARS-CoV-2 in human respiratory epithelium
SARS-CoV-2 emerged by the end of 2019 to rapidly spread in 2020. At present, it is of utmost importance to understand the virus biology and to rapidly assess the potential of existing drugs and develop new active compounds. While some animal models for such studies are under development, most of the research is carried out in the Vero E6 cells. Here, we propose fully differentiated human airway epithelium cultures as a model for studies on the SARS-CoV-2. Further, we also provide basic characteristics of the system.
1cc9ig04
1cc9ig04
2020-03-21
10.1101/2020.03.20.999029
0.5
Clinical benefit of remdesivir in rhesus macaques infected with SARS-CoV-2.
Effective therapeutics to treat COVID-19 are urgently needed. While many investigational, approved, and repurposed drugs have been suggested, preclinical data from animal models can guide the search for effective treatments by ruling out treatments without in vivo efficacy. Remdesivir (GS-5734) is a nucleotide analog prodrug with broad antiviral activity1,2, that is currently investigated in COVID-19 clinical trials and recently received Emergency Use Authorization from the US Food and Drug Administration3,4. In animal models, remdesivir treatment was effective against MERS-CoV and SARS-CoV infection.2,5,6 In vitro, remdesivir inhibited replication of SARS-CoV-2.7,8 Here, we investigated the efficacy of remdesivir treatment in a rhesus macaque model of SARS-CoV-2 infection9. In contrast to vehicle-treated animals, animals treated with remdesivir did not show signs of respiratory disease and had reduced pulmonary infiltrates on radiographs and reduced virus titers in bronchoalveolar lavages 12hrs after the first treatment administration. Virus shedding from the upper respiratory tract was not reduced by remdesivir treatment. At necropsy, lung viral loads of remdesivir-treated animals were lower and there was a reduction in damage to the lungs. Thus, therapeutic remdesivir treatment initiated early during infection had a clinical benefit in SARS-CoV-2-infected rhesus macaques. Although the rhesus macaque model does not represent the severe disease observed in a proportion of COVID-19 patients, our data support early remdesivir treatment initiation in COVID-19 patients to prevent progression to pneumonia.
1cph1uij
1cph1uij
2020-06-09
10.1038/s41586-020-2423-5
4
Structure and Inhibition of the SARS Coronavirus Envelope Protein Ion Channel
The envelope (E) protein from coronaviruses is a small polypeptide that contains at least one α-helical transmembrane domain. Absence, or inactivation, of E protein results in attenuated viruses, due to alterations in either virion morphology or tropism. Apart from its morphogenetic properties, protein E has been reported to have membrane permeabilizing activity. Further, the drug hexamethylene amiloride (HMA), but not amiloride, inhibited in vitro ion channel activity of some synthetic coronavirus E proteins, and also viral replication. We have previously shown for the coronavirus species responsible for severe acute respiratory syndrome (SARS-CoV) that the transmembrane domain of E protein (ETM) forms pentameric α-helical bundles that are likely responsible for the observed channel activity. Herein, using solution NMR in dodecylphosphatidylcholine micelles and energy minimization, we have obtained a model of this channel which features regular α-helices that form a pentameric left-handed parallel bundle. The drug HMA was found to bind inside the lumen of the channel, at both the C-terminal and the N-terminal openings, and, in contrast to amiloride, induced additional chemical shifts in ETM. Full length SARS-CoV E displayed channel activity when transiently expressed in human embryonic kidney 293 (HEK-293) cells in a whole-cell patch clamp set-up. This activity was significantly reduced by hexamethylene amiloride (HMA), but not by amiloride. The channel structure presented herein provides a possible rationale for inhibition, and a platform for future structure-based drug design of this potential pharmacological target.
1e102wrc
1e102wrc
2009-07-10
10.1371/journal.ppat.1000511
2.5
Insights into the cross-species evolution of 2019 novel coronavirus
1e28zj1d
1e28zj1d
2020-03-04
10.1016/j.jinf.2020.02.025
2
Still puzzling questions in immunology (infection and immunity)
1fdmmdll
1fdmmdll
2015-03-26
10.1186/s12865-015-0084-1
4
A Large-scale Drug Repositioning Survey for SARS-CoV-2 Antivirals
The emergence of novel SARS coronavirus 2 (SARS-CoV-2) in 2019 has triggered an ongoing global pandemic of severe pneumonia-like disease designated as coronavirus disease 2019 (COVID-19). To date, more than 2.1 million confirmed cases and 139,500 deaths have been reported worldwide, and there are currently no medical countermeasures available to prevent or treat the disease. As the development of a vaccine could require at least 12-18 months, and the typical timeline from hit finding to drug registration of an antiviral is >10 years, repositioning of known drugs can significantly accelerate the development and deployment of therapies for COVID-19. To identify therapeutics that can be repurposed as SARS-CoV-2 antivirals, we profiled a library of known drugs encompassing approximately 12,000 clinical-stage or FDA-approved small molecules. Here, we report the identification of 30 known drugs that inhibit viral replication. Of these, six were characterized for cellular dose-activity relationships, and showed effective concentrations likely to be commensurate with therapeutic doses in patients. These include the PIKfyve kinase inhibitor Apilimod, cysteine protease inhibitors MDL-28170, Z LVG CHN2, VBY-825, and ONO 5334, and the CCR1 antagonist MLN-3897. Since many of these molecules have advanced into the clinic, the known pharmacological and human safety profiles of these compounds will accelerate their preclinical and clinical evaluation for COVID-19 treatment.
1fgnfh62
1fgnfh62
2020-04-17
10.1101/2020.04.16.044016
2
Antiviral drug discovery against SARS-CoV.
Severe Acute Respiratory Syndrome (SARS) is a life-threatening infectious disease caused by SARS-CoV. In the 2003 outbreak, it infected more than 8,000 people worldwide and claimed the lives of more than 900 victims. The high mortality rate resulted, at least in part, from the absence of definitive treatment protocols or therapeutic agents. Although the virus spreading has been contained, due preparedness and planning, including the successful development of antiviral drugs against SARS-CoV, is necessary for possible reappearance of SARS. In this review, we have discussed currently available strategies for antiviral drug discovery and how these technologies have been utilized to identify potential antiviral agents for the inhibition of SARS-CoV replication. Moreover, progress in the drug development based on different molecular targets is also summarized, including 1) Compounds that block the S protein-ACE2-mediated viral entry; 2) Compounds targeting SARS-CoV M(pro); 3) Compounds targeting papain-like protease 2 (PLP2); 4) Compounds targeting SARS-CoV RdRp; 5) Compounds targeting SARS-CoV helicase; 6) Active compounds with unspecified targets; and 7) Research on siRNA. This review aims to provide a comprehensive account of drug discovery on SARS. The experiences with the SARS outbreak and drug discovery would certainly be an important lesson for the drug development for any new viral outbreaks that may emerge in the future.
1fy9edg3
1fy9edg3
2006
5
Safety and Efficacy of Avaren-Fc Lectibody Targeting HCV High-Mannose Glycans in a Human Liver Chimeric Mouse Model
Infection with hepatitis C virus (HCV) remains to be a major cause of morbidity and mortality worldwide despite the recent advent of highly effective direct-acting antivirals. The envelope glycoproteins of HCV are heavily glycosylated with a high proportion of high-mannose glycans (HMGs), which serve as a shield against neutralizing antibodies and assist in the interaction with cell-entry receptors. However, currently there is no approved therapeutic targeting this potentially druggable biomarker. Here, we investigated the therapeutic potential of the lectibody Avaren-Fc (AvFc), a HMG-binding lectin-Fc fusion protein. In vitro assays showed AvFc’s capacity to neutralize cell culture-derived HCV in a genotype independent manner with IC50 values in the low nanomolar range. A histidine buffer-based AvFc formulation was developed for in vivo studies using the PXB human liver chimeric mouse model. Systemic administration of AvFc was well tolerated; after 11 consecutive doses every other day at 25 mg/kg, there were no significant changes in body or liver weights, nor any impact noted in blood human albumin levels or serum alanine aminotransferase activity. Gross necropsy and liver pathology further confirmed the lack of discernible toxicity. This treatment regimen successfully prevented genotype 1a HCV infection in all animals, while an AvFc mutant lacking HMG binding activity failed to block the infection. These results suggest that targeting envelope HMGs is a promising therapeutic approach against HCV infection. In particular, AvFc may provide a safe and efficacious means to prevent recurrent infection upon liver transplantation in HCV-related end-stage liver disease patients.
1g0isp98
1g0isp98
2020-04-24
10.1101/2020.04.22.056754
4.5
Drug repositioning is an alternative for the treatment of coronavirus COVID-19
Given the extreme importance of the current pandemic caused by COVID-19, and as scientists agree there is no identified pharmacological treatment, where possible, therapeutic alternatives are raised through drug repositioning. This paper presents a selection of studies involving drugs from different pharmaceutical classes with activity against SARS-CoV-2 and SARS-CoV, with the potential for use in the treatment of COVID-19 disease.
1ge2dydz
1ge2dydz
2020
4.5
Phosphatidylinositol 4-Kinase IIIβ Is Required for Severe Acute Respiratory Syndrome Coronavirus Spike-mediated Cell Entry
Phosphatidylinositol kinases (PI kinases) play an important role in the life cycle of several viruses after infection. Using gene knockdown technology, we demonstrate that phosphatidylinositol 4-kinase IIIβ (PI4KB) is required for cellular entry by pseudoviruses bearing the severe acute respiratory syndrome-coronavirus (SARS-CoV) spike protein and that the cell entry mediated by SARS-CoV spike protein is strongly inhibited by knockdown of PI4KB. Consistent with this observation, pharmacological inhibitors of PI4KB blocked entry of SARS pseudovirions. Further research suggested that PI4P plays an essential role in SARS-CoV spike-mediated entry, which is regulated by the PI4P lipid microenvironment. We further demonstrate that PI4KB does not affect virus entry at the SARS-CoV S-ACE2 binding interface or at the stage of virus internalization but rather at or before virus fusion. Taken together, these results indicate a new function for PI4KB and suggest a new drug target for preventing SARS-CoV infection.
1i12ff55
1i12ff55
2012-01-17
10.1074/jbc.m111.312561
2.5
Metronomic oral vinorelbine and lung cancer therapy during the COVID 19 pandemic: a single-center experience
• Intravenous vinorelbine is a standard treatment for advanced NSCLC; • Oral vinorelbine is equally effective as compared to intravenous vinorelbine; • Metronomic oral formulation of vinorelbine is a safe and active treatment for advanced NSCLC; • No established treatment is a “gold standard” during COVID19 era; • Metronomic oral vinorelbine permitted to carry on active treatment during COVID Emergency; • Metronomic oral vinorelbine reduce side effects and hospital visits to lung cancer patients; • Management of lung cancer patients may be improved by metronomic oral vinorelbine.
1i6n6tv6
1i6n6tv6
2020-05-06
10.1016/j.lungcan.2020.05.001
3.5
Disruption of Adaptive Immunity Enhances Disease in SARS-CoV-2 Infected Syrian Hamsters
Animal models recapitulating human COVID-19 disease, especially with severe disease, are urgently needed to understand pathogenesis and evaluate candidate vaccines and therapeutics. Here, we develop novel severe disease animal models for COVID-19 involving disruption of adaptive immunity in Syrian hamsters. Cyclophosphamide (CyP) immunosuppressed or RAG2 knockout (KO) hamsters were exposed to SARS-CoV-2 by the respiratory route. Both the CyP-treated and RAG2 KO hamsters developed clinical signs of disease that were more severe than in immunocompetent hamsters, notably weight loss, viral loads, and fatality (RAG2 KO only). Disease was prolonged in transiently immunosuppressed hamsters and uniformly lethal in RAG2 KO hamsters. We evaluated the protective efficacy of a neutralizing monoclonal antibody and found that pretreatment, even in immunosuppressed animals, limited infection. Our results suggest that functional B and/or T cells are not only important for the clearance of SARS-CoV-2, but also play an early role in protection from acute disease. One Sentence Summary An antibody targeting the spike protein of SARS-CoV-2 limits infection in immunosuppressed Syrian hamster models.
1iio41wn
1iio41wn
2020-06-19
10.1101/2020.06.19.161612
5
Drug Development and Medicinal Chemistry Efforts toward SARS-Coronavirus and Covid-19 Therapeutics
The COVID-19 pandemic caused by SARS-CoV-2 infection is spreading at an alarming rate and has created an unprecedented health emergency around the globe. There is no effective vaccine or approved drug treatment against COVID-19 and other pathogenic coronaviruses. The development of antiviral agents is an urgent priority. Biochemical events critical to the coronavirus replication cycle provided a number of attractive targets for drug development. These include, spike protein for binding to host cell-surface receptors, proteolytic enzymes that are essential for processing polyproteins into mature viruses, and RNA-dependent RNA polymerase for RNA replication. There has been a lot of ground work for drug discovery and development against these targets. Also, high-throughput screening efforts have led to the identification of diverse lead structures, including natural product-derived molecules. This review highlights past and present drug discovery and medicinal-chemistry approaches against SARS-CoV, MERS-CoV and COVID-19 targets. The review hopes to stimulate further research and will be a useful guide to the development of effective therapies against COVID-19 and other pathogenic coronaviruses.
1intktsf
1intktsf
2020
3
Evaluation of the safety, immunogenicity and pharmacokinetics of equine anti-SARS–CoV F(ab′)2 in macaque
Abstract To warrant potential clinical testing, the equine anti-SARS–CoV F(ab′)2 requires evaluation in as many animal models as possible and a safety test in a primate model. In this study, we evaluated the pharmacokinetics, tolerance and immunity of this kind of antibody in macaques and rats. Results showed that the F(ab′)2 fragments had a normal metabolism in injected animals. The general physiological indexes did not differ between animals injected with anti-SARS–CoV F(ab′)2 or saline. However, a mild inflammatory response in local injection site and a moderate immune response against this antibody in the successively injected animals were observed, which however recovered 3 weeks after the last injection. The antibody titring from 1:100 to 400 against the equine anti-SARS–CoV F(ab′)2 in the inoculated hosts could be detected at week 2 during the successive injections of the equine F(ab′)2. The considerable safety of this antibody used in primates and the fact that the immune system of the host can be motivated by post-injection of the F(ab′)2 indicate that this type of anti-SARS–CoV antibody can be used for prevention and treatment of SASR, especially at the early stage of this virus infection. In addition, it can also provide the precious time for the combined use of other anti-SARS–CoV agents such as antiviral drug and vaccine.
1jeat383
1jeat383
2007-12-15
10.1016/j.intimp.2007.09.011
0.5
Development of Animal Models Against Emerging Coronaviruses: From SARS to MERS coronavirus
Two novel coronaviruses have emerged to cause severe disease in humans. While bats may be the primary reservoir for both viruses, SARS coronavirus (SARS-CoV) likely crossed into humans from civets in China, and MERS coronavirus (MERS-CoV) has been transmitted from camels in the Middle East. Unlike SARS-CoV that resolved within a year, continued introductions of MERS-CoV present an on-going public health threat. Animal models are needed to evaluate countermeasures against emerging viruses. With SARS-CoV, several animal species were permissive to infection. In contrast, most laboratory animals are refractory or only semi-permissive to infection with MERS-CoV. This host-range restriction is largely determined by sequence heterogeneity in the MERS-CoV receptor. We describe animal models developed to study coronaviruses, with a focus on host-range restriction at the level of the viral receptor and discuss approaches to consider in developing a model to evaluate countermeasures against MERS-CoV.
1k5h662u
1k5h662u
2015-05-01
10.1016/j.virol.2015.02.030
0.5
Chapter Eight Targeting the Channel Activity of Viroporins
Abstract Since the discovery that certain small viral membrane proteins, collectively termed as viroporins, can permeabilize host cellular membranes and also behave as ion channels, attempts have been made to link this feature to specific biological roles. In parallel, most viroporins identified so far are virulence factors, and interest has focused toward the discovery of channel inhibitors that would have a therapeutic effect, or be used as research tools to understand the biological roles of viroporin ion channel activity. However, this paradigm is being shifted by the difficulties inherent to small viral membrane proteins, and by the realization that protein–protein interactions and other diverse roles in the virus life cycle may represent an equal, if not, more important target. Therefore, although targeting the channel activity of viroporins can probably be therapeutically useful in some cases, the focus may shift to their other functions in following years. Small-molecule inhibitors have been mostly developed against the influenza A M2 (IAV M2 or AM2). This is not surprising since AM2 is the best characterized viroporin to date, with a well-established biological role in viral pathogenesis combined the most extensive structural investigations conducted, and has emerged as a validated drug target. For other viroporins, these studies are still mostly in their infancy, and together with those for AM2, are the subject of the present review.
1kt51viz
1kt51viz
2016-12-31
10.1016/bs.apcsb.2015.12.003
1.5
Overview of therapeutic drug research for COVID-19 in China
Since the outbreak of novel coronavirus pneumonia (COVID-19) in December 2019, more than 2,500,000 people worldwide have been diagnosed with SARS-CoV-2 as of April 22. In response to this epidemic, China has issued seven trial versions of diagnosis and treatment protocol for COVID-19. According to the information that we have collected so far, this article provides an overview of potential therapeutic drugs and compounds with much attention, including favipiravir and hydroxychloroquine, as well as traditional Chinese medicine, which have been reported with good clinical treatment effects. Moreover, with further understanding of SARS-CoV-2 virus, new drugs targeting specific SARS-CoV-2 viral components arise and investigations on these novel anti-SARS-CoV-2 agents are also reviewed.
1kzy7rts
1kzy7rts
2020-06-17
10.1038/s41401-020-0438-y
5
Stability Analysis and Numerical Simulation of SEIR Model for pandemic COVID-19 spread in Indonesia
The Aim of this research is construct the SEIR model for COVID-19, Stability Analysis and numerical simulation of the SEIR model on the spread of COVID-19. The method used to construct the model is the SEIR model by considering vaccination and isolation factors as model parameters, the analysis of the model uses the generation matrix method to obtain the basic reproduction numbers and the global stability of the COVID-19 distribution model. Numerical simulation models use secondary data on the number of COVID-19 cases in Indonesia. The results obtained are the SEIR model for COVID-19; model analysis yields global stability from the spread of COVID-19; The results of the analysis also provide information if no vaccine, Indonesia is endemic COVID-19. Then the simulation results provide a prediction picture of the number of COVID-19 in Indonesia in the following days, the simulation results also show that the vaccine can accelerate COVID-19 healing and maximum isolation can slow the spread of COVID-19. The results obtained can be used as a reference for early prevention of the spread of COVID-19 in Indonesia
1loqavom
1loqavom
2020-07-03
10.1016/j.chaos.2020.110072
5
Nonhuman Primate IFITM Proteins Are Potent Inhibitors of HIV and SIV
Interferon-induced transmembrane (IFITM) proteins are potent antiviral factors shown to restrict the infection of many enveloped viruses, including HIV. Here we report cloning and characterization of a panel of nonhuman primate IFITMs. We show that, similar to human IFITM, nonhuman primate IFITM proteins inhibit HIV and other primate lentiviruses. While some nonhuman primate IFITM proteins are more potent than human counterparts to inhibit HIV-1, they are generally not effective against HIV-2 similar to that of human IFITMs. Notably, depending on SIV strains and also IFITM species tested, nonhuman primate IFITM proteins exhibit distinct activities against SIVs; no correlation was found to support the notion that IFITM proteins are most active in non-natural primate hosts. Consistent with our recent findings for human IFITMs, nonhuman primate IFITM proteins interact with HIV-1 Env and strongly act in viral producer cells to impair viral infectivity and block cell-to-cell transmission. Accordingly, knockdown of primate IFITM3 increases HIV-1 replication in nohuman primate cells. Interestingly, analysis of DNA sequences of human and nonhuman primate IFITMs suggest that IFITM proteins have been undergoing purifying selection, rather than positive selection typical for cellular restriction factors. Overall, our study reveals some new and unexpected features of IFITMs in restricting primate lentiviruses, which enhances our understanding of virus-host interaction and AIDS pathogenesis.
1m1woscb
1m1woscb
2016-06-03
10.1371/journal.pone.0156739
1.5
COVID-19 infection: Origin, transmission, and characteristics of human coronaviruses
The coronavirus disease 19 (COVID-19) is a highly transmittable and pathogenic viral infection caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which emerged in Wuhan, China and spread around the world. Genomic analysis revealed that SARS-CoV-2 is phylogenetically related to severe acute respiratory syndrome-like (SARS-like) bat viruses, therefore bats could be the possible primary reservoir. The intermediate source of origin and transfer to humans is not known, however, the rapid human to human transfer has been confirmed widely. There is no clinically approved antiviral drug or vaccine available to be used against COVID-19. However, few broad-spectrum antiviral drugs have been evaluated against COVID-19 in clinical trials, resulted in clinical recovery. In the current review, we summarize and comparatively analyze the emergence and pathogenicity of COVID-19 infection and previous human coronaviruses severe acute respiratory syndrome coronavirus (SARS-CoV) and middle east respiratory syndrome coronavirus (MERS-CoV). We also discuss the approaches for developing effective vaccines and therapeutic combinations to cope with this viral outbreak.
1mjaycee
1mjaycee
2020-03-16
10.1016/j.jare.2020.03.005
0.5
Structural basis of SARS-CoV-2 3CLpro and anti-COVID-19 drug discovery from medicinal plants †
Abstract The recent outbreak of coronavirus disease 2019 (COVID-19) caused by SARS-CoV-2 in December 2019 raised global health concerns. The viral 3-chymotrypsin-like cysteine protease (3CLpro) enzyme controls coronavirus replication and is essential for its life cycle. 3CLpro is a proven drug discovery target in the case of severe acute respiratory syndrome coronavirus (SARS-CoV) and middle east respiratory syndrome coronavirus (MERS-CoV). Recent studies revealed that the genome sequence of SARS-CoV-2 is very similar to that of SARS-CoV. Therefore, herein, we analysed the 3CLpro sequence, constructed its 3D homology model, and screened it against a medicinal plant library containing 32,297 potential anti-viral phytochemicals/traditional Chinese medicinal compounds. Our analyses revealed that the top nine hits might serve as potential anti- SARS-CoV-2 lead molecules for further optimisation and drug development process to combat COVID-19.
1mmqfp7g
1mmqfp7g
2020-03-26
10.1016/j.jpha.2020.03.009
1
A Multibasic Cleavage Site in the Spike Protein of SARS-CoV-2 Is Essential for Infection of Human Lung Cells
Summary The pandemic coronavirus SARS-CoV-2 threatens public health worldwide. The viral spike protein mediates SARS-CoV-2 entry into host cells and harbors a S1/S2 cleavage site containing multiple arginine residues (multibasic) not found in closely related animal coronaviruses. However, the role of this multibasic cleavage site in SARS-CoV-2 infection is unknown. Here, we report that the cellular protease furin cleaves the spike protein at the S1/S2 site and that cleavage is essential for S-protein-mediated cell-cell fusion and entry into human lung cells. Moreover, optimizing the S1/S2 site increased cell-cell, but not virus-cell, fusion, suggesting that the corresponding viral variants might exhibit increased cell-cell spread and potentially altered virulence. Our results suggest that acquisition of a S1/S2 multibasic cleavage site was essential for SARS-CoV-2 infection of humans and identify furin as a potential target for therapeutic intervention.
1n0qw2a5
1n0qw2a5
2020-05-01
10.1016/j.molcel.2020.04.022
3
SARS-CoV-2 neutralizing antibody development strategies
In December 2019 a novel coronavirus was detected in Wuhan City of Hubei Province-China. Owing to a high rate of transmission from human to human, the new virus called SARS-CoV-2 differed from others by its unexpectedly rapid spread. The World Health Organization (WHO) described the most recent coronavirus epidemic as a global pandemic in March 2020. The virus spread triggered a health crisis (the COVID-19 disease) within three months, with socioeconomic implications. No approved targeted-therapies are available for COVID-19, yet. However, it is foreseen that antibody-based treatments may provide an immediate cure for patients. Current neutralizing antibody development studies primarily target the S protein among the structural elements of SARS-CoV-2, which mediates the cell entry of the virus through the angiotensin converting enzyme 2 (ACE2) receptor of host cells. This review aims to provide some of the neutralizing antibody development strategies for SARS-CoV-2 and in vitro and in vivo neutralization assays.
1njdvnjw
1njdvnjw
2020-06-21
10.3906/biy-2005-91
5
Rapid and robust bioanalytical assays are critical for SARS-CoV-2 therapeutic and vaccine development and beyond
1qhxhz7j
1qhxhz7j
2020-05-26
10.4155/bio-2020-0116
4.5
Emerging novel coronavirus (2019-nCoV)—current scenario, evolutionary perspective based on genome analysis and recent developments
Coronaviruses are the well-known cause of severe respiratory, enteric and systemic infections in a wide range of hosts including man, mammals, fish, and avian. The scientific interest on coronaviruses increased after the emergence of Severe Acute Respiratory Syndrome coronavirus (SARS-CoV) outbreaks in 2002-2003 followed by Middle East Respiratory Syndrome CoV (MERS-CoV). This decade’s first CoV, named 2019-nCoV, emerged from Wuhan, China, and declared as ‘Public Health Emergency of International Concern’ on January 30(th), 2020 by the World Health Organization (WHO). As on February 4, 2020, 425 deaths reported in China only and one death outside China (Philippines). In a short span of time, the virus spread has been noted in 24 countries. The zoonotic transmission (animal-to-human) is suspected as the route of disease origin. The genetic analyses predict bats as the most probable source of 2019-nCoV though further investigations needed to confirm the origin of the novel virus. The ongoing nCoV outbreak highlights the hidden wild animal reservoir of the deadly viruses and possible threat of spillover zoonoses as well. The successful virus isolation attempts have made doors open for developing better diagnostics and effective vaccines helping in combating the spread of the virus to newer areas.
1qkwsh6a
1qkwsh6a
2020-02-08
10.1080/01652176.2020.1727993
1
Machine intelligence design of 2019-nCoV drugs
Wuhan coronavirus, called 2019-nCoV, is a newly emerged virus that infected more than 9692 people and leads to more than 213 fatalities by January 30, 2020. Currently, there is no effective treatment for this epidemic. However, the viral protease of a coronavirus is well-known to be essential for its replication and thus is an effective drug target. Fortunately, the sequence identity of the 2019-nCoV protease and that of severe-acute respiratory syndrome virus (SARS-CoV) is as high as 96.1%. We show that the protease inhibitor binding sites of 2019-nCoV and SARS-CoV are almost identical, which means all potential anti-SARS-CoV chemotherapies are also potential 2019-nCoV drugs. Here, we report a family of potential 2019-nCoV drugs generated by a machine intelligence-based generative network complex (GNC). The potential effectiveness of treating 2019-nCoV by using some existing HIV drugs is also analyzed.
1qniriu0
1qniriu0
2020-02-04
10.1101/2020.01.30.927889
1.5
Large-scale evolutionary surveillance of the 2009 H1N1 influenza A virus using resequencing arrays
In April 2009, a new influenza A (H1N1 2009) virus emerged that rapidly spread around the world. While current variants of this virus have caused widespread disease, particularly in vulnerable groups, there remains the possibility that future variants may cause increased virulence, drug resistance or vaccine escape. Early detection of these virus variants may offer the chance for increased containment and potentially prevention of the virus spread. We have developed and field-tested a resequencing kit that is capable of interrogating all eight segments of the 2009 influenza A(H1N1) virus genome and its variants, with added focus on critical regions such as drug-binding sites, structural components and mutation hotspots. The accompanying base-calling software (EvolSTAR) introduces novel methods that utilize neighbourhood hybridization intensity profiles and substitution bias of probes on the microarray for mutation confirmation and recovery of ambiguous base queries. Our results demonstrate that EvolSTAR is highly accurate and has a much improved call rate. The high throughput and short turn-around time from sample to sequence and analysis results (30 h for 24 samples) makes this kit an efficient large-scale evolutionary biosurveillance tool.
1rhy8td0
1rhy8td0
2010-02-25
10.1093/nar/gkq089
1
What to expect from antibody assays of SARS-CoV-2?
1s29u6tq
1s29u6tq
2020
5
Composition and divergence of coronavirus spike proteins and host ACE2 receptors predict potential intermediate hosts of SARS‐CoV‐2
From the beginning of 2002 and 2012, severe respiratory syndrome coronavirus (SARS‐CoV) and Middle East respiratory syndrome coronavirus (MERS‐CoV) crossed the species barriers to infect humans, causing thousands of infections and hundreds of deaths, respectively. Currently, a novel coronavirus (SARS‐CoV‐2), which has become the cause of the outbreak of Coronavirus Disease 2019 (COVID‐19), was discovered. Until 18 February 2020, there were 72 533 confirmed COVID‐19 cases (including 10 644 severe cases) and 1872 deaths in China. SARS‐CoV‐2 is spreading among the public and causing substantial burden due to its human‐to‐human transmission. However, the intermediate host of SARS‐CoV‐2 is still unclear. Finding the possible intermediate host of SARS‐CoV‐2 is imperative to prevent further spread of the epidemic. In this study, we used systematic comparison and analysis to predict the interaction between the receptor‐binding domain (RBD) of coronavirus spike protein and the host receptor, angiotensin‐converting enzyme 2 (ACE2). The interaction between the key amino acids of S protein RBD and ACE2 indicated that, other than pangolins and snakes, as previously suggested, turtles (Chrysemys picta bellii, Chelonia mydas, and Pelodiscus sinensis) may act as the potential intermediate hosts transmitting SARS‐CoV‐2 to humans.
1s2zsqoq
1s2zsqoq
2020-03-11
10.1002/jmv.25726
2
In silico Molecular Docking Analysis Targeting SARS-CoV-2 Spike Protein and Selected Herbal Constituents
In modern drug discovery, molecular docking analysis is routinely used to understand and predict the interaction between a drug molecule and a target protein from a microbe Drugs identified in this way may inhibit the entry and replication of pathogens in host cells The SARS-CoV-2 associated coronavirus disease, COVID-19, has become the most contagious and deadly pandemic disease in the world today In abeyance of any specific vaccine or therapeutic against SARS-CoV-2, the burgeoning situation urges a need for effective drugs to treat the virus-infected patients Herbal medicines have been used as natural remedies for treating various infectious diseases since ancient times The spike (S) protein of SARS-CoV-2 is important for the attachment and pathogenesis of the virus Therefore, this study focused on the search of useful ligands for S protein among active constituents present in common herbs that could serve as efficient remedies for COVID-19 We analysed the binding efficiency of twelve compounds present in common herbs with the S protein of SARS-CoV-2 through molecular docking analysis and also results are validated with two different docking tools The binding efficiency of ligands was scored based on their predicted pharmacological interactions coupled with binding energy estimates In docking analysis, compound "I" (Epigallocatechin gallate (EGCG)) was found to have the highest binding affinity with the viral S protein, followed by compounds, "F" (Curcumin),"D" (Apigenin) and "E" (Chrysophanol) The present study corroborates that compound "I" (EGCG) mostly present in the integrants of green tea, shows the highest potentiality for acting as an inhibitor of SARS-CoV-2 Further, characterization of the amino acid residues comprising the viral binding site and the nature of the hydrogen bonding involved in the ligand-receptor interaction revealed significant findings with herbal compound "I" (EGCG) binding to the S protein at eight amino acid residues The binding sites are situated near to the amino acids which are required for virus pathogenicity The findings of the present study need in vivo experiments to prove the utility of "I", "F","D" and "E" compounds and their further use in making herb-based anti-SARS-CoV-2 product in near future This analysis may help to create a new ethno-drug formulation for preventing or curing the COVID-19
1sxhza50
1sxhza50
2020
10.22207/jpam.14.spl1.37
5
Preparation of recombinant vaccines
Abstract Vaccination is one of the most efficient ways to eradicate some infectious diseases in humans and animals. The material traditionally used as vaccines is attenuated or inactivated pathogens. This approach is sometimes limited by the fact that the material for vaccination is not efficient, not available, or generating deleterious side effects. A possible theoretical alternative is the use of recombinant proteins from the pathogens. This implies that the proteins having the capacity to vaccinate have been identified and that they can be produced in sufficient quantity at a low cost. Genetically modified organisms harboring pathogen genes can fulfil these conditions. Microorganisms, animal cells as well as transgenic plants and animals can be the source of recombinant vaccines. Each of these systems that are all getting improved has advantages and limits. Adjuvants must generally be added to the recombinant proteins to enhance their vaccinating capacity. This implies that the proteins used to vaccinate have been purified to avoid any immunization against the contaminants. The efficiency of a recombinant vaccine is poorly predictable. Multiple proteins and various modes of administration must therefore be empirically evaluated on a case-by-case basis. The structure of the recombinant proteins, the composition of the adjuvants and the mode of administration of the vaccines have a strong and not fully predictable impact on the immune response as well as the protection level against pathogens. Recombinant proteins can theoretically also be used as carriers for epitopes from other pathogens. The increasing knowledge of pathogen genomes and the availability of efficient systems to prepare large amounts of recombinant proteins greatly facilitate the potential use of recombinant proteins as vaccines. The present review is a critical analysis of the state of the art in this field.
1tjtdcug
1tjtdcug
2007-12-31
10.1016/s1387-2656(07)13004-0
1.5
Advance of promising targets and agents against COVID-19 in China
1u12qr97
1u12qr97
2020-03-18
10.1016/j.drudis.2020.02.011
1.5
Generation of predictive pharmacophore model for SARS-coronavirus main proteinase
Pharmacophore-based virtual screening is an effective, inexpensive and fast approach to discovering useful starting points for drug discovery. In this study, we developed a pharmacophore model for the main proteinase of severe acute respiratory syndrome coronavirus (SARS-CoV). Then we used this pharmacophore model to search NCI 3D database including 250, 251 compounds and identified 30 existing drugs containing the pharmacophore query. Among them are six compounds that already exhibited anti-SARS-CoV activity experimentally. This means that our pharmacophore model can lead to the discovery of potent anti-SARS-CoV inhibitors or promising lead compounds for further SARS-CoV main proteinase inhibitor development.
1v110xgs
1v110xgs
2004-11-05
10.1016/j.ejmech.2004.09.013
2.5
Yeast-Expressed SARS-CoV Recombinant Receptor-Binding Domain (RBD219-N1) Formulated with Alum Induces Protective Immunity and Reduces Immune Enhancement
We developed a severe acute respiratory syndrome (SARS) subunit recombinant protein vaccine candidate based on a highyielding, yeast- engineered, receptor-binding domain (RBD219-N1) of the SARS beta-coronavirus (SARS-CoV) spike (S) protein. When formulated with Alhydrogel®, RBD219-N1 induced high-level neutralizing antibodies against both pseudotyped virus and a clinical (mouse-adapted) isolate of SARS-CoV. Here, we report that mice immunized with RBD219N1/Alhydrogel® were fully protected from lethal SARS-CoV challenge (0% mortality), compared to ~ 30% mortality in mice when immunized with the SARS S protein formulated with Alhydrogel®, and 100% mortality in negative controls. An RBD219-N1 formulation Alhydrogel® was also superior to the S protein, unadjuvanted RBD, and AddaVax (MF59-like adjuvant)-formulated RBD in inducing specific antibodies and preventing cellular infiltrates in the lungs upon SARS-CoV challenge. Specifically, a formulation with a 1:25 ratio of RBD219-N1 to Alhydrogel® provided high neutralizing antibody titers, 100% protection with non-detectable viral loads with minimal or no eosinophilic pulmonary infiltrates. As a result, this vaccine formulation is under consideration for further development against SARS-CoV and other emerging and re-emerging beta-CoVs such as SARS-CoV-2.
1vbc8a1q
1vbc8a1q
2020-05-22
10.1101/2020.05.15.098079
5
Molecular docking and dynamic simulations for antiviral compounds against SARS-CoV-2: A computational study
The aim of this study was to develop an appropriate anti-viral drug against the SARS-CoV-2 virus. An immediately qualifying strategy would be to use existing powerful drugs from various virus treatments. The strategy in virtual screening of antiviral databases for possible therapeutic effect would be to identify promising drug molecules, as there is currently no vaccine or treatment approved against COVID-19. Targeting the main protease (pdb id: 6LU7) is gaining importance in anti-CoV drug design. In this conceptual context, an attempt has been made to suggest an in silico computational relationship between US-FDA approved drugs, plant-derived natural drugs, and Coronavirus main protease (6LU7) protein. The evaluation of results was made based on Glide (Schrödinger) dock score. Out of 62 screened compounds, the best docking scores with the targets were found for compounds: lopinavir, amodiaquine, and theaflavin digallate (TFDG). Molecular dynamic (MD) simulation study was also performed for 20 ns to confirm the stability behaviour of the main protease and inhibitor complexes. The MD simulation study validated the stability of three compounds in the protein binding pocket as potent binders.
1vujigln
1vujigln
2020
4.5
Progress in Anti-SARS Coronavirus Chemistry, Biology and Chemotherapy
Publisher Summary Proteolytic processing of the coronavirus replicase polyproteins is essential for ongoing viral ribonucleic acid (RNA) synthesis. Therefore, the severe acute respiratory syndrome (SARS)-coronaviruses (SARS-CoV) proteases are attractive targets for the development of antiviral drugs to reduce viral replication and pathogenicity. The structure and activity of the coronavirus 3C-like protease (3CLpro) has already been elucidated, and the design of inhibitors to 3CLpro as therapeutics has been proposed. The chapter discusses SARS-CoV 3CLpro inhibitors that include covalent inhibitors, noncovalent inhibitors, and inhibitors from screening. SARS-CoV papain-like protease (PLpro) is considered an equally viable target to 3CLpro for drug design because both are essential for viral replication. However, PLpro has likely not been pursued because of the paucity of structural information. Several compounds have been identified that have shown inhibitory activity against SARS-CoV. However, no information regarding their mechanism of action or the corresponding target is known. Glycyrrhizin showed inhibitory activity for SARS-CoV replication with EC50 = 300 mg/L after virus absorption in Vero cells. Some glycyrrhizin acid derivatives were found to inhibit SARS-CoV replication in vitro with EC50 values ranging from 5 to 50 μM. Unfortunately, these compounds show high cytotoxity.
1wae0134
1wae0134
2006-12-31
10.1016/s0065-7743(06)41011-3
0.5
The MERS-CoV receptor DPP4 as a candidate binding target of the SARS-CoV-2 spike
SUMMARY The ongoing outbreak of the novel coronavirus pneumonia COVID-19 has caused great number of cases and deaths, but our understanding about the pathogen SARS-CoV-2 remains largely unclear. The attachment of the virus with the cell-surface receptor and a co-factor is the first step for the infection. Here, bioinformatics approaches combining human-virus protein interaction prediction and protein docking based on crystal structures have revealed the high affinity between human dipeptidyl peptidase 4 (DPP4) and the spike (S) receptor-binding domain of SARS-CoV-2. Intriguingly, the crucial binding residues of DPP4 are identical to those as bound to the MERS-CoV-S. Moreover, E484 insertion and adjacent substitutions should be most essential for this DPP4-binding ability acquirement of SARS-CoV-2-S compared with SARS-CoV-S. This potential utilization of DPP4 as a binding target for SARS-CoV-2 may offer novel insight into the viral pathogenesis, and help the surveillance and therapeutics strategy for meeting the challenge of COVID-19.
1xf2sxtv
1xf2sxtv
2020-05-13
10.1016/j.isci.2020.101160
3.5
The within-host viral kinetics of SARS-CoV-2
In this work, we use a within-host viral dynamic model to describe the SARS-CoV-2 kinetics in host. Chest radiograph score data are used to estimate the parameters of that model. Our result shows that the basic reproductive number of SARS-CoV-2 in host growth is around 3.79. Using the same method we also estimate the basic reproductive number of MERS virus is 8.16 which is higher than SARS-CoV-2. The PRCC method is used to analyze the sensitivities of model parameters and the drug effects on virus growth are also implemented to analyze the model.
1yka7ej9
1yka7ej9
2020-03-07
10.1101/2020.02.29.965418
2.5
Persistence of SARS-CoV-2 virus RNA in feces: A case series of children
AIMS: To determine how long SARS-CoV-2 virus RNA persists in fecal specimens in children with COVID-19. METHODS: Retrospectively, ten children with confirmed COVID-19 in the Jinan Infectious Disease Hospital Affiliated to Shandong University were enrolled between January 23, 2020 to March 9, 2020. Epidemiological, clinical, laboratory, and radiological characteristics of the children were analyzed. RT-PCR assays were performed to detect the SARS-CoV-2 virus RNA in the respiratory tract and fecal specimens in the follow-up after discharge. RESULTS: Among ten patients, five (50%) were asymptomatic and five (50%) showed mild symptoms of respiratory illness. The average age of asymptomatic children was younger than that of symptomatic children (p = 0.03). The decreases in white blood cell (WBC) (p = 0.03) and lymphocyte (p = 0.03) counts were more severe in symptomatic patients than those in asymptomatic patients. During the follow-up examination after discharge, seven out of ten patients contained SARS-CoV-2 virus RNA in their fecal specimens, despite all patients showed negative results in respiratory tract specimens. One out of those seven patients relapsed. The median time from onset to being negative results in respiratory tract and fecal specimens was 9 days and 34.43 days, respectively. CONCLUSIONS: SARS-CoV-2 virus RNA persists much longer in the gastrointestinal (GI) tract than that in respiratory tract.
1z44910x
1z44910x
2020-06-07
10.1016/j.jiph.2020.05.025
4
The possible mechanisms of action of 4-aminoquinolines (chloroquine/hydroxychloroquine) against Sars-Cov-2 infection (COVID-19): A role for iron homeostasis?
The anti-malarial drugs chloroquine (CQ) and primarily the less toxic hydroxychloroquine (HCQ) are currently used to treat autoimmune diseases for their immunomodulatory and anti-thrombotic properties. They have also been proposed for the treatment of several viral infections, due to their anti-viral effects in cell cultures and animal models, and, currently, for the treatment of coronavirus disease 2019 (COVID-19), the pandemic severe acute respiratory syndrome caused by coronavirus 2 (Sars-Cov-2) infection that is spreading all over the world. Although in some recent studies a clinical improvement in COVID-19 patients has been observed, the clinical efficacy of CQ and HCQ in COVID-19 has yet to be proven with randomized controlled studies, many of which are currently ongoing, also considering pharmacokinetics, optimal dosing regimen, therapeutic level and duration of treatment and taking into account patients with different severity degrees of disease. Here we review what is currently known on the mechanisms of action of CQ and HCQ as anti-viral, anti-inflammatory and anti-thrombotic drugs and discuss the up-to-date experimental evidence on the potential mechanisms of action of CQ/HCQ in Sars-Cov2 infection and the current clinical knowledge on their efficacy in the treatment of COVID-19 patients. Given the role of iron in several human viral infections, we also propose a different insight into a number of CQ and HCQ pharmacological effects, suggesting a potential involvement of iron homeostasis in Sars-Cov-2 infection and COVID-19 clinical course.
1zhsqtwj
1zhsqtwj
2020
4.5
The ‘precautionary principle’ as a guide for future drug development
During the last decade, the ‘precautionary principle’ health has gained importance. It is an approach to manage uncertain risks and to prevent any damage to the environment or human. A key element is to take action, even if some cause and effect relationships are not fully established scientifically. Although there are also critics of this principle, it is meanwhile, also increasingly implemented in medicine. An important subject is medicinal products of human or animal origin. Manifold official precaution‐guided regulations have been stated to improve their safety, particularly to avoid any infection by viruses and pathogens causing transmissible spongiform encephalopathies. In addition to numerous regulations and decisions, it is generally recommended to substitute animal and human‐derived products with adequate alternatives wherever possible. This is a great challenge for research and drug development. One option is recombinant proteins, which however, are not generally free of any risk of contamination. Therefore, the best strategy might be the development of synthetic, specifically acting drugs. The most widely used medicinal product of animal origin at present is heparin. Although there has been no indication of any viral contamination, many other reasons suggest its substitution by alternative antithrombotics. These actually promoted the research on new anticoagulants. With the approval of fondaparinux, the first synthetic, selective factor Xa, a first alternative to the porcine‐derived heparin has become available. In addition, other synthetic antithrombotics are currently in clinical development. In principle, it is thus possible that the prophylaxis and therapy of thromboembolic diseases will become completely independent of animal‐derived drugs, which would be in line with the precautionary principle.
21pyhilq
21pyhilq
2005-02-08
10.1111/j.0960-135x.2005.01455.x
2
Quantifying the effect of quarantine control in Covid-19 infectious spread using machine learning
Since the first recording of what we now call Covid-19 infection in Wuhan, Hubei province, China on Dec 31, 2019, the disease has spread worldwide and met with a wide variety of social distancing and quarantine policies. The effectiveness of these responses is notoriously difficult to quantify as individuals travel, violate policies deliberately or inadvertently, and infect others without themselves being detected. Moreover, the publicly available data on infection rates are themselves unreliable due to limited testing and even possibly under-reporting. In this paper, we attempt to interpret and extrapolate from publicly available data using a mixed first-principles epidemiological equations and data-driven neural network model. Leveraging our neural network augmented model, we focus our analysis on four locales: Wuhan, Italy, South Korea and the United States of America, and compare the role played by the quarantine and isolation measures in each of these countries in controlling the effective reproduction number Rt of the virus. Our results unequivocally indicate that the countries in which rapid government interventions and strict public health measures for quarantine and isolation were implemented were successful in halting the spread of infection and prevent it from exploding exponentially. In the case of Wuhan especially, where the available data were earliest available, we have been able to test the predicting ability of our model by training it from data in the January 24 till March 3 window, and then matching the predictions up to April 1. Even for Italy and South Korea, we have a buffer window of one week (25 March - 1 April) to validate the predictions of our model. In the case of the US, our model captures well the current infected curve growth and predicts a halting of infection spread by 20 April 2020. We further demonstrate that relaxing or reversing quarantine measures right now will lead to an exponential explosion in the infected case count, thus nullifying the role played by all measures implemented in the US since mid March 2020.
222c1jzv
222c1jzv
2020-04-06
10.1101/2020.04.03.20052084
2
Thoughts on Higher Medical Education Under Major Public Health Emergencies: Thinking Ahead After COVID-19 Outbreak
Objective: To explore the most suitable teaching and learning pattern in medical school during COVID-19 Outbreak. Design: This study is a case-control study. We had tried to apply a new blended teaching model based on 5G network that combined team-based learning (TBL) and online interaction to the students before the outbreak and then universities responded to the COVID-19 outbreak by closing campuses and shifting to other forms of distance learning. In other word, the courses started using blended teaching model before COVID-19 outbreak and might last using other forms of distance learning throughout the pandemic. Five Point Likert Scale Questionnaires which contains 20 items were used, and the effect of the two kinds of teaching patterns was compared by evaluating the indicators of core competencies of students including professionalism, attitude towards learning, knowledge and learning skills, teamwork skills, motivation in learning, adaptability and acceptance of the courses and network environment. Setting: Our study based on a single center. Participants: Fifty fourth-year medical students receiving the 5+3 pattern courses regarding internal medicine were enrolled in the study. Exposure(s) :The teaching and learning patter started using blended teaching model before COVID-19 outbreak and might last using other forms of distance learning throughout the pandemic. Main Outcome: According to the descriptive statistical analysis of the first part of the questionnaire (question 1-16), the average score of adaptability and acceptance of the courses is 2.60 lower than 3, indicating that students are more adapted to other forms of distance learning during COVID-19 outbreak; the average score of the rest of the questions is higher than 3, indicating that blended teaching model based on 5G network is superior to other forms of distance learning. The number of male students who are inclined to the blended teaching model based on 5G network is 0.13 times as much as that of female students (95%CI:0.028~0.602, p=0.009). Results: Online forms of distance learning were accepted by the students. Female students had higher expectations on the course and were more likely to adapt well to the change during the COVID-19 outbreak. However, all students preferred the blended teaching model based on 5G network that combined team-based learning (TBL) and online interaction before the pandemic. Conclusion: It indicates that medical education based on 5G network that combined team-based learning (TBL) and online interaction is a more suitable option to teach medical students online. China's experience in online higher medical education may serve as a reference to other countries during the pandemic.
229fnvgk
229fnvgk
2020-04-07
10.1101/2020.04.06.20053918
1.5
Simulation of the clinical and pathological manifestations of Coronavirus Disease 2019 (COVID-19) in golden Syrian hamster model: implications for disease pathogenesis and transmissibility
BACKGROUND: A physiological small animal model that resembles COVID-19 with low mortality is lacking. METHODS: Molecular docking on the binding between angiotensin-converting enzyme 2 (ACE2) of common laboratory mammals and the receptor-binding domain of the surface spike protein of SARS-CoV-2 suggested that the golden Syrian hamster is an option. Virus challenge, contact transmission, and passive immunoprophylaxis were performed. Serial organ tissues and blood were harvested for histopathology, viral load and titre, chemokine/cytokine assay, and neutralising antibody titre. RESULTS: The Syrian hamster could be consistently infected by SARS-CoV-2. Maximal clinical signs of rapid breathing, weight loss, histopathological changes from the initial exudative phase of diffuse alveolar damage with extensive apoptosis to the later proliferative phase of tissue repair, airway and intestinal involvement with virus nucleocapsid protein expression, high lung viral load, and spleen and lymphoid atrophy associated with marked cytokine activation were observed within the first week of virus challenge. The lung virus titre was between 10(5)-10(7) TCID(50)/g. Challenged index hamsters consistently infected naïve contact hamsters housed within the same cage, resulting in similar pathology but not weight loss. All infected hamsters recovered and developed mean serum neutralising antibody titre ≥1:427 fourteen days post-challenge. Immunoprophylaxis with early convalescent serum achieved significant decrease in lung viral load but not in lung pathology. No consistent non-synonymous adaptive mutation of the spike was found in viruses isolated from infected hamsters. CONCLUSIONS: Besides satisfying the Koch’s postulates, this readily available hamster model is an important tool for studying transmission, pathogenesis, treatment, and vaccination against SARS-CoV-2.
242cb7b6
242cb7b6
2020-03-26
10.1093/cid/ciaa325
3
Feasibility of Known RNA Polymerase Inhibitors as Anti-SARS-CoV-2 Drugs
Coronaviruses (CoVs) are positive-stranded RNA viruses that infect humans and animals. Infection by CoVs such as HCoV-229E, -NL63, -OC43 and -HKU1 leads to the common cold, short lasting rhinitis, cough, sore throat and fever. However, CoVs such as Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV), Middle East Respiratory Syndrome Coronavirus (MERS-CoV), and the newest SARS-CoV-2 (the causative agent of COVID-19) lead to severe and deadly diseases with mortality rates ranging between ~1 to 35% depending on factors such as age and pre-existing conditions. Despite continuous global health threats to humans, there are no approved vaccines or drugs targeting human CoVs, and the recent outbreak of COVID-19 emphasizes an urgent need for therapeutic interventions. Using computational and bioinformatics tools, here we present the feasibility of reported broad-spectrum RNA polymerase inhibitors as anti- SARS-CoV-2 drugs targeting its main RNA polymerase, suggesting that investigational and approved nucleoside RNA polymerase inhibitors have potential as anti-SARS-CoV-2 drugs. However, we note that it is also possible for SARS-CoV-2 to evolve and acquire drug resistance mutations against these nucleoside inhibitors.
246qy3wb
246qy3wb
2020-04-26
10.3390/pathogens9050320
3
Hydroxychloroquine for Treatment of SARS‐CoV‐2 Infection? Improving Our Confidence in a Model‐Based Approach to Dose Selection
In less than six months, COVID-19 has spread from a marketplace in Wuhan, China to over 150 countries and territories of the world. Therapeutics are desperately needed to reduce the morbidity and mortality of this pandemic disease. It has been reported that hydroxychloroquine (HCQ) is active against SARS-CoV-2 in vitro, and this finding was quickly supported by an open label non-randomized clinical trial that provided the first published clinical evidence HCQ may be a treatment option.
248de4cj
248de4cj
2020-05-09
10.1111/cts.12797
5
Fast and accurate detection of Covid-19-related pneumonia from chest X-ray images with novel deep learning model
Background: Novel coronavirus disease has spread rapidly worldwide. As recent radiological literatures on Covid-19 related pneumonia is primarily focused on CT findings, the American College of Radiology (ACR) recommends using portable chest X-radiograph (CXR). A tool to assist for detection and monitoring of Covid-19 cases from CXR is highly required. Purpose: To develop a fully automatic framework to detect Covid-19 related pneumonia using CXR images and evaluate its performance. Materials and Methods: In this study, a novel deep learning model, named CovIDNet (Covid-19 Indonesia Neural-Network), was developed to extract visual features from chest x-ray images for the detection of Covid-19 related pneumonia. The model was trained and validated by chest x-rays datasets collected from several open source provided by GitHub and Kaggle. Results and Discussion: In the validation stage using open-source data, the accuracy to recognize Covid-19 and others classes reaches 98.44%, that is, 100% Covid-19 precision and 97% others precision. Discussion: The use of the model to classify Covid-19 and other pathologies might slightly decrease the accuracy. Although SoftMax was used to handle classification bias, this indicates the benefit of additional training upon the introduction of new set of data. Conclusion: The model has been tested and get 98.4% accuracy for open source datasets, the sensitivity and specificity are 100% and 96.97%, respectively.
24xef6ay
24xef6ay
2020-05-10
3.5
Therapeutic effect of an anti-human-TNF-alpha antibody and itraconazole on feline infectious peritonitis
Feline infectious peritonitis (FIP) is a fatal disease in wild and domestic cat species. Although several drugs are expected to be useful as treatments for FIP, no drugs are available in clinical practice. In this study, we evaluated the therapeutic effect of combined use of adalimumab (an anti-human-TNF-alpha monoclonal antibody, ADA) and itraconazole (ICZ), which are presently available to veterinarians. The neutralizing activity of ADA against fTNF-alpha-induced cytotoxicity was measured in WEHI-164 cells. Ten specific pathogen-free (SPF) cats were inoculated intraperitoneally with type I FIPV KU-2. To the cats that developed FIP, ADA (10 mg/animal) was administered twice between day 0 and day 4 after the start of treatment. ICZ (50 mg/head, SID) was orally administered daily from day 0 after the start of treatment. ADA demonstrated dose-dependent neutralizing activity against rfTNF-alpha. In an animal experiment, 2 of 3 cats showed improvements in FIP clinical symptoms and blood chemistry test results, an increase in the peripheral blood lymphocyte count, and a decrease in the plasma alpha 1-AGP level were observed after the beginning of treatment. One of the cats failed to respond to treatment and was euthanized, although the viral gene level in ascites temporarily decreased after the start of treatment. ADA was found to have neutralizing activity against rfTNF-alpha. The combined use of ADA and ICZ showed a therapeutic effect for experimentally induced FIP. We consider these drugs to be a treatment option until effective anti-FIPV drugs become available.
25bhy3w8
25bhy3w8
2020-03-31
10.1007/s00705-020-04605-7
4
The Pathogenicity of SARS-CoV-2 in hACE2 Transgenic Mice
Severe acute respiratory syndrome CoV-2 (SARS-CoV-2) caused the Corona Virus Disease 2019 (COVID-19) cases in China has become a public health emergency of international concern (PHEIC). Based on angiotensin converting enzyme 2 (ACE2) as cell entry receptor of SARS-CoV, we used the hACE2 transgenic mice infected with SARS-CoV-2 to study the pathogenicity of the virus. Weight loss and virus replication in lung were observed in hACE2 mice infected with SARS-CoV-2. The typical histopathology was interstitial pneumonia with infiltration of significant lymphocytes and monocytes in alveolar interstitium, and accumulation of macrophages in alveolar cavities. Viral antigens were observed in the bronchial epithelial cells, alveolar macrophages and alveolar epithelia. The phenomenon was not found in wild type mice with SARS-CoV-2 infection. The pathogenicity of SARS-CoV-2 in hACE2 mice was clarified and the Koch’s postulates were fulfilled as well, and the mouse model may facilitate the development of therapeutics and vaccines against SARS-CoV-2.
25uy4lrw
25uy4lrw
2020-02-11
10.1101/2020.02.07.939389
4
Phylogenetic Analysis and Structural Modeling of SARS-CoV-2 Spike Protein Reveals an Evolutionary Distinct and Proteolytically Sensitive Activation Loop
The 2019 novel coronavirus (2019-nCoV/SARS-CoV-2) originally arose as part of a major outbreak of respiratory disease centered on Hubei province, China. It is now a global pandemic and is a major public health concern. Taxonomically, SARS-CoV-2 was shown to be a Betacoronavirus (lineage B) closely related to SARS-CoV and SARS-related bat coronaviruses, and it has been reported to share a common receptor with SARS-CoV (ACE-2). Subsequently, betacoronaviruses from pangolins were identified as close relatives to SARS-CoV-2. Here, we perform structural modeling of the SARS-CoV-2 spike glycoprotein. Our data provide support for the similar receptor utilization between SARS-CoV-2 and SARS-CoV, despite a relatively low amino acid similarity in the receptor binding module. Compared to SARS-CoV and all other coronaviruses in Betacoronavirus lineage B, we identify an extended structural loop containing basic amino acids at the interface of the receptor binding (S1) and fusion (S2) domains. We suggest this loop confers fusion activation and entry properties more in line with betacoronaviruses in lineages A and C, and be a key component in the evolution of SARS-CoV-2 with this structural loop affecting virus stability and transmission.
26pcjts9
26pcjts9
2020-04-19
10.1016/j.jmb.2020.04.009
3
BARICITINIB - A JANUASE KINASE INHIBITOR - NOT AN IDEAL OPTION FOR MANAGEMENT OF COVID 19
• Several studies suggested Baricitinib as a potential drug for the management of COVID 19 infection through drug repurposing strategies because of its ability to act on AT2 cells and AAK1 mediated endocytosis. • Baricitinib, a Januase Kinase Inhibitor, have known to cause Lymphocytopenia, Neutropenia and Viral Reactivation. • Reported Epidemiological studies have shown that COVID 19 patients have a lesser absolute lymphocyte count closer to the threshold value. • Moreover, incidence of Co-infection for COVID 19 patients is one of the leading causes of Mortality. Baricitinib may enhance the incidence of Co-infection. • Hence, Baricitinib may not be an ideal option for Management of COVID 19.
270msv5l
270msv5l
2020-04-04
10.1016/j.ijantimicag.2020.105967
1.5
MERS-coronavirus replication induces severe in vitro cytopathology and is strongly inhibited by cyclosporin A or interferon-α treatment
Coronavirus (CoV) infections are commonly associated with respiratory and enteric disease in humans and animals. The 2003 outbreak of severe acute respiratory syndrome (SARS) highlighted the potentially lethal consequences of CoV-induced disease in humans. In 2012, a novel CoV (Middle East Respiratory Syndrome coronavirus; MERS-CoV) emerged, causing 49 human cases thus far, of which 23 had a fatal outcome. In this study, we characterized MERS-CoV replication and cytotoxicity in human and monkey cell lines. Electron microscopy of infected Vero cells revealed extensive membrane rearrangements, including the formation of double-membrane vesicles and convoluted membranes, which have been implicated previously in the RNA synthesis of SARS-CoV and other CoVs. Following infection, we observed rapidly increasing viral RNA synthesis and release of high titres of infectious progeny, followed by a pronounced cytopathology. These characteristics were used to develop an assay for antiviral compound screening in 96-well format, which was used to identify cyclosporin A as an inhibitor of MERS-CoV replication in cell culture. Furthermore, MERS-CoV was found to be 50–100 times more sensitive to alpha interferon (IFN-α) treatment than SARS-CoV, an observation that may have important implications for the treatment of MERS-CoV-infected patients. MERS-CoV infection did not prevent the IFN-induced nuclear translocation of phosphorylated STAT1, in contrast to infection with SARS-CoV where this block inhibits the expression of antiviral genes. These findings highlight relevant differences between these distantly related zoonotic CoVs in terms of their interaction with and evasion of the cellular innate immune response.
279ur6zt
279ur6zt
2013-08-16
10.1099/vir.0.052910-0
0.5
Identification of potential treatments for COVID-19 through artificial intelligence-enabled phenomic analysis of human cells infected with SARS-CoV-2
To identify potential therapeutic stop-gaps for SARS-CoV-2, we evaluated a library of 1,670 approved and reference compounds in an unbiased, cellular image-based screen for their ability to suppress the broad impacts of the SARS-CoV-2 virus on phenomic profiles of human renal cortical epithelial cells using deep learning. In our assay, remdesivir is the only antiviral tested with strong efficacy, neither chloroquine nor hydroxychloroquine have any beneficial effect in this human cell model, and a small number of compounds not currently being pursued clinically for SARS-CoV-2 have efficacy. We observed weak but beneficial class effects of β-blockers, mTOR/PI3K inhibitors and Vitamin D analogues and a mild amplification of the viral phenotype with β-agonists.
27f9241x
27f9241x
2020-04-23
10.1101/2020.04.21.054387
2.5
The anti-viral facet of anti-rheumatic drugs: Lessons from COVID-19
Abstract The outbreak of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has posed the world at a pandemic risk. Coronavirus-19 disease (COVID-19) is an infectious disease caused by SARS-CoV-2, which causes pneumonia, requires intensive care unit hospitalization in about 10% of cases and can lead to a fatal outcome. Several efforts are currently made to find a treatment for COVID-19 patients. So far, several anti-viral and immunosuppressive or immunomodulating drugs have demonstrated some efficacy on COVID-19 both in vitro and in animal models as well as in cases series. In COVID-19 patients a pro-inflammatory status with high levels of interleukin (IL)-1B, IL-1 receptor (R)A and tumor necrosis factor (TNF)-α has been demonstrated. Moreover, high levels of IL-6 and TNF-α have been observed in patients requiring intensive-care-unit hospitalization. This provided rationale for the use of anti-rheumatic drugs as potential treatments for this severe viral infection. Other agents, such as hydroxychloroquine and chloroquine might have a direct anti-viral effect. The anti-viral aspect of immunosuppressants towards a variety of viruses has been known since long time and it is herein discussed in the view of searching for a potential treatment for SARS-CoV-2 infection.
29h189tx
29h189tx
2020-04-17
10.1016/j.jaut.2020.102468
2
Potential therapeutic agents against COVID-19: What we know so far
The emerging outbreak of coronavirus disease 2019 (COVID-19) caused by the severe acute respiratory syndrome coronavirus 2 continues to spread all over the world. Agents or vaccines of proven efficacy to treat or prevent human coronavirus infection are in urgent need and are being investigated vigorously worldwide. This review summarizes the current evidence of potential therapeutic agents, such as lopinavir/ritonavir, remdesivir, favipiravir, chloroquine, hydroxychloroquine, interferon, ribavirin, tocilizumab, and sarilumab. More clinical trials are being conducted for further confirmation of the efficacy and safety of these agents in treating COVID-19.
29kjytsn
29kjytsn
2020-04-21
10.1097/jcma.0000000000000318
2.5
Chloroquine for the 2019 novel coronavirus SARS-CoV-2
2cuts3d9
2cuts3d9
2020-03-31
10.1016/j.ijantimicag.2020.105923
1
Molecular docking and dynamic simulations for antiviral compounds against SARS-CoV-2: A computational study
The aim of this study was to develop an appropriate anti-viral drug against the SARS-CoV-2 virus. An immediately qualifying strategy would be to use existing powerful drugs from various virus treatments. The strategy in virtual screening of antiviral databases for possible therapeutic effect would be to identify promising drug molecules, as there is currently no vaccine or treatment approved against COVID-19. Targeting the main protease (pdb id: 6LU7) is gaining importance in anti-CoV drug design. In this conceptual context, an attempt has been made to suggest an in silico computational relationship between US-FDA approved drugs, plant-derived natural drugs, and Coronavirus main protease (6LU7) protein. The evaluation of results was made based on Glide (Schrödinger) dock score. Out of 62 screened compounds, the best docking scores with the targets were found for compounds: lopinavir, amodiaquine, and theaflavin digallate (TFDG). Molecular dynamic (MD) simulation study was also performed for 20 ns to confirm the stability behaviour of the main protease and inhibitor complexes. The MD simulation study validated the stability of three compounds in the protein binding pocket as potent binders.
2dtrvxic
2dtrvxic
2020-05-11
10.1016/j.imu.2020.100345
3
Antiviral activity of Glucosylceramide synthase inhibitors against SARS-CoV-2 and other RNA virus infections
The need for antiviral drugs is real and relevant. Broad spectrum antiviral drugs have a particular advantage when dealing with rapid disease outbreaks, such as the current COVID-19 pandemic. Since viruses are completely dependent on internal cell mechanisms, they must cross cell membranes during their lifecycle, creating a dependence on processes involving membrane dynamics. Thus, in this study we examined whether the synthesis of glycosphingolipids, biologically active components of cell membranes, can serve as an antiviral therapeutic target. We examined the antiviral effect of two specific inhibitors of GlucosylCeramide synthase (GCS); (i) Genz-123346, an analogue of the FDA-approved drug Cerdelga®, (ii) GENZ-667161, an analogue of venglustat which is currently under phase III clinical trials. We found that both GCS inhibitors inhibit the replication of four different enveloped RNA viruses of different genus, organ-target and transmission route: (i) Neuroinvasive Sindbis virus (SVNI), (ii) West Nile virus (WNV), (iii) Influenza A virus, and (iv) SARS-CoV-2. Moreover, GCS inhibitors significantly increase the survival rate of SVNI-infected mice. Our data suggest that GCS inhibitors can potentially serve as a broad-spectrum antiviral therapy and should be further examined in preclinical and clinical trial. Analogues of the specific compounds tested have already been studied clinically, implying they can be fast-tracked for public use. With the current COVID-19 pandemic, this may be particularly relevant to SARS-CoV-2 infection. One Sentence Summary An analogue of Cerdelga®, an FDA-approved drug, is effective against a broad range of RNA-viruses including the newly emerging SARS-CoV-2.
2ejg2ngh
2ejg2ngh
2020-05-19
10.1101/2020.05.18.103283
4.5
Prediction of potential commercially inhibitors against SARS-CoV-2 by multi-task deep model
The outbreak of novel coronavirus pneumonia (COVID-19) caused thousands of deaths worldwide, and the number of total infections is still rising. However, the development of effective vaccine for this novel virus would take a few months. Thus it is urgent to identify some potentially effective old drugs that can be used immediately. Fortunately, some compounds that can inhibit coronavirus in vitro have been reported. In this study, the coronavirus-specific dataset was used to fine-tune our pre-trained multi-task deep model. Next we used the re-trained model to select available commercial drugs against targeted proteins of SARS-CoV-2. The results show that abacavir, a powerful nucleoside analog reverse transcriptase inhibitor used to treat HIV, is predicted to have high binding affinity with several proteins of SARS-CoV-2. Almitrine mesylate and roflumilast which are used for respiratory diseases such as chronic obstructive pulmonary disease are also predicted to have inhibitory effect. Overall, ten drugs are listed as potential inhibitors and the important sites for these binding by our model are exhibited. We hope these results would be useful in the fight against SARS-CoV-2.
2fs8oui2
2fs8oui2
2020-03-02
2
Respiratory disease in rhesus macaques inoculated with SARS-CoV-2.
An outbreak of a novel coronavirus, named SARS-CoV-2, causing respiratory disease and a ~2% case fatality rate started in Wuhan, China in December 20191,2. Following unprecedented global spread3, the World Health Organization declared COVID-19 a pandemic on March 11, 2020. Although data on disease in humans are emerging at a steady pace, certain aspects of the pathogenesis of SARS-CoV-2 can only be studied in detail in animal models, where repeated sampling and tissue collection is possible. Here, we show that SARS-CoV-2 causes respiratory disease in infected rhesus macaques, with disease lasting 8-16 days. Pulmonary infiltrates, a hallmark of human disease, were visible in lung radiographs. High viral loads were detected in swabs from the nose and throat of all animals as well as in bronchoalveolar lavages; in one animal we observed prolonged rectal shedding. Taken together, the rhesus macaque recapitulates moderate disease observed in the majority of human cases. The establishment of the rhesus macaque as a model of COVID-19 will increase our understanding of the pathogenesis of this disease and will aid development and testing of medical countermeasures.
2gaealcc
2gaealcc
2020-05-12
10.1038/s41586-020-2324-7
4.5
Immunogenicity and protective efficacy in mice and hamsters of a β-propiolactone inactivated whole virus SARS-CoV vaccine.
The immunogenicity and efficacy of β-propiolactone (BPL) inactivated whole virion SARS-CoV (WI-SARS) vaccine was evaluated in BALB/c mice and golden Syrian hamsters. The vaccine preparation was tested with or without adjuvants. Adjuvant Systems AS01(B) and AS03(A) were selected and tested for their capacity to elicit high humoral and cellular immune responses to WI-SARS vaccine. We evaluated the effect of vaccine dose and each adjuvant on immunogenicity and efficacy in mice, and the effect of vaccine dose with or without the AS01(B) adjuvant on the immunogenicity and efficacy in hamsters. Efficacy was evaluated by challenge with wild-type virus at early and late time points (4 and 18 wk post-vaccination). A single dose of vaccine with or without adjuvant was poorly immunogenic in mice; a second dose resulted in a significant boost in antibody levels, even in the absence of adjuvant. The use of adjuvants resulted in higher antibody titers, with the AS01(B)-adjuvanted vaccine being slightly more immunogenic than the AS03(A)-adjuvanted vaccine. Two doses of WI-SARS with and without Adjuvant Systems were highly efficacious in mice. In hamsters, two doses of WI-SARS with and without AS01(B) were immunogenic, and two doses of 2 μg of WI-SARS with and without the adjuvant provided complete protection from early challenge. Although antibody titers had declined in all groups of vaccinated hamsters 18 wk after the second dose, the vaccinated hamsters were still partially protected from wild-type virus challenge. Vaccine with adjuvant provided better protection than non-adjuvanted WI-SARS vaccine at this later time point. Enhanced disease was not observed in the lungs or liver of hamsters following SARS-CoV challenge, regardless of the level of serum neutralizing antibodies.
2gsy750k
2gsy750k
2010
10.1089/vim.2010.0028
1.5
SARS-CoV-2 Seroconversion in Humans: A Detailed Protocol for a Serological Assay, Antigen Production, and Test Setup
In late 2019, cases of atypical pneumonia were detected in China. The etiological agent was quickly identified as a betacoronavirus (named SARS-CoV-2), which has since caused a pandemic. Several methods allowing for the specific detection of viral nucleic acids have been established, but these only allow detection of the virus during a short period of time, generally during acute infection. Serological assays are urgently needed to conduct serosurveys, to understand the antibody responses mounted in response to the virus, and to identify individuals who are potentially immune to re-infection. Here we describe a detailed protocol for expression of antigens derived from the spike protein of SARS-CoV-2 that can serve as a substrate for immunological assays, as well as a two-stage serological enzyme-linked immunosorbent assay (ELISA). These assays can be used for research studies and for testing in clinical laboratories. © 2020 The Authors. Basic Protocol 1: Mammalian cell transfection and protein purification Basic Protocol 2: A two-stage ELISA for high-throughput screening of human serum samples for antibodies binding to the spike protein of SARS-CoV-2.
2hv5ohsf
2hv5ohsf
2020
3.5
State-of-the-art tools unveil potent drug targets amongst clinically approved drugs to inhibit helicase in SARS-CoV-2
INTRODUCTION: The extreme health and economic problems in the world due to the SARS-CoV-2 infection have led to an urgent need to identify potential drug targets for treating coronavirus disease 2019 (COVID-19). The present state-of-the-art tool-based screening was targeted to identify drug targets among clinically approved drugs by uncovering SARS-CoV-2 helicase inhibitors through molecular docking analysis. MATERIAL AND METHODS: Helicase is a vital viral replication enzyme, which unwinds nucleic acids and separates the double-stranded nucleic acids into single-stranded nucleic acids. Hence, the SARS-CoV-2 helicase protein 3D structure was predicted, validated, and used to screen the druggable targets among clinically approved drugs such as protease inhibitor, nucleoside reverse transcriptase inhibitor, and non-nucleoside reverse transcriptase inhibitors, used to treat HIV infection using molecular docking analysis. RESULTS: Interaction with SARS-CoV-2 helicase, approved drugs, vapreotide (affinity: –12.88; S score: –9.84 kcal/mol), and atazanavir (affinity: –11.28; S score: –9.32 kcal/mol), approved drugs for treating AIDS-related diarrhoea and HIV infection, respectively, are observed with significantly low binding affinity and MOE score or binding free energy. The functional binding pockets of the clinically approved drugs on SARS-CoV-2 helicase protein molecule suggest that vapreotide and atazanavir may interrupt the activities of the SARS-CoV-2 helicase. CONCLUSIONS: The study suggests that vapreotide may be a choice of drug for wet lab studies to inhibit the infection of SARS-CoV-2.
2j56et4p
2j56et4p
2020-04-17
10.5114/aoms.2020.94567
3
Therapeutic strategies in an outbreak scenario to treat the novel coronavirus originating in Wuhan, China
A novel coronavirus (2019-nCoV) originating in Wuhan, China presents a potential respiratory viral pandemic to the world population. Current efforts are focused on containment and quarantine of infected individuals. Ultimately, the outbreak could be controlled with a protective vaccine to prevent 2019-nCoV infection. While vaccine research should be pursued intensely, there exists today no therapy to treat 2019-nCoV upon infection, despite an urgent need to find options to help these patients and preclude potential death. Herein, I review the potential options to treat 2019-nCoV in patients, with an emphasis on the necessity for speed and timeliness in developing new and effective therapies in this outbreak. I consider the options of drug repurposing, developing neutralizing monoclonal antibody therapy, and an oligonucleotide strategy targeting the viral RNA genome, emphasizing the promise and pitfalls of these approaches. Finally, I advocate for the fastest strategy to develop a treatment now, which could be resistant to any mutations the virus may have in the future. The proposal is a biologic that blocks 2019-nCoV entry using a soluble version of the viral receptor, angiotensin-converting enzyme 2 (ACE2), fused to an immunoglobulin Fc domain (ACE2-Fc), providing a neutralizing antibody with maximal breath to avoid any viral escape, while also helping to recruit the immune system to build lasting immunity. The ACE2-Fc therapy would also supplement decreased ACE2 levels in the lungs during infection, thereby directly treating acute respiratory distress pathophysiology as a third mechanism of action. The sequence of the ACE2-Fc protein is provided to investigators, allowing its possible use in recombinant protein expression systems to start producing drug today to treat patients under compassionate use, while formal clinical trials are later undertaken. Such a treatment could help infected patients before a protective vaccine is developed and widely available in the coming months to year(s).
2jq626ye
2jq626ye
2020-02-07
10.12688/f1000research.22211.2
1
Drug treatments affecting ACE2 in COVID-19 infection: a systematic review protocol
Abstract Background: The SARS-CoV-2 virus causing COVID-19 binds human angiotensin-converting enzyme 2 (ACE2) receptors in human tissues. ACE2 expression may be associated with COVID-19 infection and mortality rates. Routinely prescribed drugs which up- or down-regulate ACE2 expression are therefore of critical research interest as agents which might promote or reduce risk of COVID-19 infection in a susceptible population. Aim: To review evidence on routinely prescribed drug treatments in the UK that could up- or down-regulate ACE2 and potentially affect COVID-19 infection. Design and setting: Systematic review of studies published in MEDLINE, EMBASE, CINAHL, the Cochrane Library and Web of Science from inception to April 1st 2020. Method: A systematic review will be conducted in line with PRISMA guidelines. Inclusion criteria will be: i) assess effect of drug exposure on ACE2 level; ii) drug is included in British National Formulary (BNF) and therefore available to prescribe in UK; iii) a control, placebo or sham group is included as comparator. Exclusion criteria will be: i) ACE2 measurement in utero; ii) ACE2 measurement in children under 18 years; iii) drug not in BNF; iv) review article. Quality will be assessed using the Cochrane risk of bias tool for human studies, and the SYRCLE risk of bias tool for animal studies. Results: Data will be reported in summary tables and narrative synthesis. Conclusion: This systematic review will identify drug therapies which may increase or decrease ACE2 expression. This might identify medications increasing risk of COVID-19 transmission, or as targets for intervention in mitigating transmission.
2jyjuhov
2jyjuhov
2020-05-26
10.1101/2020.05.25.20100438
4.5
COVID-19: Drug Targets and Potential Treatments
[Image: see text] Currently, humans are immersed in a pandemic caused by the emerging severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which threatens public health worldwide. To date, no drug or vaccine has been approved to treat the severe disease caused by this coronavirus, COVID-19. In this paper, we will focus on the main virus-based and host-based targets that can guide efforts in medicinal chemistry to discover new drugs for this devastating disease. In principle, all CoV enzymes and proteins involved in viral replication and the control of host cellular machineries are potentially druggable targets in the search for therapeutic options for SARS-CoV-2. This Perspective provides an overview of the main targets from a structural point of view, together with reported therapeutic compounds with activity against SARS-CoV-2 and/or other CoVs. Also, the role of innate immune response to coronavirus infection and the related therapeutic options will be presented.
2kfmgr7k
2kfmgr7k
2020-06-08
10.1021/acs.jmedchem.0c00606
5
Searching for MERS and Novel Flu with Limited Resources
2mwahvq0
2mwahvq0
2014-04-29
10.5210/ojphi.v6i1.5163
1
Severe acute respiratory syndrome
Severe acute respiratory syndrome (SARS) was caused by a previously unrecognized animal coronavirus that exploited opportunities provided by 'wet markets' in southern China to adapt to become a virus readily transmissible between humans. Hospitals and international travel proved to be 'amplifiers' that permitted a local outbreak to achieve global dimensions. In this review we will discuss the substantial scientific progress that has been made towards understanding the virus—SARS coronavirus (SARS-CoV)—and the disease. We will also highlight the progress that has been made towards developing vaccines and therapies The concerted and coordinated response that contained SARS is a triumph for global public health and provides a new paradigm for the detection and control of future emerging infectious disease threats.
2p209g2p
2p209g2p
2004-11-30
10.1038/nm1143
0.5
Exposure to air pollution and COVID-19 mortality in the United States: A nationwide cross-sectional study
Objectives: United States government scientists estimate that COVID-19 may kill tens of thousands of Americans. Many of the pre-existing conditions that increase the risk of death in those with COVID-19 are the same diseases that are affected by long-term exposure to air pollution. We investigated whether long-term average exposure to fine particulate matter (PM2.5) is associated with an increased risk of COVID-19 death in the United States. Design: A nationwide, cross-sectional study using county-level data. Data sources: COVID-19 death counts were collected for more than 3,000 counties in the United States (representing 98% of the population) up to April 22, 2020 from Johns Hopkins University, Center for Systems Science and Engineering Coronavirus Resource Center. Main outcome measures: We fit negative binomial mixed models using county-level COVID-19 deaths as the outcome and county-level long-term average of PM2.5 as the exposure. In the main analysis, we adjusted by 20 potential confounding factors including population size, age distribution, population density, time since the beginning of the outbreak, time since state issuance of the stay-at-home order, hospital beds, number of individuals tested, weather, and socioeconomic and behavioral variables such as obesity and smoking. We included a random intercept by state to account for potential correlation in counties within the same state. We conducted more than 68 additional sensitivity analyses. Results: We found that an increase of only 1 μg/m3 in PM2.5 is associated with an 8% increase in the COVID-19 death rate (95% confidence interval [CI]: 2%, 15%). The results were statistically significant and robust to secondary and sensitivity analyses. Conclusions: A small increase in long-term exposure to PM2.5 leads to a large increase in the COVID-19 death rate. Despite the inherent limitations of the ecological study design, our results underscore the importance of continuing to enforce existing air pollution regulations to protect human health both during and after the COVID-19 crisis. The data and code are publicly available so our analyses can be updated routinely.
2q6qmex3
2q6qmex3
2020-04-07
10.1101/2020.04.05.20054502
1.5
Development of remdesivir repositioning as a nucleotide analog against COVID-19 RNA dependent RNA polymerase
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative representative of a severe respiratory illness resulted in widespread human infections and deaths in nearly all of the countries since late 2019. There is no therapeutic FDA-approved drug against SARS-CoV-2 infection, although a combination of anti-viral drugs is directly being practiced in some countries. A broad-spectrum of antiviral agents are being currently evaluated in clinical trials, and in this review, we specifically focus on the application of Remdesivir (RVD) as a potential anti-viral compound against Middle East respiratory syndrome (MERS) -CoV, SARS-CoV and SARS-CoV-2. First, we overview the general information about SARS-CoV-2, followed by application of RDV as a nucleotide analogue which can potentially inhibits RNA-dependent RNA polymerase of COVs. Afterwards, we discussed the kinetics of SARS- or MERS-CoV proliferation in animal models which is significantly different compared to that in humans. Finally, some ongoing challenges and future perspective on the application of RDV either alone or in combination with other anti-viral agents against CoVs infection were surveyed to determine the efficiency of RDV in preclinical trials. As a result, this paper provides crucial evidence of the potency of RDV to prevent SARS-CoV-2 infections. Communicated by Ramaswamy H. Sarma
2ro2p77q
2ro2p77q
2020-05-20
10.1080/07391102.2020.1767210
3
SARS coronavirus Accessory Proteins
The emergence of the severe acute respiratory syndrome coronavirus (SARS-CoV) has led to a renewed interest in studying the role of accessory proteins in regulating coronavirus infections in the natural host. A significant body of evidence has accumulated in the area of SARS-CoV and host interactions that indicate that the accessory proteins might play an important role in modulating the host response to virus infection and thereby, contribute to pathogenesis. In this review, we have compiled the current knowledge about SARS-CoV accessory proteins, obtained from studies in cell culture systems, reverse genetics and animal models, to shed some light into the possible role of these proteins in the propagation and virulence of SARS-CoV in its natural host. We conclude by providing some questions for future studies that will greatly advance our knowledge about the biological significance and contributions of the accessory proteins in the development of SARS in humans.
2rvs0jxj
2rvs0jxj
2008-04-01
10.1016/j.virusres.2007.10.009
0.5
Retinal findings in patients with COVID-19
2s07tvk4
2s07tvk4
2020-05-12
10.1016/s0140-6736(20)31014-x
4
Rationale of a loading dose initiation for hydroxychloroquine treatment in COVID-19 infection in the DisCoVeRy trial
Around the world, several dose regimens of hydroxychloroquine have been used for COVID-19 infection treatment, with the objective of identifying a short-term course. Hydroxychloroquine was found to decrease the viral replication in a concentration-dependent manner in vitro and to be more active when added prior to the viral challenge. A loading dose is used to rapidly attain a target drug concentration, which is usually considered as approximately the steady-state concentration. With a loading dose, the minimum effective concentration is reached much more rapidly than when using only the maintenance dose from the start. Thus, we propose a hydroxychloroquine sulphate dose regimen of 400 mg twice daily at Day 1 then 400 mg once daily from Day 2 to Day 10. We aim to evaluate this in the C-20-15 DisCoVeRy trial.
2t3ot02y
2t3ot02y
2020-05-30
10.1093/jac/dkaa191
5
Duration of serum neutralizing antibodies for SARS-CoV-2: Lessons from SARS-CoV infection
2u1cylk4
2u1cylk4
2020-03-25
10.1016/j.jmii.2020.03.015
3.5
Clinical Characteristics of Two Human to Human Transmitted Coronaviruses: Corona Virus Disease 2019 versus Middle East Respiratory Syndrome Coronavirus.
After the outbreak of the middle east respiratory syndrome (MERS) worldwide in 2012. Currently, a novel human coronavirus has caused a major disease outbreak, and named corona virus disease 2019 (COVID-19). The emergency of MRES-COV and COVID-19 has caused global panic and threatened health security. Unfortunately, the similarities and differences between the two coronavirus diseases remain to be unknown. The aim of this study, therefore, is to perform a systematic review to compare epidemiological, clinical and laboratory features of COVID-19 and MERS-COV population. We searched PubMed, EMBASE and Cochrane Register of Controlled Trials database to identify potential studies reported COVID-19 or MERS-COV. Epidemiological, clinical and laboratory outcomes, the admission rate of intensive cure unit (ICU), discharge rate and fatality rate were evaluated using GraphPad Prism software. Thirty-two studies involving 3770 patients (COVID-19 = 1062, MERS-COV = 2708) were included in this study. The present study revealed that compared with COVID-19 population, MERS-COV population had a higher rate of ICU admission, discharge and fatality and longer incubation time. It pointed out that fever, cough and generalised weakness and myalgia were main clinical manifestations of both COVID-19 and MERS-COV, whereas ARDS was main complication. The most effective drug for MERS-COV is ribavirin and interferon.
2u6ki9dv
2u6ki9dv
2020-03-10
10.1101/2020.03.08.20032821
1.5
Mobilizing animal models against a pandemic.
2u7bnouk
2u7bnouk
2020-05-12
10.1038/s41684-020-0558-5
3.5
Preliminary Identification of Potential Vaccine Targets for the COVID-19 Coronavirus (SARS-CoV-2) Based on SARS-CoV Immunological Studies
The beginning of 2020 has seen the emergence of COVID-19 outbreak caused by a novel coronavirus, Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). There is an imminent need to better understand this new virus and to develop ways to control its spread. In this study, we sought to gain insights for vaccine design against SARS-CoV-2 by considering the high genetic similarity between SARS-CoV-2 and SARS-CoV, which caused the outbreak in 2003, and leveraging existing immunological studies of SARS-CoV. By screening the experimentally-determined SARS-CoV-derived B cell and T cell epitopes in the immunogenic structural proteins of SARS-CoV, we identified a set of B cell and T cell epitopes derived from the spike (S) and nucleocapsid (N) proteins that map identically to SARS-CoV-2 proteins. As no mutation has been observed in these identified epitopes among the 120 available SARS-CoV-2 sequences (as of 21 February 2020), immune targeting of these epitopes may potentially offer protection against this novel virus. For the T cell epitopes, we performed a population coverage analysis of the associated MHC alleles and proposed a set of epitopes that is estimated to provide broad coverage globally, as well as in China. Our findings provide a screened set of epitopes that can help guide experimental efforts towards the development of vaccines against SARS-CoV-2.
2uwnamao
2uwnamao
2020-02-25
10.3390/v12030254
1
SARS-CoV-2 is sensitive to type I interferon pretreatment.
SARS-CoV-2, a novel coronavirus (CoV), has recently emerged causing an ongoing outbreak of viral pneumonia around the world. While genetically distinct from the original SARS-CoV, both group 2B CoVs share similar genome organization and origins to coronaviruses harbored in bats. Importantly, initial guidance has used insights from SARS-CoV infection to inform treatment and public health strategies. In this report, we evaluate type-I Interferon (IFN-I) sensitivity of SARS-CoV-2 relative to the original SARS-CoV. Our results indicate that while SARS-CoV-2 maintains similar viral replication kinetics to SARS-CoV in Vero cell, the novel CoV is much more sensitive to IFN-I pretreatment. Examining transcriptional factor activation and interferon stimulated gene (ISG) induction, SARS-CoV-2 in the context of type I IFN induces phosphorylation of STAT1 and increased ISG proteins. In contrast, the original SARS-CoV has no evidence for STAT1 phosphorylation or ISG protein increases even in the presence of type I IFN pretreatment. Next, we examined IFN competent Calu3 2B4 cells finding SARS-CoV-2 had reduced viral replication relative to SARS-CoV and induced STAT1 phosphorylation late during infection. Finally, we examined homology between SARS-CoV and SARS-CoV-2 in viral proteins shown to be interferon antagonist. The absence of open reading frame (ORF) 3b and significant changes to ORF6 suggest the two key IFN antagonists may not maintain equivalent function in SARS-CoV-2. Together, the results identify key differences in susceptibility to the IFN-I response between SARS-CoV and SARS-CoV-2. that could help inform disease progression, treatment options, and animal model development.
2w0zr9c0
2w0zr9c0
2020-04-09
10.1101/2020.03.07.982264
0.5
Expanding the frontiers of existing antiviral drugs: Possible effects of HIV-1 protease inhibitors against SARS and avian influenza
Abstract When unexpected diseases such as the severe acute respiratory syndrome (SARS) and avian influenza become a serious threat to public health, an immediate response is imperative. This should take into consideration existing licensed antiviral drugs against other viral diseases already known to be safe for use in humans. In this report, evidence is presented that HIV-1 protease inhibitors (PIs) currently used in anti-HIV-1 therapies might exert some effects on SARS and perhaps, on avian influenza. Evidence for the potential benefits of PIs against the SARS coronavirus (SARS-CoV) is provided by empirical clinical studies, in vivo viral inhibition assays and computational simulations of the docking of these compounds to the active site of the main SARS-CoV protease. As suggested by in silico docking of these molecules to a theoretical model of a subunit of type A influenza virus RNA-dependent RNA polymerase, there also exists a remote possibility that these PIs may have an effect on avian influenza viruses. Although this evidence is still far from being definitive, the results so far obtained suggest that PIs should be seriously taken into consideration for further testing as potential therapeutic agents for SARS and avian influenza.
2w6vgd92
2w6vgd92
2005-11-30
10.1016/j.jcv.2005.03.005
0.5
Recombinant SARS-CoV-2 spike S1-Fc fusion protein induced high levels of neutralizing responses in nonhuman primates
Abstract The COVID-19 outbreak has become a global pandemic responsible for over 2,000,000 confirmed cases and over 126,000 deaths worldwide. In this study, we examined the immunogenicity of CHO-expressed recombinant SARS-CoV-2 S1-Fc fusion protein in mice, rabbits, and monkeys as a potential candidate for a COVID-19 vaccine. We demonstrate that the S1-Fc fusion protein is extremely immunogenic, as evidenced by strong antibody titers observed by day 7. Strong virus neutralizing activity was observed on day 14 in rabbits immunized with the S1-Fc fusion protein using a pseudovirus neutralization assay. Most importantly, in less than 20 days and three injections of the S1-Fc fusion protein, two monkeys developed higher virus neutralizing titers than a recovered COVID-19 patient in a live SARS-CoV-2 infection assay. Our data strongly suggests that the CHO-expressed SARS-CoV-2 S1-Fc recombinant protein could be a strong candidate for vaccine development against COVID-19.
2x4y403o
2x4y403o
2020-06-24
10.1016/j.vaccine.2020.06.066
5
Identification of a new region of SARS-CoV S protein critical for viral entry
Infection by SARS-CoV is initiated by specific interactions between the SARS-CoV spike (S) protein and its receptor ACE2. In this report, we screened a peptide library representing the SARS-CoV S protein sequence using an HIV-based pseudotyping system to identify specific regions that affect viral entry. One of the 169 peptides screened, peptide 9626 (S residues 217–234), inhibited SARS-CoV S-mediated entry of the pseudotyped virions in 293T cells expressing a functional SARS-CoV receptor (hACE2) in a dose dependent manner (IC50 ~11 µM). Alanine scanning mutagenesis was performed to assess the roles of individual residues within this region of S, which was previously uncharacterized. The effects included significant reductions in expression (K223A), viral incorporation (L218A, I230A and N232A), and reduced viral entry (L224A, L226A, I228A, T231A and F233A). Taken together, these results reveal a new region of S protein that is crucial for SARS-CoV entry.
2xxqqjj0
2xxqqjj0
2009-12-01
10.1016/j.jmb.2009.10.032
3
Automatic Detection of Coronavirus Disease (COVID-19) Using X-ray Images and Deep Convolutional Neural Networks
The 2019 novel coronavirus (COVID-19), with a starting point in China, has spread rapidly among people living in other countries, and is approaching approximately 12,245,417 cases worldwide according to the statistics of European Centre for Disease Prevention and Control. There are a limited number of COVID-19 test kits available in hospitals due to the increasing cases daily. Therefore, it is necessary to implement an automatic detection system as a quick alternative diagnosis option to prevent COVID-19 spreading among people. In this study, three different convolutional neural network based models (ResNet50, InceptionV3 and Inception-ResNetV2) have been proposed for the detection of coronavirus pneumonia infected patient using chest X-ray radiographs. ROC analyses and confusion matrices by these three models are given and analyzed using 5-fold cross validation. Considering the performance results obtained, it is seen that the pre-trained ResNet50 model provides the highest classification performance with 98% accuracy among other two proposed models (97% accuracy for InceptionV3 and 87% accuracy for Inception-ResNetV2).
2zmel98u
2zmel98u
2020-03-24
2.5
Letter to the editor: The role of angiotensin-converting enzyme inhibitors and angiotensin receptor blockers in developing a COVID-19 comorbidity-based host risk score
30cc414n
30cc414n
2020-05-19
10.1186/s13054-020-02903-9
5
A Review on SARS-CoV-2 Virology, Pathophysiology, Animal Models, and Anti-Viral Interventions
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of CoV disease 2019 (COVID-19) is a highly pathogenic and transmissible CoV that is presently plaguing the global human population and economy. No proven effective antiviral therapy or vaccine currently exists, and supportive care remains to be the cornerstone treatment. Through previous lessons learned from SARS-CoV-1 and MERS-CoV studies, scientific groups worldwide have rapidly expanded the knowledge pertaining to SARS-CoV-2 virology that includes in vitro and in vivo models for testing of antiviral therapies and randomized clinical trials. In the present narrative, we review SARS-CoV-2 virology, clinical features, pathophysiology, and animal models with a specific focus on the antiviral and adjunctive therapies currently being tested or that require testing in animal models and randomized clinical trials.
30tftimd
30tftimd
2020-05-29
10.3390/pathogens9060426
4
Endothelin receptor antagonists for pulmonary arterial hypertension and COVID-19: friend or foe ?
31urk6xn
31urk6xn
2020-04-17
10.1016/j.healun.2020.04.007
2.5
Molecular docking identifies the binding of 3-chloropyridine moieties specifically to the S1 pocket of SARS-CoV Mpro
Abstract The 3C-like main proteinase of the severe acute respiratory syndrome (SARS) coronavirus, SARS-CoV Mpro, is widely considered to be a major drug target for the development of anti-SARS treatment. Based on the chemical structure of a lead compound from a previous screening, we have designed and synthesized a number of non-peptidyl inhibitors, some of which have shown significantly improved inhibitory activity against SARS-CoV Mpro with IC50 values of ∼60nM. In the absence of SARS-CoV Mpro crystal structures in complex with these synthetic inhibitors, molecular docking tools have been employed to study possible interactions between these inhibitors and SARS-CoV Mpro. The docking results suggest two major modes for the initial binding of these inhibitors to the active site of SARS-CoV Mpro. They also establish a structural basis for the ‘core design’ of these inhibitors by showing that the 3-chloropyridine functions common to all of the present inhibitors tend to cluster in the S1 specificity pocket. In addition, intrinsic flexibility in the S4 pocket allows for the accommodation of bulky groups such as benzene rings, suggesting that this structural plasticity can be further exploited for optimizing inhibitor–enzyme interactions that should promote a tighter binding mode. Most importantly, our results provide the structural basis for rational design of wide-spectrum antiviral drugs targeting the chymotrypsin-like cysteine proteinases from coronaviruses and picornaviruses.
32ju2h1g
32ju2h1g
2008-01-01
10.1016/j.bmc.2007.09.034
0.5
Fiches maladies
32qjtj79
32qjtj79
2019-05-22
10.1016/b978-2-294-76382-3.00012-7
2
Differential Diagnosis of Common Acute Toxicologic Versus Nontoxicologic Illness
This table outlines common toxicologic versus nontoxicologic rule outs based on clinical abnormalities seen in an acutely ill animal. The purpose is to provide an initial guideline for considering toxicologic versus nontoxicologic rule outs when a patient is presented to a practicing veterinarian. Major clinical abnormalities followed by common toxicologic rule outs and non-toxicologic rule outs have been listed so that practicing veterinarians can narrow down an etiology quickly. Based on history, physical examination findings, and blood work changes, once a reasonable etiology has been narrowed down or established, the reader is encouraged to review a more detailed discussion on management of the particular poisoning or disease listed in this or other references.
33l4u1lc
33l4u1lc
2012-02-27
10.1016/j.cvsm.2012.01.001
3
Structural Basis of SARS-CoV-2 Spike Protein Priming by TMPRSS2
Entry of SARS-CoV-2, etiological agent of COVID-19, in the host cell is driven by the interaction of its spike protein with human ACE2 receptor and a serine protease, TMPRSS2. Although complex between SARS-CoV-2 spike protein and ACE2 has been structurally resolved, the molecular details of the SARS-CoV-2 and TMPRSS2 complex are still elusive. TMPRSS2 is responsible for priming of the viral spike protein that entails cleavage of the spike protein at two potential sites, Arg685/Ser686 and Arg815/Ser816. The present study aims to investigate the conformational details of complex between TMPRSS2 and SARS-CoV-2 spike protein, in order to discern the finer details of the priming of viral spike and to point candidate drug targets. Briefly, full length structural model of TMPRSS2 was developed and docked against the resolved structure of SARS-CoV-2 spike protein with directional restraints of both cleavage sites. The docking simulations showed that TMPRSS2 interacts with the two different loops of SARS-CoV-2 spike protein, each containing different cleavage sites. Key functional residues of TMPRSS2 (His296, Ser441 and Ser460) were found to interact with immediate flanking residues of cleavage sites of SARS-CoV-2 spike protein. Compared to the N-terminal cleavage site (Arg685/Ser686), TMPRSS2 region that interact with C-terminal cleavage site (Arg815/Ser816) of the SARS-CoV-2 spike protein was predicted as relatively more druggable. In summary, the present study provide structural characteristics of molecular complex between human TMPRSS2 and SARS-CoV-2 spike protein and points to the candidate drug targets that could further be exploited to direct structure base drug designing.
34ljq0qt
34ljq0qt
2020-04-21
10.1101/2020.04.21.052639
2.5
Development of a Coronavirus Disease 2019 Nonhuman Primate Model Using Airborne Exposure
Airborne transmission is predicted to be a prevalent route of human exposure with SARS-CoV-2. Aside from African green monkeys, nonhuman primate models that replicate airborne transmission of SARS-CoV-2 have not been investigated. A comprehensive and comparative evaluation of COVID-19 in African green monkeys, rhesus macaques, and cynomolgus macaques following airborne exposure to SARS-CoV-2 was performed to define parameters critical to disease progression and the extent to which they correlate with human COVID-19. Respiratory abnormalities and viral shedding were noted for all animals, indicating successful infection. Cynomolgus macaques developed fever, and thrombocytopenia was measured for African green monkeys and rhesus macaques. Type II pneumocyte hyperplasia and alveolar fibrosis were more frequently observed in lung tissue from cynomolgus macaques and African green monkeys. The data indicate that, in addition to African green monkeys, macaques can be successfully infected by airborne SARS-CoV-2, providing viable macaque natural transmission models for medical countermeasure evaluation. One Sentence Summary Nonhuman primates develop COVID-19 following airborne virus exposure.
35ckxycq
35ckxycq
2020-06-26
10.1101/2020.06.26.174128
5
Building a COVID-19 Vulnerability Index
COVID-19 is an acute respiratory disease that has been classified as a pandemic by the World Health Organization. Information regarding this particular disease is limited, however, it is known to have high mortality rates, particularly among individuals with preexisting medical conditions. Creating models to identify individuals who are at the greatest risk for severe complications due to COVID-19 will be useful to help for outreach campaigns in mitigating the diseases worst effects. While information specific to COVID-19 is limited, a model using complications due to other upper respiratory infections can be used as a proxy to help identify those individuals who are at the greatest risk. We present the results for three models predicting such complications, with each model having varying levels of predictive effectiveness at the expense of ease of implementation.
37dadupn
37dadupn
2020-03-21
10.1101/2020.03.16.20036723
1.5
Targeting potential drivers of COVID-19: Neutrophil extracellular traps
Coronavirus disease 2019 (COVID-19) is a novel, viral-induced respiratory disease that in ∼10–15% of patients progresses to acute respiratory distress syndrome (ARDS) triggered by a cytokine storm. In this Perspective, autopsy results and literature are presented supporting the hypothesis that a little known yet powerful function of neutrophils—the ability to form neutrophil extracellular traps (NETs)—may contribute to organ damage and mortality in COVID-19. We show lung infiltration of neutrophils in an autopsy specimen from a patient who succumbed to COVID-19. We discuss prior reports linking aberrant NET formation to pulmonary diseases, thrombosis, mucous secretions in the airways, and cytokine production. If our hypothesis is correct, targeting NETs directly and/or indirectly with existing drugs may reduce the clinical severity of COVID-19.
37i62atc
37i62atc
2020-04-16
10.1084/jem.20200652
2.5
A data-driven hypothesis on the epigenetic dysregulation of host metabolism by SARS coronaviral infection: potential implications for the SARS-CoV-2 modus operandi
COVID-19, the disease caused by the novel SARS-CoV-2, a betacoronavirus structurally similar to SARS-CoV. Based on both structural and syndromic similarities with SARS-CoV, a hypothesis is formed on SARS-CoV-2 potential to affect the host’s metabolism as part of its lifecycle. This hypothesis is evaluated by (a) exploratory analysis of SARS-CoV / human transcriptomic interaction data and gene set enrichment analysis (b) a confirmatory, focused review of the literature based on the findings by (a). A STRING Viruses (available search for human – SARS-CoV (NCBI taxonomy Id: 9606 vs. NCBI taxonomy Id: 694009) genomic interactions reveals ten human proteins, interacting with SARS-CoV: SGTA, FGL2, SPECC1, STAT3, PHB, BCL2L1, PPP1CA, CAV1, JUN, XPO1. Gene set enrichment analyses (GSEA) with STRING on this network revealed their role as a putative protein – protein interaction network (PPI; Enrichment p-value=0.0296) mediating, viral parasitism, interleukin as well as insulin signaling, diabetes and triglyceride catabolism. In the literature, SARS-CoV has been known to cause de novo diabetes by ACE2-dependent uptake on pancreatic isle cells, and furthermore dysregulate lipid autophagy in favor of the viral lifecycle. Conversely, currently there are only non-causative, observational evidence of worse outcomes for COVID-19 patients with comorbid diabetes or hyperglycemia. No study has reported on the lipid profiles of COVID-19 patients; however, lipid-targeting molecules have been proposed as agents against SARS-CoV-2. Future studies, reporting on lipid and glucose metabolism of COVID-19 patients could help elucidate the disease’s seculae and aid drug design.
3854ddb9
3854ddb9
2020-04-23
10.1016/j.mehy.2020.109759
2.5
A SARS-CoV-2-Human Protein-Protein Interaction Map Reveals Drug Targets and Potential Drug-Repurposing
An outbreak of the novel coronavirus SARS-CoV-2, the causative agent of COVID-19 respiratory disease, has infected over 290,000 people since the end of 2019, killed over 12,000, and caused worldwide social and economic disruption(1,2). There are currently no antiviral drugs with proven efficacy nor are there vaccines for its prevention. Unfortunately, the scientific community has little knowledge of the molecular details of SARS-CoV-2 infection. To illuminate this, we cloned, tagged and expressed 26 of the 29 viral proteins in human cells and identified the human proteins physically associated with each using affinity- purification mass spectrometry (AP-MS), which identified 332 high confidence SARS-CoV-2-human protein-protein interactions (PPIs). Among these, we identify 66 druggable human proteins or host factors targeted by 69 existing FDA-approved drugs, drugs in clinical trials and/or preclinical compounds, that we are currently evaluating for efficacy in live SARS-CoV-2 infection assays. The identification of host dependency factors mediating virus infection may provide key insights into effective molecular targets for developing broadly acting antiviral therapeutics against SARS-CoV-2 and other deadly coronavirus strains.
38d6gb7o
38d6gb7o
2020-03-22
10.1101/2020.03.22.002386
0.5
Total Elbow Arthroplasty: Clinical Outcomes, Complications, and Revision Surgery.
Total elbow arthroplasty is a common surgical procedure used in the management of advanced rheumatoid arthritis, posttraumatic arthritis, osteoarthritis, and unfixable fracture in elderly patients. Total elbow prostheses have evolved over the years and now include the linked, unlinked, and convertible types. However, long-term complications, including infection, aseptic loosening, instability, and periprosthetic fracture, remain a challenge. Here, we introduce each type of implant and evaluate clinical outcomes and complications by reviewing the previous literature.
38eddqa4
38eddqa4
2019-12-01
10.4055/cios.2019.11.4.369
3.5
Current data on the cardiovascular effects of the COVID-19
3afy5ent
3afy5ent
2020-04-18
10.1016/j.hjc.2020.04.001
2
Dose selection of chloroquine phosphate for treatment of COVID-19 based on a physiologically based pharmacokinetic model
Chloroquine (CQ) phosphate has been suggested to be clinically effective in the treatment of coronavirus disease 2019 (COVID-19). To develop a physiologically-based pharmacokinetic (PBPK) model for predicting tissue distribution of CQ and apply it to optimize dosage regimens, a PBPK model, with parameterization of drug distribution extrapolated from animal data, was developed to predict human tissue distribution of CQ. The physiological characteristics of time-dependent accumulation was mimicked through an active transport mechanism. Several dosing regimens were proposed based on PBPK simulation combined with known clinical exposure–response relationships. The model was finally validated by clinical data from Chinese patients with COVID-19. The novel PBPK model allows in-depth description of the pharmacokinetics of CQ in several key organs (lung, heart, liver, and kidney), and was applied to design dosing strategies in patients with acute COVID-19 (Day 1: 750 mg BID, Days 2–5: 500 mg BID, CQ phosphate), patients with moderate COVID-19 (Day 1: 750 mg and 500 mg, Days 2–3: 500 mg BID, Days 4–5250 mg BID, CQ phosphate), and other vulnerable populations (e.g., renal and hepatic impairment and elderly patients, Days 1–5: 250 mg BID, CQ phosphate). A PBPK model of CQ was successfully developed to optimize dosage regimens for patients with COVID-19.
3b9u9xpx
3b9u9xpx
2020-04-20
10.1016/j.apsb.2020.04.007
5
Potent binding of 2019 novel coronavirus spike protein by a SARS coronavirus-specific human monoclonal antibody
The newly identified 2019 novel coronavirus (2019-nCoV) has caused more than 11,900 laboratory-confirmed human infections, including 259 deaths, posing a serious threat to human health. Currently, however, there is no specific antiviral treatment or vaccine. Considering the relatively high identity of receptor-binding domain (RBD) in 2019-nCoV and SARS-CoV, it is urgent to assess the cross-reactivity of anti-SARS CoV antibodies with 2019-nCoV spike protein, which could have important implications for rapid development of vaccines and therapeutic antibodies against 2019-nCoV. Here, we report for the first time that a SARS-CoV-specific human monoclonal antibody, CR3022, could bind potently with 2019-nCoV RBD (KD of 6.3 nM). The epitope of CR3022 does not overlap with the ACE2 binding site within 2019-nCoV RBD. These results suggest that CR3022 may have the potential to be developed as candidate therapeutics, alone or in combination with other neutralizing antibodies, for the prevention and treatment of 2019-nCoV infections. Interestingly, some of the most potent SARS-CoV-specific neutralizing antibodies (e.g. m396, CR3014) that target the ACE2 binding site of SARS-CoV failed to bind 2019-nCoV spike protein, implying that the difference in the RBD of SARS-CoV and 2019-nCoV has a critical impact for the cross-reactivity of neutralizing antibodies, and that it is still necessary to develop novel monoclonal antibodies that could bind specifically to 2019-nCoV RBD.
3e6u4aza
3e6u4aza
2020-02-17
10.1080/22221751.2020.1729069
4.5
Contentious issues and evolving concepts in the clinical presentation and management of patients with COVID-19 infectionwith reference to use of therapeutic and other drugs used in Co-morbid diseases (Hypertension, diabetes etc)
Abstract Background and aims Multiple issues in management of COVID have emerged, but confusion persists regarding rational interpretation. Aim of this brief review is to review these issues based on current literature. Methods This is a narrative review with Pubmed and Google Scholar search till 23 March 2020. Search terms were, COVID-19, treatment of coronavirus, COVID 19 and following terms; chloroquine, hydroxychloroquine, ibuprofen, ACE-inhibitors or angiotensin receptor blockers, cardiovascular disease, diarrhoea, liver, testis and gastrointestinal disease. Results We discuss evidence regarding role of chloroquine and hydroxychloroquine in treatment and prophylaxis, use of inhibitors of the renin angiotensin system, safety of ibuprofen, unusual clinical features like gastrointestinal symptoms and interpretation of tests for cardiac enzymes and biomarkers. Conclusions While our conclusions on management of COVID-19 patients with co-morbidities are based on current evidence, however, data is limited and there is immediate need for fast track research.
3egv50vb
3egv50vb
2020-06-30
10.1016/j.dsx.2020.03.012
1
SARS-CoV-2 infection of primary human lung epithelium for COVID-19 modeling and drug discovery
Coronavirus disease 2019 (COVID-19) is the latest respiratory pandemic resulting from zoonotic transmission of severe acute respiratory syndrome-related coronavirus 2 (SARS-CoV-2). Severe symptoms include viral pneumonia secondary to infection and inflammation of the lower respiratory tract, in some cases causing death. We developed primary human lung epithelial infection models to understand responses of proximal and distal lung epithelium to SARS-CoV-2 infection. Differentiated air-liquid interface cultures of proximal airway epithelium and 3D organoid cultures of alveolar epithelium were readily infected by SARS-CoV-2 leading to an epithelial cell-autonomous proinflammatory response. We validated the efficacy of selected candidate COVID-19 drugs confirming that Remdesivir strongly suppressed viral infection/replication. We provide a relevant platform for studying COVID-19 pathobiology and for rapid drug screening against SARS-CoV-2 and future emergent respiratory pathogens.
3fr1p9gs
3fr1p9gs
2020-06-29
10.1101/2020.06.29.174623
5
COVID-19: Pathogenesis, cytokine storm and therapeutic potential of interferons
ABSTRACT The outbreak of the novel SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) responsible for coronavirus disease 2019 (COVID-19) has developed into a major health hazard across the globe. The rapid escalation of the COVID-19 and the considerable associated illness leading to death has transformed it into a critical global public health issue. The current clinical investigation in patients with COVID-19 has showed strong upregulation of cytokine and interferon production after critical infection with SARS-CoV2- induced pneumonia. The current research suggests that few groups of patients with COVID-19 might have a cytokine storm syndrome. Thus, identification and treatment of hyperinflammation using existing, approved therapies with proven safety profiles to address the immediate need to reduce the rising mortality. To date, no specific therapeutic drug or vaccine has been discovered to treat this COVID-19. Intensive research is in progress to identify a promising drug therapy. Hence, several options were proposed to control this fast-emerging pandemic, including antiviral drugs, vaccines, small-molecules, monoclonal antibodies, oligonucleotides, peptides, and interferons (IFNs).
3g06zxmx
3g06zxmx
2020-05-07
10.1016/j.cytogfr.2020.05.002
3
Detection of Nucleocapsid Antibody to SARS-CoV-2 is More Sensitive than Antibody to Spike Protein in COVID-19 Patients
Background: SARS-CoV-2, the cause of coronavirus disease 2019 (COVID-19), is associated with respiratory-related morbidity and mortality. Assays to detect virus-specific antibodies are important to understand the prevalence of infection and the course of the immune response. Methodology: Quantitative measurements of plasma or serum antibodies by luciferase immunoprecipitation assay systems (LIPS) to the nucleocapsid and spike proteins were analyzed in 100 cross-sectional or longitudinal samples from SARS-CoV-2-infected patients. A subset of samples was tested with and without heat inactivation. Results: Fifteen or more days after symptom onset, antibodies against SARS-CoV-2 nucleocapsid protein showed 100% sensitivity and 100% specificity, while antibodies to spike protein were detected with 91% sensitivity and 100% specificity. Neither antibody levels nor the rate of seropositivity were significantly reduced by heat inactivation of samples. Analysis of daily samples from six patients with COVID-19 showed anti-nucleocapsid and spike antibodies appearing between day 8 to day 14 after initial symptoms. Immunocompromised patients generally had a delayed antibody response to SARS-CoV-2 compared to immunocompetent patients. Conclusions: Antibody to the nucleocapsid protein of SARS-CoV-2 is more sensitive than spike protein antibody for detecting early infection. Analyzing heat-inactivated samples by LIPS is a safe and sensitive method for detecting SARS-CoV-2 antibodies.
3g67hjk8
3g67hjk8
2020-04-24
10.1101/2020.04.20.20071423
2
Association of COVID-19 Infections in San Francisco in Early March 2020 with Travel to New York and Europe
Real-time dissemination of epidemiological survey data from positive COVID-19 cases is critical to support efforts to contain or reduce spread of viral infection in the community. Here we detected a significant association between domestic travel or travel to Europe and the identification of new cases in San Francisco, California, USA. These findings suggest that domestic and European travelers may need to be prioritized for evaluation of acute infection from COVID-19 in the setting of limited testing capacity.
3go7thqh
3go7thqh
2020-04-07
10.1101/2020.04.04.20053629
1.5
Social big data: Recent achievements and new challenges
Abstract Big data has become an important issue for a large number of research areas such as data mining, machine learning, computational intelligence, information fusion, the semantic Web, and social networks. The rise of different big data frameworks such as Apache Hadoop and, more recently, Spark, for massive data processing based on the MapReduce paradigm has allowed for the efficient utilisation of data mining methods and machine learning algorithms in different domains. A number of libraries such as Mahout and SparkMLib have been designed to develop new efficient applications based on machine learning algorithms. The combination of big data technologies and traditional machine learning algorithms has generated new and interesting challenges in other areas as social media and social networks. These new challenges are focused mainly on problems such as data processing, data storage, data representation, and how data can be used for pattern mining, analysing user behaviours, and visualizing and tracking data, among others. In this paper, we present a revision of the new methodologies that is designed to allow for efficient data mining and information fusion from social media and of the new applications and frameworks that are currently appearing under the “umbrella” of the social networks, social media and big data paradigms.
3gv6469y
3gv6469y
2016-03-31
10.1016/j.inffus.2015.08.005
1.5
Retinal pathology in multiple sclerosis: insight into the mechanisms of neuronal pathology
3h3ktqgz
3h3ktqgz
2010-05-28
10.1093/brain/awq133
3
Emerging health care-associated infections in the geriatric population.
The increasing number of persons >65 years of age form a special population at risk for nosocomial and other health care-associated infections. The vulnerability of this age group is related to impaired host defenses such as diminished cell-mediated immunity. Lifestyle considerations, e.g., travel and living arrangements, and residence in nursing homes, can further complicate the clinical picture. The magnitude and diversity of health care-associated infections in the aging population are generating new arenas for prevention and control efforts.
3hbbpmnt
3hbbpmnt
2001
3.5
Ivermectin as a potential COVID-19 treatment from the pharmacokinetic point of view
The broad-spectrum antiparasitic agent ivermectin has been very recently found to inhibit SARS-CoV-2 in vitro and proposed as a candidate for drug repurposing in COVID-19. In the present report the in vitro antiviral activity end-points are analyzed from the pharmacokinetic perspective. The available pharmacokinetic data from clinically relevant and excessive dosing studies indicate that the SARS-CoV-2 inhibitory concentrations are not likely to be attainable in humans.
3hgmuyn4
3hgmuyn4
2020-04-17
10.1101/2020.04.11.20061804
2
Animal Models of Aspiration Pneumonia
Appropriate animal models of aspiration pneumonia may be required for studying the mechanism of aspiration and aspiration-induced pneumonia. Animal models of AP allow us to investigate distinct types of pneumonia at various disease stages, studies that are not possible in patients. AP animal models should have features of bacterial pneumonia and swallowing abnormality. Our animal model of aspiration, using recombinant E1-deleted Ad vectors, may be advantageous relative to earlier models for assessing the development of aspiration pneumonia in association with disturbed upper airway reflexes, since DNA virus infection of bronchiolar epithelial cells in the lower respiratory tract can be assessed by the localization and intensity of LacZ gene expression The other candidate model of aspiration was applied for the experimental stroke in mice induced by occlusion of the middle cerebral artery. Aspiration pneumonia was caused by intranasal application of a small amount of Streptococcus pneumoniae. Acid pneumonitis is a major cause of sterile acute lung injury (ALI), resulting in acute respiratory distress syndrome (ARDS) or Mendelson’s syndrome. Several types of animal models of acid aspiration are available using a wide range of developed transgenic models. Different types of animal models of both aspiration pneumonia and aspiration pneumonitis have considerably aided our understanding of disease pathogenesis and testing and developing of new treatment strategies.
3hjnqf3r
3hjnqf3r
2020-04-01
10.1007/978-981-15-4506-1_14
4
Viral targets of acylguanidines
Acylguanidines are a new class of antiviral compounds with the unique ability to target both RNA polymerase and transmembrane proteins of viruses from different families. Importantly, they inhibit proteins which are not targeted by existing antiviral therapies, for example, Vpu of HIV type 1, p7 of hepatitis C virus, E of severe acute respiratory syndrome coronavirus and RNA-dependent RNA polymerase of coxsackievirus B3. BIT225, developed by Biotron Limited, is the first acylguanidine in clinical trials against HIV type 1 and hepatitis C virus. In this article we focus on the mechanisms of inhibition of viral proteins by acylguanidines.
3jnszsrg
3jnszsrg
2012-09-30
10.1016/j.drudis.2012.05.002
3.5
A review of genetic methods and models for analysis of coronavirus-induced severe pneumonitis
Coronaviruses (CoVs) have been studied for over 60 years, but have only recently gained notoriety as deadly human pathogens with the emergence of severe respiratory syndrome CoV and Middle East respiratory syndrome virus. The rapid emergence of these viruses has demonstrated the need for good models to study severe CoV respiratory infection and pathogenesis. There are, currently, different methods and models for the study of CoV disease. The available genetic methods for the study and evaluation of CoV genetics are reviewed here. There are several animal models, both mouse and alternative animals, for the study of severe CoV respiratory disease that have been examined, each with different pros and cons relative to the actual pathogenesis of the disease in humans. A current limitation of these models is that no animal model perfectly recapitulates the disease seen in humans. Through the review and analysis of the available disease models, investigators can employ the most appropriate available model to study various aspects of CoV pathogenesis and evaluate possible antiviral treatments that may potentially be successful in future treatment and prevention of severe CoV respiratory infections.
3jr8a2p7
3jr8a2p7
2015-03-01
10.1099/vir.0.069732-0
2.5
Studies of SARS virus vaccines.
1. Intranasal vaccination using inactivated SARS coronavirus (SARS-CoV) vaccine with adjuvant can induce strong systemic (serum immunoglobulin [Ig] G) and respiratory tract local (tracheal-lung wash fluid IgA) antibody responses with neutralising activity. 2. RBD-Fc (protein-based vaccine) is able to induce effective neutralising antibodies able to provide protection from SARS-CoV infection in animal models. 3. A single dose of RBD-rAAV vaccination can induce adequate neutralising antibody against SARS-CoV infection. 4. Additional doses of vaccine increased the production of neutralising antibody 5-fold compared with a single dose. 5. RBD-rAAV vaccination provoked a prolonged antibody response with continually increasing levels of neutralising activity. 6. Intranasal vaccination with RBD-rAAV induced local IgA and systemic IgG neutralising antibodies and specific T-cell responses, able to protect against SARS-CoV infection in animal models. 7. When compared with the RBD-rAAV prime/boost vaccination, RBD-rAAV prime/RBD-peptide boost induced similar levels of Th1 and neutralising antibody responses that protected vaccinated mice from subsequent SARS-CoV challenges,but stronger Th2 and CTL responses. 8. Overall, our findings suggest that the inactivated vaccine, RBD-Fc and RBD-rAAV, can be further developed into effective and safe vaccines against SARS and that intranasal vaccination may be the preferred route of administration.
3kvb1yjn
3kvb1yjn
2008
3
Repositionnement de la chlorpromazine dans le traitement du COVID-19: étude reCoVery
Abstract OBJECTIVES: The ongoing COVID-19 pandemic comprises a total of more than 2 350 000 cases and 160 000 deaths. The interest in anti-coronavirus drug development has been limited so far and effective methods to prevent or treat coronavirus infections in humans are still lacking. Urgent action is needed to fight this fatal coronavirus infection by reducing the number of infected people along with the infection contagiousness and severity. Since the beginning of the COVID-19 outbreak several weeks ago, we observe in GHU PARIS Psychiatrie & Neurosciences (Sainte-Anne hospital, Paris, France) a lower prevalence of symptomatic and severe forms of COVID-19 infections in psychiatric patients (∼4 %) compared to health care professionals (∼14 %). Similar observations have been noted in other psychiatric units in France and abroad. Our hypothesis is that psychiatric patients could be protected from the severe form of COVID-19 by their psychotropic treatments. Chlorpromazine (CPZ) is a phenothiazine derivative widely used in clinical routine in the treatment of acute and chronic psychoses. This first antipsychotic medication has been discovered in 1952 by Jean Delay and Pierre Deniker at Sainte-Anne hospital. In addition to its antipsychotic effects, several in vitro studies have also demonstrated a CPZ antiviral activity via the inhibition of clathrin-mediated endocytosis. Recently, independent studies revealed that CPZ is an anti-MERS-CoV and an anti-SARS-CoV-1 drug. In comparison to other antiviral drugs, the main advantages of CPZ lie in its biodistribution: (i) preclinical and clinical studies have reported a high CPZ concentration in the lungs (20--200 times higher than in plasma), which is critical because of the respiratory tropism of SARS-CoV-2; (ii) CPZ is highly concentrated in saliva (20-60 times higher than in plasma) and could therefore reduce the contagiousness of COVID-19; (iii) CPZ can cross the blood-brain barrier and could therefore prevent the neurological forms of COVID-19. METHODS: In this context, we will test the hypothesis that CPZ could decrease the unfavorable evolution of COVID-19 infection in oxygen-requiring patients without the need for intensive care, but also reduce the contagiousness of SARS-CoV-2. At this end, we designed a pilot, phase III, multicenter, single blind, randomized controlled therapeutic trial. Efficacy of CPZ will be assessed according to clinical, biological and radiological criteria. The main objective is to demonstrate a shorter Time To Response (TTR) to treatment in the CPZ + standard-of-care (CPZ + SOC) group, compared to the SOC group. Response to treatment is defined by a reduction of at least one level of severity on the WHO-Ordinal Scale for Clinical Improvement (WHO-OSCI). The secondary objectives are to demonstrate in the CPZ + SOC group, compared to the SOC group: A) superior clinical improvement; B) a greater decrease in the biological markers of viral attack by SARS-CoV-2 (PCR, viral load); C) a greater decrease in inflammatory markers (e.g. CRP and lymphopenia); D) a greater decrease in parenchymal involvement (chest CT) on the seventh day post-randomization; E) to define the optimal dosage of CPZ and its tolerance; F) to evaluate the biological parameters of response to treatment, in particular the involvement of inflammatory cytokines. Patient recruitment along with the main and secondary objectives are in line with WHO 2020 COVID-19 guidelines. CONCLUSION: This repositioning of CPZ as anti-SARS-CoV-2 activity offers an alternative and rapid strategy to alleviate the virus propagation and the infection severity and lethality. This CPZ repositioning strategy also avoids numerous developmental and experimental steps, can save precious time to rapidly establish an anti-COVID-19 therapy with well-known, limited and easy to manage side effects. Indeed, CPZ is an FDA-approved drug with an excellent tolerance profile, prescribed for around 70 years, in psychiatry but also in clinical routine in nausea and vomiting of pregnancy, in advanced cancer and also to treat headaches in various neurological conditions. The broad spectrum of CPZ treatment - including antipsychotic, anxiolytic, antiemetic, antiviral, immunomodulatory effects along with inhibition of clathrin-mediated endocytosis and modulation of blood-brain barrier - is in line with the historical French commercial name for CPZ, i.e. LARGACTIL, chosen as a reference to its 'LARGe ACTion' properties. The discovery of those CPZ properties, as for many other molecules in psychiatry, is both the result of serendipity and careful clinical observations. Using this approach, the field of mental illness could provide innovative therapeutic approaches to fight SARS-CoV-2.
3l4mntw2
3l4mntw2
2020-04-29
10.1016/j.encep.2020.04.010
2
Covid-19: the renin–angiotensin system imbalance hypothesis
The emergency of SARS-CoV-2 in China started a novel challenge to the scientific community. As the virus turns pandemic, scientists try to map the cellular mechanisms and pathways of SARS-CoV-2 related to the pathogenesis of Coronavirus Disease 2019 (Covid-19). After transmembrane angiotensin-converting enzyme 2 (ACE2) has been found to be SARS-CoV-2 receptor, we hypothesized an immune-hematological mechanism for Covid-19 based on renin–angiotensin system (RAS) imbalance to explain clinical, laboratory and imaging findings on disease course. We believe that exaggerated activation of ACE/Angiotensin II (Ang II)/Angiotensin Type 1 (AT1) receptor RAS axis in line with reduction of ACE2/Angiotensin-(1-7)/Mas receptor may exert a pivotal role in the pathogenesis of Covid-19. In this perspective, we discuss potential mechanisms and evidence on this hypothesis.
3l7unh5v
3l7unh5v
2020-06-08
10.1042/cs20200492
4
Modeling layered non-pharmaceutical interventions against SARS-CoV-2 in the United States with Corvid
Background: The novel coronavirus SARS-CoV-2 has rapidly spread across the globe and is poised to cause millions of deaths worldwide. There are currently no proven pharmaceutical treatments, and vaccines are likely over a year away. At present, non-pharmaceutical interventions (NPIs) are the only effective option to reduce transmission of the virus, but it is not clear how to deploy these potentially expensive and disruptive measures. Modeling can be used to understand the potential effectiveness of NPIs for both suppression and mitigation efforts. Methods and Findings: We developed Corvid, an adaptation of the agent-based influenza model called FluTE to SARS-CoV-2 transmission. To demonstrate features of the model relevant for studying the effects of NPIs, we simulated transmission of SARS-CoV-2 in a synthetic population representing a metropolitan area in the United States. Transmission in the model occurs in several settings, including at home, at work, and in schools. We simulated several combinations of NPIs that targeted transmission in these settings, such as school closures and work-from-home policies. We also simulated three strategies for testing and isolating symptomatic cases. For our demonstration parameters, we show that testing followed by home isolation of ascertained cases reduced transmission by a modest amount. We also show how further reductions may follow by isolating cases in safe facilities away from susceptible family members or by quarantining all family members to prevent transmission from likely infections that have yet to manifest. Conclusions: Models that explicitly include settings where individuals interact such as the home, work, and school are useful for studying the effectiveness of NPIs, as these are more dependent on community structure than pharmaceutical interventions such as vaccination. Corvid can be used to help evaluate complex combinations of interventions, although there is no substitute for real-world observations. Our results on NPI effectiveness summarize the behavior of the model for an assumed set of parameters for demonstration purposes. Model results can be sensitive to the assumptions made about disease transmission and the natural history of the disease, both of which are not yet sufficiently characterized for SARS-CoV-2 for quantitative modeling. Models of SARS-CoV-2 transmission will need to be updated as the pathogen becomes better-understood.
3oovwwem
3oovwwem
2020-04-11
10.1101/2020.04.08.20058487
2.5
Age‐related rhesus macaque models of COVID‐19
BACKGROUND: Since December 2019, an outbreak of the Corona Virus disease 2019 (COVID‐19) caused by severe acute respiratory syndrome coronavirus (SARS‐CoV‐2) in Wuhan, China, has become a public health emergency of international concern. The high fatality of aged cases caused by SARS‐CoV‐2 was a need to explore the possible age‐related phenomena with non‐human primate models. METHODS: Three 3‐5 years old and two 15 years old rhesus macaques were intratracheally infected with SARS‐CoV‐2, and then analyzed by clinical signs, viral replication, chest X‐ray, histopathological changes and immune response. RESULTS: Viral replication of nasopharyngeal swabs, anal swabs and lung in old monkeys was more active than that in young monkeys for 14 days after SARS‐CoV‐2 challenge. Monkeys developed typical interstitial pneumonia characterized by thickened alveolar septum accompanied with inflammation and edema, notably, old monkeys exhibited diffuse severe interstitial pneumonia. Viral antigens were detected mainly in alveolar epithelial cells and macrophages. CONCLUSION: SARS‐CoV‐2 caused more severe interstitial pneumonia in old monkeys than that in young monkeys. Rhesus macaque models infected with SARS‐CoV‐2 provided insight into the pathogenic mechanism and facilitated the development of vaccines and therapeutics against SARS‐CoV‐2 infection.
3oyivuxv
3oyivuxv
2020-03-30
10.1002/ame2.12108
2
Time series modelling to forecast the confirmed and recovered cases of COVID-19
Coronaviruses are enveloped RNA viruses from the Coronaviridae family affecting neurological, gastrointestinal, hepatic and respiratory systems. In late 2019 a new member of this family belonging to the Betacoronavirus genera (referred to as COVID-19) originated and spread quickly across the world calling for strict containment plans and policies. In most countries in the world, the outbreak of the disease has been serious and the number of confirmed COVID-19 cases has increased daily, while, fortunately the recovered COVID-19 cases have also increased. Clearly, forecasting the “confirmed” and “recovered” COVID-19 cases helps planning to control the disease and plan for utilization of health care resources. Time series models based on statistical methodology are useful to model time-indexed data and for forecasting. Autoregressive time series models based on two-piece scale mixture normal distributions, called TP–SMN–AR models, is a flexible family of models involving many classical symmetric/asymmetric and light/heavy tailed autoregressive models. In this paper, we use this family of models to analyze the real world time series data of confirmed and recovered COVID-19 cases.
3pkncxgb
3pkncxgb
2020-05-13
10.1016/j.tmaid.2020.101742
3
Binding interaction of quercetin-3-β-galactoside and its synthetic derivatives with SARS-CoV 3CL(pro): Structure–activity relationship studies reveal salient pharmacophore features
The 3C-like protease (3CL(pro)) of severe acute respiratory syndrome-associated coronavirus (SARS-CoV) is one of the most promising targets for discovery of drugs against SARS, because of its critical role in the viral life cycle. In this study, a natural compound called quercetin-3-β-galactoside was identified as an inhibitor of the protease by molecular docking, SPR/FRET-based bioassays, and mutagenesis studies. Both molecular modeling and Q189A mutation revealed that Gln189 plays a key role in the binding. Furthermore, experimental evidence showed that the secondary structure and enzymatic activity of SARS-CoV 3CL(pro) were not affected by the Q189A mutation. With the help of molecular modeling, eight new derivatives of the natural product were designed and synthesized. Bioassay results reveal salient features of the structure–activity relationship of the new compounds: (1) removal of the 7-hydroxy group of the quercetin moiety decreases the bioactivity of the derivatives; (2) acetoxylation of the sugar moiety abolishes inhibitor action; (3) introduction of a large sugar substituent on 7-hydroxy of quercetin can be tolerated; (4) replacement of the galactose moiety with other sugars does not affect inhibitor potency. This study not only reveals a new class of compounds as potential drug leads against the SARS virus, but also provides a solid understanding of the mechanism of inhibition against the target enzyme.
3pmor8yi
3pmor8yi
2006-12-15
10.1016/j.bmc.2006.09.014
0.5
Pathology of infectious diseases: new agents, opportunistic, neglectable, emergent, reemergent diseases and why not super resistant nosocomial bacteria?
3pnpaer4
3pnpaer4
2019-09-27
10.4322/acr.2019.126
3
Ribavirin, Remdesivir, Sofosbuvir, Galidesivir, and Tenofovir against SARS-CoV-2 RNA dependent RNA polymerase (RdRp): A molecular docking study
Abstract Aims A new human coronavirus (HCoV), which has been designated SARS-CoV-2, began spreading in December 2019 in Wuhan City, China causing pneumonia called COVID-19. The spread of SARS-CoV-2 has been faster than any other coronaviruses that have succeeded in crossing the animal-human barrier. There is concern that this new virus will spread around the world as did the previous two HCoVs—Severe Acute Respiratory Syndrome (SARS) and Middle East Respiratory Syndrome (MERS)—each of which caused approximately 800 deaths in the years 2002 and 2012, respectively. Thus far, 11,268 deaths have been reported from the 258,842 confirmed infections in 168 countries. Main methods In this study, the RNA-dependent RNA polymerase (RdRp) of the newly emerged coronavirus is modeled, validated, and then targeted using different anti-polymerase drugs currently on the market that have been approved for use against various viruses. Key findings The results suggest the effectiveness of Ribavirin, Remdesivir, Sofosbuvir, Galidesivir, and Tenofovir as potent drugs against SARS-CoV-2 since they tightly bind to its RdRp. In addition, the results suggest guanosine derivative (IDX-184), Setrobuvir, and YAK as top seeds for antiviral treatments with high potential to fight the SARS-CoV-2 strain specifically. Significance The availability of FDA-approved anti-RdRp drugs can help treat patients and reduce the danger of the mysterious new viral infection COVID-19. The drugs mentioned above can tightly bind to the RdRp of the SARS-CoV-2 strain and thus may be used to treat the disease. No toxicity measurements are required for these drugs since they were previously tested prior to their approval by the FDA.
3pxc5wot
3pxc5wot
2020-03-25
10.1016/j.lfs.2020.117592
0.5
Repurposing of clinically approved drugs for treatment of coronavirus disease 2019 in a 2019-novel coronavirus-related coronavirus model
BACKGROUND: Medicines for the treatment of 2019-novel coronavirus (2019-nCoV) infections are urgently needed. However, drug screening using live 2019-nCoV requires high-level biosafety facilities, which imposes an obstacle for those institutions without such facilities or 2019-nCoV. This study aims to repurpose the clinically approved drugs for the treatment of coronavirus disease 2019 (COVID-19) in a 2019-nCoV-related coronavirus model. METHODS: A 2019-nCoV-related pangolin coronavirus GX_P2V/pangolin/2017/Guangxi was described. Whether GX_P2V uses angiotensin-converting enzyme 2 (ACE2) as the cell receptor was investigated by using small interfering RNA (siRNA)-mediated silencing of ACE2. The pangolin coronavirus model was used to identify drug candidates for treating 2019-nCoV infection. Two libraries of 2406 clinically approved drugs were screened for their ability to inhibit cytopathic effects on Vero E6 cells by GX_P2V infection. The anti-viral activities and anti-viral mechanisms of potential drugs were further investigated. Viral yields of RNAs and infectious particles were quantified by quantitative real-time polymerase chain reaction (qRT-PCR) and plaque assay, respectively. RESULTS: The spike protein of coronavirus GX_P2V shares 92.2% amino acid identity with that of 2019-nCoV isolate Wuhan-hu-1, and uses ACE2 as the receptor for infection just like 2019-nCoV. Three drugs, including cepharanthine (CEP), selamectin, and mefloquine hydrochloride, exhibited complete inhibition of cytopathic effects in cell culture at 10 µmol/L. CEP demonstrated the most potent inhibition of GX_P2V infection, with a concentration for 50% of maximal effect [EC50] of 0.98 µmol/L. The viral RNA yield in cells treated with 10 µmol/L CEP was 15,393-fold lower than in cells without CEP treatment ([6.48â±â0.02]â×â10vs. 1.00â±â0.12, tâ=â150.38, Pâ<â0.001) at 72 h post-infection (p.i.). Plaque assays found no production of live viruses in media containing 10 µmol/L CEP at 48 h p.i. Furthermore, we found CEP had potent anti-viral activities against both viral entry (0.46â±â0.12, vs.1.00â±â0.37, tâ=â2.42, Pâ<â0.05) and viral replication ([6.18â±â0.95]â×â10vs. 1.00â±â0.43, tâ=â3.98, Pâ<â0.05). CONCLUSIONS: Our pangolin coronavirus GX_P2V is a workable model for 2019-nCoV research. CEP, selamectin, and mefloquine hydrochloride are potential drugs for treating 2019-nCoV infection. Our results strongly suggest that CEP is a wide-spectrum inhibitor of pan-betacoronavirus, and further study of CEP for treatment of 2019-nCoV infection is warranted.
3pxo0j42
3pxo0j42
2020
3
The SARS-CoV-2 conserved macrodomain is a highly efficient ADP-ribosylhydrolase
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and other SARS-like-CoVs encode 3 tandem macrodomains within non-structural protein 3 (nsp3). The first macrodomain, Mac1, is conserved throughout CoVs, binds to and hydrolyzes mono-ADP-ribose (MAR) from target proteins. Mac1 likely counters host-mediated anti-viral ADP-ribosylation, a posttranslational modification that is part of the host response to viral infections. Mac1 is essential for pathogenesis in multiple animal models of CoV infection, implicating it as a virulence factor and potential therapeutic target. Here we report the crystal structure of SARS-CoV-2 Mac1 in complex with ADP-ribose. SARS-CoV-2, SARS-CoV and MERS-CoV Mac1 exhibit similar structural folds and all 3 proteins bound to ADP-ribose with low μM affinities. In contrast, we found that only the MERS-CoV Mac1 protein bound to poly-ADP-ribose (PAR), and none of these enzymes could hydrolyze PAR. Importantly, using ADP-ribose detecting antibodies and both gel-based assay and novel ELISA assays, we demonstrated highly efficient de-MARylating activity for all 3 CoV Mac1 proteins. We conclude that the SARS-CoV-2 and other CoV Mac1 proteins are highly efficient MAR-hydrolases with strikingly similar activity, indicating that compounds targeting CoV Mac1 proteins may have broad anti-CoV activity. IMPORTANCE SARS-CoV-2 has recently emerged into the human population and has led to a worldwide pandemic of COVID-19 that has caused nearly 350 thousand deaths worldwide. With, no currently approved treatments, novel therapeutic strategies are desperately needed. All coronaviruses encode for a highly conserved macrodomain (Mac1) that binds to and removes ADP-ribose adducts from proteins in a dynamic post-translational process increasingly recognized as an important factor that regulates viral infection. The macrodomain is essential for CoV pathogenesis and may be a novel therapeutic target. Thus, understanding its biochemistry and enzyme activity are critical first steps for these efforts. Here we report the crystal structure of SARS-CoV-2 Mac1 in complex with ADP-ribose, and describe its ADP-ribose binding and hydrolysis activities in direct comparison to SARS-CoV and MERS-CoV Mac1 proteins. These results are an important first step for the design and testing of potential therapies targeting this unique protein domain.
3qpq62ac
3qpq62ac
2020-06-01
10.1101/2020.05.11.089375
4.5
Caring for persons in detention suffering with mental illness during the Covid-19 outbreak
3qqzthx8
3qqzthx8
2020-11-30
10.1016/j.fsiml.2020.100013
3
Pharmacy Administration and Pharmaceutical Care Practice in a Module Hospital during the COVID-19 Epidemic
Abstract Objective To describe the pharmacy administration and pharmaceutical care in a module hospital during COVID-19 epidemic and provide reference for domestic and foreign pharmacists participating in the epidemic prevention and control. Design The new COVID-19 “module” pharmaceutical care model was equipped with new features such as pharmacy emergency command group, organizational structure for pharmacy administration, electronic control of drug prescription, and “zero contact” pharmaceutical care relying on the new media platform “WeChat”. This platform provided relevant pharmaceutical care for patients, such as ensuring drug supply, setting up critical care drug trolleys, designing specific drug packaging bags, creating a module radio station to broadcast rational drug use information to the patients, and other aspects. Setting and participants The study was performed in Jianghan module hospital constructed at the Wuhan Convention and Exhibition Center in Wuhan, China. This is one of the first three module hospitals. Outcome measures Pharmacists successfully completed the tasks of purchase, storage, and free distribution of 1033844.3 RMB worth of drugs (about $146,000 US dollars), reviewed about 20,000 electronic orders, provided one-on-one online medication consultation for 484 patients, and held five lectures on rational drug use knowledge, which could help reduce irrational drug use and minimize the risk involved. Results The pharmacists provided pharmaceutical care for 1848 patients with mild COVID-19 disease. They not only ensured the timely supply of the drugs but also reduced the incidence of drug-induced risks through medication review and guidance, thereby improving patient compliance and helping the patients rebuild their confidence in overcoming the disease. Conclusion The new COVID-19 “module” pharmaceutical care model has played an important role in overcoming the epidemic situation of COVID-19 in China and thus can be implemented on a broader scale.
3r1tqnr3
3r1tqnr3
2020-04-10
10.1016/j.japh.2020.04.006
2
Current global vaccine and drug efforts against COVID-19: Pros and cons of bypassing animal trials
COVID-19 has become one of the biggest health concern, along with huge economic burden. With no clear remedies to treat the disease, doctors are repurposing drugs like chloroquine and remdesivir to treat COVID-19 patients. In parallel, research institutes in collaboration with biotech companies have identified strategies to use viral proteins as vaccine candidates for COVID-19. Although this looks promising, they still need to pass the test of challenge studies in animal models. As various models for SARS-CoV-2 are under testing phase, biotech companies have bypassed animal studies and moved to Phase I clinical trials. In view of the present outbreak, this looks a justified approach, but the problem is that in the absence of animal studies, we can never predict the outcomes in humans. Since animal models are critical for vaccine development and SARS-CoV-2 has different transmission dynamics, in this review we compare different animal models of SARS-CoV-2 with humans for their pathogenic, immune response and transmission dynamics that make them ideal models for vaccine testing for COVID-19. Another issue of using animal model is the ethics of using animals for research; thus, we also discuss the pros and cons of using animals for vaccine development studies.
3sepefqa
3sepefqa
2020-06-12
10.1007/s12038-020-00053-2
4
Identification of potential inhibitors against SARS-CoV-2 by targeting proteins responsible for envelope formation and virion assembly using docking based virtual screening, and pharmacokinetics approaches
WHO has declared the outbreak of COVID-19 as a public health emergency of international concern. The ever-growing new cases have called for an urgent emergency for specific anti-COVID-19 drugs. Three structural proteins (Membrane, Envelope and Nucleocapsid protein) play an essential role in the assembly and formation of the infectious virion particles. Thus, the present study was designed to identify potential drug candidates from the unique collection of 548 anti-viral compounds (natural and synthetic anti-viral), which target SARS-CoV-2 structural proteins. High-end molecular docking analysis was performed to characterize the binding affinity of the selected drugs-the ligand, with the SARS-CoV-2 structural proteins, while high-level Simulation studies analyzed the stability of drug-protein interactions. The present study identified rutin, a bioflavonoid and the antibiotic, doxycycline, as the most potent inhibitor of SARS-CoV-2 envelope protein. Caffeic acid and ferulic acid were found to inhibit SARS-CoV-2 membrane protein while the anti-viral agent's simeprevir and grazoprevir showed a high binding affinity for nucleocapsid protein. All these compounds not only showed excellent pharmacokinetic properties, absorption, metabolism, minimal toxicity and bioavailability but were also remain stabilized at the active site of proteins during the MD simulation. Thus, the identified lead compounds may act as potential molecules for the development of effective drugs against SARS-CoV-2 by inhibiting the envelope formation, virion assembly and viral pathogenesis.
3tea19f3
3tea19f3
2020-07-05
10.1016/j.meegid.2020.104451
5
Eltrombopag is a potential target for drug intervention in SARS-CoV-2 spike protein
The COVID-19 pandemic, caused by the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), is a current global threat for which there is an urgent need to search for an effective therapy. The transmembrane spike (S) glycoprotein of SARS-CoV-2 directly binds to the host angiotensin-converting enzyme 2 (ACE2) and mediates viral entrance, which is therefore considered as a promising drug target. Considering that new drug development is a time-consuming process, drug repositioning may facilitate rapid drug discovery dealing with sudden infectious diseases. Here, we compared the differences between the virtual structural proteins of SARS-CoV-2 and SARS-CoV, and selected a pocket mainly localizing in the fusion cores of S2 domain for drug screening. A virtual drug design algorithm screened the Food and Drug Administration-approved drug library of 1234 compounds, and 13 top scored compounds were obtained through manual screening. Through in vitro molecular interaction experiments, eltrombopag was further verified to possess a high binding affinity to S protein plus human ACE2 and could potentially affect the stability of the ACE2-S protein complex. Hence, it is worth further exploring eltrombopag as a potential drug for the treatment of SARS-CoV-2 infection.
3u1odzon
3u1odzon
2020-06-12
10.1016/j.meegid.2020.104419
4
Dieckol, a SARS-CoV 3CLpro inhibitor, isolated from the edible brown algae Ecklonia cava
Phlorotannins have been isolated and are the first of their type showing competitively inhibitory activity toward SARS-CoV 3CLpro. Dieckol showed the most potent SARS-CoV 3CLpro trans/cis-cleavage inhibitory effects with high association rate. [Figure: see text]
3uhjmocf
3uhjmocf
2013-07-01
10.1016/j.bmc.2013.04.026
3
An animal model of SARS produced by infection of Macaca mulatta with SARS coronavirus
A new SARS animal model was established by inoculating SARS coronavirus (SARS‐CoV) into rhesus macaques (Macaca mulatta) through the nasal cavity. Pathological pulmonary changes were successively detected on days 5–60 after virus inoculation. All eight animals showed a transient fever 2–3 days after inoculation. Immunological, molecular biological, and pathological studies support the establishment of this SARS animal model. Firstly, SARS‐CoV‐specific IgGs were detected in the sera of macaques from 11 to 60 days after inoculation. Secondly, SARS‐CoV RNA could be detected in pharyngeal swab samples using nested RT‐PCR in all infected animals from 5 days after virus inoculation. Finally, histopathological changes of interstitial pneumonia were found in the lungs during the 60 days after viral inoculation: these changes were less marked at later time points, indicating that an active healing process together with resolution of an acute inflammatory response was taking place in these animals. This animal model should provide insight into the mechanisms of SARS‐CoV‐related pulmonary disease and greatly facilitate the development of vaccines and therapeutics against SARS. Copyright © 2005 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
3vwxsuao
3vwxsuao
2005-05-13
10.1002/path.1769
5
Key residues of the receptor binding motif in the spike protein of SARS-CoV-2 that interact with ACE2 and neutralizing antibodies
Coronavirus disease 2019 (COVID-19), caused by the novel human coronavirus SARS-CoV-2, is currently a major threat to public health worldwide. The viral spike protein binds the host receptor angiotensin-converting enzyme 2 (ACE2) via the receptor-binding domain (RBD), and thus is believed to be a major target to block viral entry. Both SARS-CoV-2 and SARS-CoV share this mechanism. Here we functionally analyzed the key amino acid residues located within receptor binding motif of RBD that may interact with human ACE2 and available neutralizing antibodies. The in vivo experiments showed that immunization with either the SARS-CoV RBD or SARS-CoV-2 RBD was able to induce strong clade-specific neutralizing antibodies in mice; however, the cross-neutralizing activity was much weaker, indicating that there are distinct antigenic features in the RBDs of the two viruses. This finding was confirmed with the available neutralizing monoclonal antibodies against SARS-CoV or SARS-CoV-2. It is worth noting that a newly developed SARS-CoV-2 human antibody, HA001, was able to neutralize SARS-CoV-2, but failed to recognize SARS-CoV. Moreover, the potential epitope residues of HA001 were identified as A475 and F486 in the SARS-CoV-2 RBD, representing new binding sites for neutralizing antibodies. Overall, our study has revealed the presence of different key epitopes between SARS-CoV and SARS-CoV-2, which indicates the necessity to develop new prophylactic vaccine and antibody drugs for specific control of the COVID-19 pandemic although the available agents obtained from the SARS-CoV study are unneglectable.
3w0j096l
3w0j096l
2020
4
Why the WHO won't use the p-word
There are no criteria for a pandemic, but covid-19 looks like one, says Debora MacKenzie
3wk36h9p
3wk36h9p
2020-03-07
10.1016/s0262-4079(20)30474-7
2
Understand Research Hotspots Surrounding COVID-19 and Other Coronavirus Infections Using Topic Modeling
Background: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a virus that causes severe respiratory illness in humans, which eventually results in the current outbreak of novel coronavirus disease (COVID-19) around the world. The research community is interested to know what are the hotspots in coronavirus (CoV) research and how much is known about COVID-19. This study aimed to evaluate the characteristics of publications involving coronaviruses as well as COVID-19 by using a topic modeling analysis. Methods: We extracted all abstracts and retained the most informative words from the COVID-19 Open Research Dataset, which contains all the 35,092 pieces of coronavirus related literature published up to March 20, 2020. Using Latent Dirichlet Allocation modeling, we trained an eight-topic model from the corpus. We then analyzed the semantic relationships between topics and compared the topic distribution between COVID-19 and other CoV infections. Results: Eight topics emerged overall: clinical characterization, pathogenesis research, therapeutics research, epidemiological study, virus transmission, vaccines research, virus diagnostics, and viral genomics. It was observed that COVID-19 research puts more emphasis on clinical characterization, epidemiological study, and virus transmission at present. In contrast, topics about diagnostics, therapeutics, vaccines, genomics and pathogenesis only accounted for less than 10% or even 4% of all the COVID-19 publications, much lower than those of other CoV infections. Conclusions: These results identified knowledge gaps in the area of COVID-19 and offered directions for future research. Keywords: COVID-19, coronavirus, topic modeling, hotspots, text mining
3wuh6k6g
3wuh6k6g
2020-03-30
10.1101/2020.03.26.20044164
1
Infection of bat and human intestinal organoids by SARS-CoV-2
A novel coronavirus-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-emerged in humans in Wuhan, China, in December 2019 and has since disseminated globally1,2. As of April 16, 2020, the confirmed case count of coronavirus disease 2019 (COVID-19) had surpassed 2 million. Based on full-genome sequence analysis, SARS-CoV-2 shows high homology to SARS-related coronaviruses identified in horseshoe bats1,2. Here we show the establishment and characterization of expandable intestinal organoids derived from horseshoe bats of the Rhinolophus sinicus species that can recapitulate bat intestinal epithelium. These bat enteroids are fully susceptible to SARS-CoV-2 infection and sustain robust viral replication. Development of gastrointestinal symptoms in some patients with COVID-19 and detection of viral RNA in fecal specimens suggest that SARS-CoV-2 might cause enteric, in addition to respiratory, infection3,4. Here we demonstrate active replication of SARS-CoV-2 in human intestinal organoids and isolation of infectious virus from the stool specimen of a patient with diarrheal COVID-19. Collectively, we established the first expandable organoid culture system of bat intestinal epithelium and present evidence that SARS-CoV-2 can infect bat intestinal cells. The robust SARS-CoV-2 replication in human intestinal organoids suggests that the human intestinal tract might be a transmission route of SARS-CoV-2.
3y15awzt
3y15awzt
2020
5
Risks of ACE Inhibitor and ARB Usage in COVID‐19: Evaluating the Evidence
Concerns have been raised regarding the safety of angiotensin converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) in patients with coronavirus disease of 2019 (COVID‐19), based on the hypothesis that such medications may raise expression of ACE2, the receptor for severe acute respiratory syndrome‐coronavirus 2 (SARS‐CoV‐2). We conducted a literature review of studies (n = 12) in experimental animals and human subjects (n = 12) and evaluated the evidence regarding the impact of administration of ACEIs and ARBs on ACE2 expression. We prioritized studies that assessed ACE2 protein expression data, measured directly or inferred from ACE2 activity assays. The findings in animals are inconsistent with respect to an increase in ACE2 expression in response to treatment with ACEIs or ARBs. Control/sham animals show little to no effect in the plurality of studies. Those studies that report increases in ACE2 expression tend to involve acute injury models and/or higher doses of ACEIs or ARBs than are typically administered to patients. Data from human studies overwhelmingly imply that administration of ACEIs/ARBs does not increase ACE2 expression. Available evidence, in particular, data from human studies, does not support the hypothesis that ACEI/ARB use increases ACE2 expression and the risk of complications from COVID‐19. We conclude that patients being treated with ACEIs and ARBs should continue their use for approved indications.
3ysa4twk
3ysa4twk
2020-05-10
10.1002/cpt.1863
3
A comprehensive Chinese experience against SARS-CoV-2 in ophthalmology
The 2019 novel coronavirus disease (COVID-19) has now swept through the continents and poses a global threat to public health. Several investigations have been conducted to identify whether COVID-19 can be transmitted through the ocular route, and the conclusion is that it is a potential route but remains uncertain. Due to the face-to-face communication with patients, frequent exposure to tears and ocular discharge, and the unavoidable use of equipment which requires close proximity, ophthalmologists carry a high risk of contracting severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Based on 33 articles published by Chinese scholars, guidelines and clinical practice experience in domestic hospitals, we have summarized the Chinese experience through the lens of ophthalmology, hoping to make a contribution to protecting ophthalmologists and patients around the world.
3yxrqa22
3yxrqa22
2020-04-07
10.1186/s40662-020-00187-2
1.5
The current understanding and potential therapeutic options to combat COVID-19
Abstract The ongoing wreaking global outbreak of the novel human beta coronavirus (CoV) pathogen was presumed to be from a seafood wholesale market in Wuhan, China, belongs to the Coronaviridae family in the Nidovirales order. The virus is highly contagious with potential human-human transmission which was named as the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), has spread across six continents and emerged as a global pandemic in short span with alarming levels of spread and severity. This virus associated symptoms and infectious respiratory illness is designated as coronavirus disease 19 (COVID-19). The SARS-CoV-2 possesses enveloped club-like spike protein projections with positive-sense large RNA genome and has a unique replication strategy. This virus was believed to have zoonotic origin with genetical identity to bat and pangolin CoV. In the current review, we introduce a general overview about the human CoVs and the associated diseases, the origin, structure, replication and key clinical events that occur in the COVID-19 pathogenicity. Furthermore, we focused on possible therapeutic options such as repurposing drugs including antimalarials, antivirals, antiparasitic drugs, and anti-HIV drugs, as well as monoclonal antibodies, vaccines as potential treatment options. Also we have summarized the latest research progress on the usage of stem cell therapy, human convalescent serum, interferon's, in the treatment of COVID-19.
3zy5dgxz
3zy5dgxz
2020-05-08
10.1016/j.lfs.2020.117765
3
Renin–Angiotensin–Aldosterone System Inhibitors in Patients with Covid-19
405jvqyv
405jvqyv
2020-03-30
10.1056/nejmsr2005760
1.5
Bioinformatics Resources and Tools for Phage Display
Databases and computational tools for mimotopes have been an important part of phage display study. Five special databases and eighteen algorithms, programs and web servers and their applications are reviewed in this paper. Although these bioinformatics resources have been widely used to exclude target-unrelated peptides, characterize small molecules-protein interactions and map protein-protein interactions, a lot of problems are still waiting to be solved. With the improvement of these tools, they are expected to serve the phage display community better.
407bthqj
407bthqj
2011-01-18
10.3390/molecules16010694
1
Receptor tyrosine kinase inhibitors block proliferation of TGEV mainly through p38 mitogen-activated protein kinase pathways
Abstract Emerging coronaviruses (CoVs) primarily cause severe gastroenteric or respiratory diseases in humans and animals, and no approved therapeutics are currently available. Here, A9, a receptor tyrosine kinase inhibitor (RTKI) of the tyrphostin class, is identified as a robust inhibitor of transmissible gastroenteritis virus (TGEV) infection in cell-based assays. Moreover, A9 exhibited potent antiviral activity against the replication of various CoVs, including murine hepatitis virus (MHV), porcine epidemic diarrhea virus (PEDV) and feline infectious peritonitis virus (FIPV). We further performed a comparative phosphoproteomic analysis to investigate the mechanism of action of A9 against TGEV infection in vitro. We specifically identified p38 and JNK1, which are the downstream molecules of receptor tyrosine kinases (RTKs) required for efficient TGEV replication, as A9 targets through plaque assays, qRT-PCR and Western blotting assays. p38 and JNK1 inhibitors and RNA interference further showed that the inhibitory activity of A9 against TGEV infection was mainly mediated by the p38 mitogen-activated protein kinase (MAPK) signaling pathway. All these findings indicated that the RTKI A9 directly inhibits TGEV replication and that its inhibitory activity against TGEV replication mainly occurs by targeting p38, which provides vital clues to the design of novel drugs against CoVs.
40bshqly
40bshqly
2020-01-31
10.1016/j.antiviral.2019.104651
2.5
Gene of the month: the 2019-nCoV/SARS-CoV-2 novel coronavirus spike protein.
The year 2020 has seen a major and sustained outbreak of a novel betacoronavirus (severe acute respiratory syndrome (SARS)-coronavirus (CoV)-2) infection that causes fever, severe respiratory illness and pneumonia, a disease called Covid-19. At the time of writing, the death toll was greater than 120 000 worldwide with more than 2 million documented infections. The genome of the CoV encodes a number of structural proteins that facilitate cellular entry and assembly of virions, of which the spike protein S appears to be critical for cellular entry. The spike protein guides the virus to attach to the host cell. The spike protein contains a receptor-binding domain (RBD), a fusion domain and a transmembrane domain. The RBD of spike protein S binds to Angiotensin Converting Enzyme 2 (ACE2) to initiate cellular entry. The spike protein of SARS-CoV-2 shows more than 90% amino acid similarity to the pangolin and bat CoVs and these also use ACE2 as a receptor. Binding of the spike protein to ACE2 exposes the cleavage sites to cellular proteases. Cleavage of the spike protein by transmembrane protease serine 2 and other cellular proteases initiates fusion and endocytosis. The spike protein contains an addition furin cleavage site that may allow it to be 'preactivated' and highly infectious after replication. The fundamental role of the spike protein in infectivity suggests that it is an important target for vaccine development, blocking therapy with antibodies and diagnostic antigen-based tests. This review briefly outlines the structure and function of the 2019 novel CoV/SARS-CoV-2 spike protein S.
40ejbv5j
40ejbv5j
2020-05-06
10.1136/jclinpath-2020-206658
3
Discovery of clinically approved drugs capable of inhibiting SARS-CoV-2 in vitro infection using a phenotypic screening strategy and network-analysis to predict their potential to treat covid-19
The disease caused by SARS-CoV2, covid-19, rapidly spreads worldwide, causing the greatest threat to global public health in the last 100 years. This scenario has become catastrophic as there are no approved vaccines to prevent the disease, and the main measures to contain the virus transmission are confinement and social distancing. One priority strategy is based on drug repurposing by pursuing antiviral chemotherapy that can control transmission and prevent complications associated with covid-19. With this aim, we performed a high content screening assay for the discovery of anti-SARS-CoV-2 compounds. From the 65 screened compounds, we have found four drugs capable to selectively inhibit SARS-CoV-2 in vitro infection: brequinar, abiraterone acetate, neomycin, and the extract of Hedera helix. Brequinar and abiraterone acetate had higher inhibition potency against SARS-CoV-2 than neomycin and Hedera helix extract, respectively. Drugs with reported antiviral activity and in clinical trials for covid-19, chloroquine, ivermectin, and nitazoxanide, were also included in the screening, and the last two were found to be non-selective. We used a data mining approach to build drug-host molecules-biological function-disease networks to show in a holistic way how each compound is interconnected with host node molecules and virus infection, replication, inflammatory response, and cell apoptosis. In summary, the present manuscript identified four drugs with active inhibition effect on SARS-CoV-2 in vitro infection, and by network analysis, we provided new insights and starting points for the clinical evaluation and repurposing process to treat SARS-CoV-2 infection. Summary sentence Discovery of drug repurposing candidates, inhibitors of SARS-CoV-2 infection in vitro, using a phenotypic screening strategy and network analysis.
40fz5r90
40fz5r90
2020-07-10
10.1101/2020.07.09.196337
5
Coronaviruses and the human airway: a universal system for virus-host interaction studies
Human coronaviruses (HCoVs) are large RNA viruses that infect the human respiratory tract. The emergence of both Severe Acute Respiratory Syndrome and Middle East Respiratory syndrome CoVs as well as the yearly circulation of four common CoVs highlights the importance of elucidating the different mechanisms employed by these viruses to evade the host immune response, determine their tropism and identify antiviral compounds. Various animal models have been established to investigate HCoV infection, including mice and non-human primates. To establish a link between the research conducted in animal models and humans, an organotypic human airway culture system, that recapitulates the human airway epithelium, has been developed. Currently, different cell culture systems are available to recapitulate the human airways, including the Air-Liquid Interface (ALI) human airway epithelium (HAE) model. Tracheobronchial HAE cultures recapitulate the primary entry point of human respiratory viruses while the alveolar model allows for elucidation of mechanisms involved in viral infection and pathogenesis in the alveoli. These organotypic human airway cultures represent a universal platform to study respiratory virus-host interaction by offering more detailed insights compared to cell lines. Additionally, the epidemic potential of this virus family highlights the need for both vaccines and antivirals. No commercial vaccine is available but various effective antivirals have been identified, some with potential for human treatment. These morphological airway cultures are also well suited for the identification of antivirals, evaluation of compound toxicity and viral inhibition.
40zyv1h8
40zyv1h8
2016-02-06
10.1186/s12985-016-0479-5
2
Remdesivir for Treatment of COVID-19: Combination of Pulmonary and IV Administration May Offer Aditional Benefit
Remdesivir is one of the most promising drugs to treat COVID-19 based on the following facts: remdesivir has a broad-spectrum antiviral mechanism of action; it demonstrated in vitro activity against SARS-CoV-2 and in vivo efficacy in animal models against the similar coronavirus MERS-CoV; its safety profile has been tested in Ebola patients and in compassionate use in COVID-19 patients. Currently, remdesivir is being investigated in ten randomized controlled trials against COVID-19. The dose regimen of remdesivir is an IV loading dose of 200 mg on day 1 followed by daily IV maintenance doses of 100 mg for 5–9 days. Based on our data analysis, however, remdesivir with IV administration alone is unlikely to achieve excellent clinical efficacy. This analysis is based on the following observations: plasma exposures of remdesivir and its active metabolite are unlikely to be correlated with its clinical efficacy; remdesivir and its active metabolites are unlikely to be adequate in the lung to kill the SARS-CoV-2 virus. Even if remdesivir demonstrates benefits in the current randomized controlled trials, its efficacy may be limited. We suggest that a combination of an IV and pulmonary delivery dose regimen should be studied immediately to realize a potentially more effective antiviral therapy against COVID-19. [Figure: see text]
4178ui2c
4178ui2c
2020-05-26
10.1208/s12248-020-00459-8
4.5
Chloroquine and hydroxychloroquine in the treatment of COVID-19 with or without diabetes: A systematic search and a narrative review with a special reference to India and other developing countries
Abstract Background and aims No drugs are currently approved for Coronavirus Disease-2019 (COVID-19), although some have been tried. In view of recent studies and discussion on chloroquine and hydroxychloroquine (HCQ), we aimed to review existing literature and relevant websites regarding these drugs and COVID-19, adverse effects related to drugs, and related guidelines. Aims and methods We systematically searched the PubMed database up till March 21, 2020 and retrieved all the articles published on chloroquine and HCQ and COVID-19. Results Two small human studies have been conducted with both these drugs in COVID-19, and have shown significant improvement in some parameters in patients with COVID-19. Conclusion Considering minimal risk upon use, a long experience of use in other diseases, cost-effectiveness and easy availability across India, we propose that both these drugs are worthy of fast track clinical trial for treatment, and may be carefully considered for clinical use as experimental drugs. Since HCQ has been approved for treatment of diabetes in India, it should be further researched in diabetes and COVID-19, a subgroup where significant mortality has been shown.
41jqgsv0
41jqgsv0
2020-06-30
10.1016/j.dsx.2020.03.011
1
Zoonotic Viruses Associated with Illegally Imported Wildlife Products
The global trade in wildlife has historically contributed to the emergence and spread of infectious diseases. The United States is the world's largest importer of wildlife and wildlife products, yet minimal pathogen surveillance has precluded assessment of the health risks posed by this practice. This report details the findings of a pilot project to establish surveillance methodology for zoonotic agents in confiscated wildlife products. Initial findings from samples collected at several international airports identified parts originating from nonhuman primate (NHP) and rodent species, including baboon, chimpanzee, mangabey, guenon, green monkey, cane rat and rat. Pathogen screening identified retroviruses (simian foamy virus) and/or herpesviruses (cytomegalovirus and lymphocryptovirus) in the NHP samples. These results are the first demonstration that illegal bushmeat importation into the United States could act as a conduit for pathogen spread, and suggest that implementation of disease surveillance of the wildlife trade will help facilitate prevention of disease emergence.
425rd7ul
425rd7ul
2012-01-10
10.1371/journal.pone.0029505
1.5
Cell entry of SARS-CoV-2 conferred by angiotensin-converting enzyme 2 (ACE2) of different species
The outbreak of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) poses a huge threat to many countries around the world. However, where is it origin and which animals are sensitive to cross-species transmission is unclear. The interaction of virus and cell receptor is a key determinant of host range for the novel coronavirus. Angiotensin-converting enzyme 2 (ACE2) is demonstrated as the primary entry receptor for SARS-CoV-2. In this study, we evaluated the SARS-CoV-2 entry mediated by ACE2 of 11 different species of animals, and discovered that ACE2 of Rhinolophus sinicus (Chinese horseshoe bat), Felis catus (domestic cat), Canis lupus familiaris (dog), Sus scrofa (pig), Capra hircus (goat) and especially Manis javanica (Malayan pangolin) were able to render SARS-CoV-2 entry in non-susceptible cells. This is the first report that ACE2 of Pangolin could mediate SARS-CoV-2 entry which increases the presume that SARS-CoV-2 may have a pangolin origin. However, none of the ACE2 proteins from Rhinolophus ferrumequinum (greater horseshoe bat), Gallus gallus (chicken), Notechis scutatus (mainland tiger snake), Mus musculus (house mouse) rendered SARS-CoV-2 entry. Specifically, a natural isoform of Macaca mulatta (Rhesus monkey) ACE2 with a mutation of Y217N was resistance to infection, which rises the possible impact of this type of ACE2 during monkey studies of SARS-CoV-2. Overall, these results clarify that SARS-CoV-2 could engage receptors of multiple species of animals and it is a perplexed work to track SARS-CoV-2 origin and its intermediate hosts. IMPORTANCE In this study, we illustrated that SARS-CoV-2 is able to engage receptors of multiple species of animals. This indicated that it may be a perplexed work to track SARS-CoV-2 origin and discover its intermediate hosts. This feature of virus is considered to potentiate its diverse cross-species transmissibility. Of note, here is the first report that ACE2 of Pangolin could mediate SARS-CoV-2 entry which increases the possibility that SARS-CoV-2 may have a pangolin origin. And we also demonstrated that not all species of bat were sensitive to SARS-CoV-2 infection. At last, it is also important to detect the expression ratio of the Y217N ACE2 to the prototype in Rhesus monkeys to be recruited for studies on SARS-CoV-2 infection.
42wv7zl6
42wv7zl6
2020-06-16
10.1101/2020.06.15.153916
5
Understanding novel COVID-19: its impact on organ failure and risk assessment for diabetic and cancer patients
Abstract The current pandemic outbreak of COVID-19 originated from Wuhan, China. It is caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) with significant mortality and morbidity rate. The severe risk factors are commonly detected in patients of older age and with medical comorbidities like cancer and diabetes. Scientists and doctors have scrambled to gain knowledge about the novel virus and its pathophysiology in order to discover possible therapeutic regimens and vaccines for COVID-19. The therapeutic strategies like targeting the viral genome emphasize the promising approach to target COVID-19. Additionally, blocking the receptor, ACE2 via the neutralizing antibodies for viral escape that prevents it from entering into the cells provides another therapeutic regimen. In this review article, we have presented the effect of SARS-CoV-2 infection in comorbid patients and discussed organ failure caused by this virus. Based on the data available from the scientific literature and ongoing clinical trials, we have focused on therapeutic strategies. We hope that we would fill the gaps that puzzled the researchers and clinicians with the best of our knowledge collected for the betterment of the patients for the coming future.
431buxxr
431buxxr
2020-05-06
10.1016/j.cytogfr.2020.05.001
3.5
Potential inhibitors of coronavirus 3-chymotrypsin-like protease (3CLpro): an in silico screening of alkaloids and terpenoids from African medicinal plants
The novel coronavirus disease 2019 (COVID-19) caused by SARS-COV-2 has raised myriad of global concerns. There is currently no FDA approved antiviral strategy to alleviate the disease burden. The conserved 3-chymotrypsin-like protease (3CLpro), which controls coronavirus replication is a promising drug target for combating the coronavirus infection. This study screens some African plants derived alkaloids and terpenoids as potential inhibitors of coronavirus 3CLpro using in silico approach. Bioactive alkaloids (62) and terpenoids (100) of plants native to Africa were docked to the 3CLpro of the novel SARS-CoV-2. The top twenty alkaloids and terpenoids with high binding affinities to the SARS-CoV-2 3CLpro were further docked to the 3CLpro of SARS-CoV and MERS-CoV. The docking scores were compared with 3CLpro-referenced inhibitors (Lopinavir and Ritonavir). The top docked compounds were further subjected to ADEM/Tox and Lipinski filtering analyses for drug-likeness prediction analysis. This ligand-protein interaction study revealed that more than half of the top twenty alkaloids and terpenoids interacted favourably with the coronaviruses 3CLpro, and had binding affinities that surpassed that of lopinavir and ritonavir. Also, a highly defined hit-list of seven compounds (10-Hydroxyusambarensine, Cryptoquindoline, 6-Oxoisoiguesterin, 22-Hydroxyhopan-3-one, Cryptospirolepine, Isoiguesterin and 20-Epibryonolic acid) were identified. Furthermore, four non-toxic, druggable plant derived alkaloids (10-Hydroxyusambarensine, and Cryptoquindoline) and terpenoids (6-Oxoisoiguesterin and 22-Hydroxyhopan-3-one), that bind to the receptor-binding site and catalytic dyad of SARS-CoV-2 3CLpro were identified from the predictive ADME/tox and Lipinski filter analysis. However, further experimental analyses are required for developing these possible leads into natural anti-COVID-19 therapeutic agents for combating the pandemic.Communicated by Ramaswamy H. Sarma.
44mz0jbd
44mz0jbd
2020
5
Discovery of the FDA-approved drugs bexarotene, cetilistat, diiodohydroxyquinoline, and abiraterone as potential COVID-19 treatments with a robust two-tier screening system
Coronavirus Disease 2019 (COVID-19) caused by the emerging severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is associated with a crude case fatality rate of about 0.5-10 % depending on locality. A few clinically approved drugs, such as remdesivir, chloroquine, hydroxychloroquine, nafamostat, camostat, and ivermectin, exhibited anti-SARS-CoV-2 activity in vitro and/or in a small number of patients. However, their clinical use may be limited by anti-SARS-CoV-2 50 % maximal effective concentrations (EC50) that exceeded their achievable peak serum concentrations (Cmax), side effects, and/or availability. To find more immediately available COVID-19 antivirals, we established a two-tier drug screening system that combines SARS-CoV-2 enzyme-linked immunosorbent assay and cell viability assay, and applied it to screen a library consisting 1528 FDA-approved drugs. Cetilistat (anti-pancreatic lipase), diiodohydroxyquinoline (anti-parasitic), abiraterone acetate (synthetic androstane steroid), and bexarotene (antineoplastic retinoid) exhibited potent in vitro anti-SARS-CoV-2 activity (EC50 1.13-2.01 µM). Bexarotene demonstrated the highest Cmax:EC50 ratio (1.69) which was higher than those of chloroquine, hydroxychloroquine, and ivermectin. These results demonstrated the efficacy of the two-tier screening system and identified potential COVID-19 treatments which can achieve effective levels if given by inhalation or systemically depending on their pharmacokinetics.
458smf3g
458smf3g
2020
4.5
Automatic X-ray COVID-19 Lung Image Classification System based on Multi-Level Thresholding and Support Vector Machine
Abstract- The early detection of SARS-CoV-2, the causative agent of (COVID-19) is now a critical task for the clinical practitioners. The COVID-19 spread is announced as pandemic outbreak between people worldwide by WHO since 11/ March/ 2020. In this consequence, it is top critical priority to become aware of the infected people so that prevention procedures can be processed to minimize the COVID-19 spread and to begin early medical health care of those infected persons. In this paper, the deep studying based totally methodology is usually recommended for the detection of COVID-19 infected patients using X-ray images. The help vector gadget classifies the corona affected X-ray images from others through usage of the deep features. The technique is useful for the clinical practitioners for early detection of COVID-19 infected patients. The suggested system of multi-level thresholding plus SVM presented high accuracy in classification of the infected lung with Covid-19. All images were of the same size and stored in JPEG format with 512 * 512 pixels. The average sensitivity, specificity, and accuracy of the lung classification using the proposed model results were 95.76%, 99.7%, and 97.48%, respectively.
45dpoepu
45dpoepu
2020-04-06
10.1101/2020.03.30.20047787
1
The spike protein of SARS-CoV — a target for vaccine and therapeutic development
Severe acute respiratory syndrome (SARS) is a newly emerging infectious disease caused by a novel coronavirus, SARS-coronavirus (SARS-CoV). The SARS-CoV spike (S) protein is composed of two subunits; the S1 subunit contains a receptor-binding domain that engages with the host cell receptor angiotensin-converting enzyme 2 and the S2 subunit mediates fusion between the viral and host cell membranes. The S protein plays key parts in the induction of neutralizing-antibody and T-cell responses, as well as protective immunity, during infection with SARS-CoV. In this Review, we highlight recent advances in the development of vaccines and therapeutics based on the S protein.
48ay8yl3
48ay8yl3
2009-02-09
10.1038/nrmicro2090
3.5
A Strategy to Treat COVID-19 Disease with Targeted Delivery of Inhalable Liposomal Hydroxychloroquine: A Non-clinical Pharmacokinetic Study
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a newly identified pathogen causing coronavirus disease 2019 (COVID-19) pandemic. Hydroxychloroquine (HCQ), an antimalarial and anti-inflammatory drug, has been shown to inhibit SARS-CoV-2 infection in vitro and tested in clinical studies. However, lung concentration (6.7 µg/mL) to predict the in vivo antiviral efficacy might not be achievable with the currently proposed oral dosing regimen. Further, a high cumulative doses of HCQ may raise concerns of systemic toxicity, including cardiotoxicity. Here, we described a non-clinical study to investigate the pharmacokinetics of a novel formulation of liposomal HCQ administrated by intratracheal (IT) instillation in Sprague-Dawley (SD) rats which achieved 129.4 µg/g (Cmax) in the lung. Compared to unformulated HCQ administered intravenous (IV), liposomal HCQ with normalized dose showed higher (∼30-fold) lung exposure, longer (∼2.5-fold) half-life in lung, but lower blood exposure with ∼20% of Cmax and 74% of AUC and lower heart exposure with 24% of Cmax and 58% of AUC. In conclusion, the pharmacokinetics results in an animal model demonstrate the proof of concept that inhalable liposomal HCQ may provide clinical benefit and serve as a potential treatment for COVID-19.
4al9fv9g
4al9fv9g
2020-07-10
10.1101/2020.07.09.196618
5
DECISION MAKING, DETECTION, PREVENTION AND CONTROL
4ba4h18s
4ba4h18s
2012-12-02
10.1016/b978-0-12-095785-9.50043-3
1.5
The challenging pathway towards the identification of SARS-CoV-2/COVID-19 therapeutics
The development of therapeutic agents against SARS-CoV-2/COVID-19 faces numerous barriers and a multidisciplinary approach to evaluating drug efficacy and toxicity is essential. Experimental and preclinical data should be integrated into a comprehensive analysis, where drug potency, the timing of therapy initiation, drug combinations, variability in systemic and local drug exposure and short- and long-term toxicities represent fundamental factors for the rational identification of candidates and prioritization of clinical investigations. Although the identification of SARS-CoV-2 therapeutics is a priority, rigorous and transparent methodologies are crucial to ensure that accelerated research programmes result in high-quality and reproducible findings.
4c0t3w29
4c0t3w29
2020-06-26
10.1093/jac/dkaa272
5
Preliminary Estimates of the Prevalence of Selected Underlying Health Conditions Among Patients with Coronavirus Disease 2019 — United States, February 12–March 28, 2020
On March 11, 2020, the World Health Organization declared Coronavirus Disease 2019 (COVID-19) a pandemic (1). As of March 28, 2020, a total of 571,678 confirmed COVID-19 cases and 26,494 deaths have been reported worldwide (2). Reports from China and Italy suggest that risk factors for severe disease include older age and the presence of at least one of several underlying health conditions (3,4). U.S. older adults, including those aged ≥65 years and particularly those aged ≥85 years, also appear to be at higher risk for severe COVID-19-associated outcomes; however, data describing underlying health conditions among U.S. COVID-19 patients have not yet been reported (5). As of March 28, 2020, U.S. states and territories have reported 122,653 U.S. COVID-19 cases to CDC, including 7,162 (5.8%) for whom data on underlying health conditions and other known risk factors for severe outcomes from respiratory infections were reported. Among these 7,162 cases, 2,692 (37.6%) patients had one or more underlying health condition or risk factor, and 4,470 (62.4%) had none of these conditions reported. The percentage of COVID-19 patients with at least one underlying health condition or risk factor was higher among those requiring intensive care unit (ICU) admission (358 of 457, 78%) and those requiring hospitalization without ICU admission (732 of 1,037, 71%) than that among those who were not hospitalized (1,388 of 5,143, 27%). The most commonly reported conditions were diabetes mellitus, chronic lung disease, and cardiovascular disease. These preliminary findings suggest that in the United States, persons with underlying health conditions or other recognized risk factors for severe outcomes from respiratory infections appear to be at a higher risk for severe disease from COVID-19 than are persons without these conditions.
4cy3er3y
4cy3er3y
2020-04-03
10.15585/mmwr.mm6913e2
3
Computational Drug Repositioning and Elucidation of Mechanism of Action of Compounds against SARS-CoV-2
The COVID-19 crisis called for rapid reaction from all the fields of biomedical research. Traditional drug development involves time consuming pipelines that conflict with the urgence of identifying effective therapies during a health and economic emergency. Drug repositioning, that is the discovery of new clinical applications for drugs already approved for different therapeutic contexts, could provide an effective shortcut to bring COVID-19 treatments to the bedside in a timely manner. Moreover, computational approaches can help accelerate the process even further. Here we present the application of computational drug repositioning tools based on transcriptomics data to identify drugs that are potentially able to counteract SARS-CoV-2 infection, and also to provide insights on their mode of action. We believe that mucolytics and HDAC inhibitors warrant further investigation. In addition, we found that the DNA Mismatch repair pathway is strongly modulated by drugs with experimental in vitro activity against SARS-CoV-2 infection. Both full results and methods are publicly available.
4fntk91q
4fntk91q
2020-04-16
2
Determination and application of immunodominant regions of SARS coronavirus spike and nucleocapsid proteins recognized by sera from different animal species
Abstract Knowledge of immunodominant regions in major viral antigens is important for rational design of effective vaccines and diagnostic tests. Although there have been many reports of such work done for SARS–CoV, these were mainly focused on the immune responses of humans and mice. In this study, we aim to search for and compare immunodominant regions of the spike (S) and nucleocapsid (N) proteins which are recognized by sera from different animal species, including mouse, rat, rabbit, civet, pig and horse. Twelve overlapping recombinant protein fragments were produced in Escherichia coli, six each for the S and N proteins, which covered the entire coding region of the two proteins. Using a membrane-strip based Western blot approach, the reactivity of each antigen fragment against a panel of animal sera was determined. Immunodominant regions containing linear epitopes, which reacted with sera from all the species tested, were identified for both proteins. The S3 fragment (aa 402–622) and the N4 fragment (aa 220–336) were the most immunodominant among the six S and N fragments, respectively. Antibodies raised against the S3 fragment were able to block the binding of a panel of S-specific monoclonal antibodies (mAb) to SARS–CoV in ELISA, further demonstrating the immunodominance of this region. Based on these findings, one-step competition ELISAs were established which were able to detect SARS–CoV antibodies from human and at least seven different animal species. Considering that a large number of animal species are known to be susceptible to SARS–CoV, these assays will be a useful tool to trace the origin and transmission of SARS–CoV and to minimise the risk of animal-to-human transmission.
4hqhty5o
4hqhty5o
2008-02-29
10.1016/j.jim.2007.11.009
4.5
Strong evolutionary convergence of receptor-binding protein spike between COVID-19 and SARS-related coronaviruses
Coronavirus Disease 2019 (COVID-19) and severe acute respiratory syndrome (SARS)-related coronaviruses (e.g., 2019-nCoV and SARS-CoV) are phylogenetically distantly related, but both are capable of infecting human hosts via the same receptor, angiotensin-converting enzyme 2, and cause similar clinical and pathological features, suggesting their phenotypic convergence. Yet, the molecular basis that underlies their phenotypic convergence remains unknown. Here, we used a recently developed molecular phyloecological approach to examine the molecular basis leading to their phenotypic convergence. Our genome-level analyses show that the spike protein, which is responsible for receptor binding, has undergone significant Darwinian selection along the branches related to 2019-nCoV and SARS-CoV. Further examination shows an unusually high proportion of evolutionary convergent amino acid sites in the receptor binding domain (RBD) of the spike protein between COVID-19 and SARS-related CoV clades, leading to the phylogenetic uniting of their RBD protein sequences. In addition to the spike protein, we also find the evolutionary convergence of its partner protein, ORF3a, suggesting their possible co-evolutionary convergence. Our results demonstrate a strong adaptive evolutionary convergence between COVID-19 and SARS-related CoV, possibly facilitating their adaptation to similar or identical receptors. Finally, it should be noted that many observed bat SARS-like CoVs that have an evolutionary convergent RBD sequence with 2019-nCoV and SARS-CoV may be pre-adapted to human host receptor ACE2, and hence would be potential new coronavirus sources to infect humans in the future.
4ihv80au
4ihv80au
2020-03-04
10.1101/2020.03.04.975995
1
Coronaviruses — drug discovery and therapeutic options
In humans, infections with the human coronavirus (HCoV) strains HCoV-229E, HCoV-OC43, HCoV-NL63 and HCoV-HKU1 usually result in mild, self-limiting upper respiratory tract infections, such as the common cold. By contrast, the CoVs responsible for severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS), which were discovered in Hong Kong, China, in 2003, and in Saudi Arabia in 2012, respectively, have received global attention over the past 12 years owing to their ability to cause community and health-care-associated outbreaks of severe infections in human populations. These two viruses pose major challenges to clinical management because there are no specific antiviral drugs available. In this Review, we summarize the epidemiology, virology, clinical features and current treatment strategies of SARS and MERS, and discuss the discovery and development of new virus-based and host-based therapeutic options for CoV infections. SUPPLEMENTARY INFORMATION: The online version of this article (doi:10.1038/nrd.2015.37) contains supplementary material, which is available to authorized users.
4j8b8z4t
4j8b8z4t
2016-02-12
10.1038/nrd.2015.37
1
Several FDA-approved drugs effectively inhibit SARS-CoV-2 infection in vitro
To identify drugs that are potentially used for the treatment of COVID-19, the potency of 1403 FDA-approved drugs were evaluated using a robust pseudovirus assay and the candidates were further confirmed by authentic SARS-CoV-2 assay. Four compounds, Clomiphene (citrate), Vortioxetine, Vortioxetine (hydrobromide) and Asenapine (hydrochloride), showed potent inhibitory effects in both pseudovirus and authentic virus assay. The combination of Clomiphene (citrate), Vortioxetine and Asenapine (hydrochloride) is much more potent than used alone, with IC50 of 0.34 μM.
4k7qymqd
4k7qymqd
2020-06-05
10.1101/2020.06.05.135996
4.5
Serological and molecular findings during SARS-CoV-2 infection: the first case study in Finland, January to February 2020
The first case of coronavirus disease (COVID-19) in Finland was confirmed on 29 January 2020. No secondary cases were detected. We describe the clinical picture and laboratory findings 3–23 days since the first symptoms. The SARS-CoV-2/Finland/1/2020 virus strain was isolated, the genome showing a single nucleotide substitution to the reference strain from Wuhan. Neutralising antibody response appeared within 9 days along with specific IgM and IgG response, targeting particularly nucleocapsid and spike proteins.
4mj7n0ax
4mj7n0ax
2020-03-19
10.2807/1560-7917.es.2020.25.11.2000266
1.5
Structural variations in human ACE2 may influence its binding with SARS-CoV-2 spike protein
The recent pandemic of COVID-19, caused by SARS-CoV-2, is unarguably the most fearsome compared with the earlier outbreaks caused by other coronaviruses, SARS-CoV and MERS-CoV. Human ACE2 is now established as a receptor for the SARS-CoV-2 spike protein. Where variations in the viral spike protein, in turn, lead to the cross-species transmission of the virus, genetic variations in the host receptor ACE2 may also contribute to the susceptibility and/or resistance against the viral infection. This study aims to explore the binding of the proteins encoded by different human ACE2 allelic variants with SARS-CoV-2 spike protein. Briefly, coding variants of ACE2 corresponding to the reported binding sites for its attachment with coronavirus spike protein were selected and molecular models of these variants were constructed by homology modeling. The models were then superimposed over the native ACE2 and ACE2-spike protein complex, to observe structural changes in the ACE2 variants and their intermolecular interactions with SARS-CoV-2 spike protein, respectively. Despite strong overall structural similarities, the spatial orientation of the key interacting residues varies in the ACE2 variants compared with the wild-type molecule. Most ACE2 variants showed a similar binding affinity for SARS-CoV-2 spike protein as observed in the complex structure of wild-type ACE2 and SARS-CoV-2 spike protein. However, ACE2 alleles, rs73635825 (S19P) and rs143936283 (E329G) showed noticeable variations in their intermolecular interactions with the viral spike protein. In summary, our data provide a structural basis of potential resistance against SARS-CoV-2 infection driven by ACE2 allelic variants.
4nfxdppt
4nfxdppt
2020
3
Angiotensin‐converting enzyme‐2 (ACE2), SARS‐CoV‐2 and pathophysiology of coronavirus disease 2019 (COVID‐19)
Angiotensin‐converting enzyme‐2 (ACE2) has been established as the functional host receptor for severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2), the virus responsible for the current devastating worldwide pandemic of coronavirus disease 2019 (COVID‐19). ACE2 is abundantly expressed in a variety of cells residing in many different human organs. In human physiology, ACE2 is a pivotal counter‐regulatory enzyme to ACE by the breakdown of angiotensin II, the central player in the renin‐angiotensin‐aldosterone system (RAAS) and the main substrate of ACE2. Many factors have been associated with both altered ACE2 expression and COVID‐19 severity and progression, including age, sex, ethnicity, medication and several co‐morbidities, such as cardiovascular disease and metabolic syndrome. Although ACE2 is widely distributed in various human tissues and many of its determinants have been well recognised, ACE2‐expressing organs do not equally participate in COVID‐19 pathophysiology, implying that other mechanisms are involved in orchestrating cellular infection resulting in tissue damage. Reports of pathologic findings in tissue specimens of COVID‐19 patients are rapidly emerging and confirm the established role of ACE2 expression and activity in disease pathogenesis. Identifying pathologic changes caused by SARS‐CoV‐2 infection is crucially important as it has major implications for understanding COVID‐19 pathophysiology and the development of evidence‐based treatment strategies. Currently, many interventional strategies are being explored in ongoing clinical trials, encompassing many drug classes and strategies, including antiviral drugs, biological response modifiers and RAAS inhibitors. Ultimately, prevention is key to combat COVID‐19 and appropriate measures are being taken accordingly, including development of effective vaccines. In this review, we describe the role of ACE2 in COVID‐19 pathophysiology, including factors influencing ACE2 expression and activity in relation to COVID‐19 severity. In addition, we discuss the relevant pathological changes resulting from SARS‐CoV‐2 infection. Finally, we highlight a selection of potential treatment modalities for COVID‐19. This article is protected by copyright. All rights reserved.
4oa9hfb4
4oa9hfb4
2020-05-17
10.1002/path.5471
4.5
Systematic review of the efficacy and safety of antiretroviral drugs against SARS, MERS or COVID‐19: initial assessment
INTRODUCTION: Several antiretroviral drugs are being considered for the treatment of COVID‐19, the disease caused by a newly identified coronavirus, (SARS‐CoV‐2). We systematically reviewed the clinical outcomes of using antiretroviral drugs for the prevention and treatment of coronaviruses and planned clinical trials. METHODS: Three databases were screened from inception to 30 March 2020 for studies reporting clinical outcomes of patients with SARS, MERS or COVID‐19 treated with antiretrovirals. RESULTS: From an initial screen of 433 titles, two randomized trials and 24 observational studies provided clinical outcome data on the use of antiretroviral drugs; most studies reported outcomes using LPV/r as treatment. Of the 21 observational studies reporting treatment outcomes, there were three studies among patients with SARS, six studies among patients with MERS and 12 studies among patients with COVID‐19. In one randomized trial 99 patients with severe COVID‐19 illness were randomized to receive LPV/r (400/100 mg twice a day) and 100 patients to standard of care for 14 days: LPV/r was not associated with a statistically significant difference in time to clinical improvement, although LPV/r given within 12 days of symptoms was associated with shorter time to clinical improvement; 28 day mortality was numerically lower in the LPV/r group (14/99) compared to the control group (25/100), but this difference was not statistically significant. The second trial found no benefit. The certainty of the evidence for the randomized trials was low. In the observational studies 3 out of 361 patients who received LPV/r died; the certainty of evidence was very low. Three studies reported a possible protective effect of LPV/r as post‐exposure prophylaxis. Again, the certainty of the evidence was very low due to uncertainty due to limited sample size. CONCLUSIONS: On the basis of the available evidence it is uncertain whether LPV/r and other antiretrovirals improve clinical outcomes or prevent infection among patients at high risk of acquiring COVID‐19.
4obggisp
4obggisp
2020-04-15
10.1002/jia2.25489
2
Informational needs assessment of non‐Hodgkin lymphoma survivors and their physicians
4owe9lf5
4owe9lf5
2010-03-29
10.1002/ajh.21725
4.5
Renin-angiotensin system: The unexpected flaw inside the human immune system revealed by SARS-CoV-2
4ozwhcyi
4ozwhcyi
2020-03-21
10.1016/j.mehy.2020.109686
1
Comparative analysis of antiviral efficacy of FDA-approved drugs against SARS-CoV-2 in human lung cells: Nafamostat is the most potent antiviral drug candidate
Drug repositioning represents an effective way to control the current COVID-19 pandemic. Previously, we identified 24 FDA-approved drugs which exhibited substantial antiviral effect against SARS-CoV-2 in Vero cells. Since antiviral efficacy could be altered in different cell lines, we developed an antiviral screening assay with human lung cells, which is more appropriate than Vero cell. Comparative analysis of antiviral activities revealed that nafamostat is the most potent drug in human lung cells (IC50 = 0.0022µM).
4pywvaxi
4pywvaxi
2020-05-12
10.1101/2020.05.12.090035
3
National Institute for the Infectious Diseases “L. Spallanzani”, IRCCS. Recommendations for COVID-19 clinical management
On January 9 2020, the World Health Organization (WHO) declared the identification, by Chinese Health authorities, of a novel coronavirus, further classified as SARS-CoV-2 responsible of a disease (COVID-19) ranging from asymptomatic cases to severe respiratory involvement. On March 9 2020, WHO declared COVID-19 a global pandemic. Italy is the second most affected country by COVID-19 infection after China. The “L. Spallanzani” National Institute for the Infectious Diseases, IRCCS, Rome, Italy, has been the first Italian hospital to admit and manage patients affected by COVID-19. Hereby, we show our recommendations for the management of COVID-19 patients, based on very limited clinical evidences; they should be considered as expert opinions, which may be modified according to newly produced literature data.
4r0t3q7j
4r0t3q7j
2020-03-16
10.4081/idr.2020.8543
1
Baculovirus surface display of SARS coronavirus (SARS-CoV) spike protein and immunogenicity of the displayed protein in mice models.
The baculovirus surface display technique has provided an ideal tool to display foreign proteins with natural conformation, functions, and immunogenicity. In this work, we explored the application of this technique on SARS-associated coronavirus (SARS-CoV) spike (S) protein, and further analyzed the immunogenicity of displayed S protein. The entire ectodomain of S protein was fused between the gp64 signal peptide and the VSV-G membrane anchor and successfully displayed on the baculovirus surface. Subcutaneous injection with purified S-displayed baculoviruses without adjuvant elicited highly effective production of specific and neutralizing antibodies against S protein in mice. These results confirmed a successful surface display of S protein on baculoviruse, and suggested a potential role of S-displayed baculoviruses as a novel live virus-based vaccine candidate for SARS-CoV.
4r6vh006
4r6vh006
2006
3
Identification of natural compounds with antiviral activities against SARS-associated coronavirus
Abstract More than 200 Chinese medicinal herb extracts were screened for antiviral activities against Severe Acute Respiratory Syndrome-associated coronavirus (SARS-CoV) using 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium inner salt (MTS) assay for virus-induced cytopathic effect (CPE). Four of these extracts showed moderate to potent antiviral activities against SARS-CoV with 50% effective concentration (EC50) ranging from 2.4±0.2 to 88.2±7.7μg/ml. Out of the four, Lycoris radiata was most potent. To identify the active component, L. radiata extract was subjected to further fractionation, purification, and CPE/MTS assays. This process led to the identification of a single substance lycorine as an anti-SARS-CoV component with an EC50 value of 15.7±1.2nM. This compound has a CC50 value of 14980.0±912.0nM in cytotoxicity assay and a selective index (SI) greater than 900. The results suggested that four herbal extracts and the compound lycorine are candidates for the development of new anti-SARS-CoV drugs in the treatment of SARS.
4s57ls6y
4s57ls6y
2005-07-31
10.1016/j.antiviral.2005.02.007
0.5
Comparison of SARS-CoV-2 spike protein binding to ACE2 receptors from human, pets, farm animals, and putative intermediate hosts.
The emergence of a novel coronavirus, SARS-CoV-2, resulted in a pandemic. Here, we used X-ray structures of human ACE2 bound to the receptor-binding domain (RBD) of the spike protein (S) from SARS-CoV-2 to predict its binding to ACE2 proteins from different animals, including pets, farm animals, and putative intermediate hosts of SARS-CoV-2. Comparing the interaction sites of ACE2 proteins known to serve or not serve as receptor allows to define residues important for binding. From the 20 amino acids in ACE2 that contact S up to seven can be replaced and ACE2 can still function as the SARS-CoV-2 receptor. These variable amino acids are clustered at certain positions, mostly at the periphery of the binding site, while changes of the invariable residues prevent S-binding or infection of the respective animal. Some ACE2 proteins even tolerate the loss or the acquisition of N-glycosylation sites located near the S-interface. Of note, Pigs and dogs, which are not or not effectively infected and have only a few changes in the binding site, exhibit relatively low levels of ACE2 in the respiratory tract. Comparison of the RBD of S of SARS-CoV-2 with viruses from Bat-CoV-RaTG13 and Pangolin-CoV revealed that the latter contains only one substitution, whereas the Bat-CoV-RaTG13 exhibits five. However, ACE2 of pangolin exhibit seven changes relative to human ACE2, a similar number of substitutions is present in ACE2 of bats, raccoon, and civet suggesting that SARS-CoV-2 may not especially adapted to ACE2 of any of its putative intermediate hosts. These analyses provide new insight into the receptor usage and animal source/origin of SARS-CoV-2.IMPORTANCE SARS-CoV-2 is threatening people worldwide and there are no drugs or vaccines available to mitigate its spread. The origin of the virus is still unclear and whether pets and livestock can be infected and transmit SARS-CoV-2 are important and unknown scientific questions. Effective binding to the host receptor ACE2 is the first prerequisite for infection of cells and determines the host range. Our analysis provides a framework for the prediction of potential hosts of SARS-CoV-2. We found that ACE2 from species known to support SARS-CoV-2 infection tolerate many amino acid changes indicating that the species barrier might be low. An exception are dogs and especially pigs, which, however, revealed relatively low ACE2 expression levels in the respiratory tract. Monitoring of animals is necessary to prevent the generation of a new coronavirus reservoir. Finally, our analysis also showed that SARS-CoV-2 may not be specifically adapted to any of its putative intermediate hosts.
4sfgha4z
4sfgha4z
2020-05-13
10.1128/jvi.00831-20
3.5
Cathepsin L-selective inhibitors: A potentially promising treatment for COVID-19 patients
The widespread coronavirus SARS-CoV-2 has already infected over 4 million people worldwide, with a death toll over 280,000. Current treatment of COVID-19 patients relies mainly on antiviral drugs lopinavir/ritonavir, arbidol, and remdesivir, the anti-malarial drugs hydroxychloroquine and chloroquine, and traditional Chinese medicine. There are over 2118 on-going clinical trials underway, but to date none of these drugs have consistently proven effective. Cathepsin L (CatL) is an endosomal cysteine protease. It mediates the cleavage of the S1 subunit of the coronavirus surface spike glycoprotein. This cleavage is necessary for coronavirus entry into human host cells, virus and host cell endosome membrane fusion, and viral RNA release for next round of replication. Here we summarize data regarding seven CatL-selective inhibitors that block coronavirus entry into cultured host cells and provide a mechanism to block SARS-CoV-2 infection in humans. Given the rapid growth of the SARS-CoV-2-positive population worldwide, ready-to-use CatL inhibitors should be explored as a treatment option. We identify ten US FDA-approved drugs that have CatL inhibitory activity. We provide evidence that supports the combined use of serine protease and CatL inhibitors as a possibly safer and more effective therapy than other available therapeutics to block coronavirus host cell entry and intracellular replication, without compromising the immune system.
4sgs60e6
4sgs60e6
2020
4.5
The discovery of potential natural products for targeting SARS-CoV-2 spike protein by virtual screening
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) enters into the cells through its spike proteins binding to human angiotensin-converting enzyme 2 (ACE2) protein and causes virus infection in host cells. Until now, there are no available antiviral drugs have been reported that can effectively block virus infection. The study aimed to discover the potential compounds to prevent viral spike proteins to bind to the human ACE2 proteins from Taiwan Database of Extracts and Compounds (TDEC) by structure-based virtual screening. In this study, to rapidly discover potential inhibitors against SARS-CoV-2 spike proteins, the molecular docking calculation was performed by AutoDock Vina program. Herein, we found that 39 potential compounds may have good binding affinities and can respectively bind to the viral receptor-binding domain (RBD) of spike protein in the prefusion conformation and spike-ACE2 complex protein in silico. Among those compounds, especially natural products thioflexibilolide A and candidine that were respectively isolated from the soft corals Sinularia flexibilis and Phaius mishmensis may have better binding affinity than others. This study provided the predictions that these compounds may have the potential to prevent SARS-CoV-2 spike protein from entry into cells.
4skamxby
4skamxby
2020-06-25
10.1101/2020.06.25.170639
5
Mice with humanized-lungs and immune system - an idealized model for COVID-19 and other respiratory illness
Lack of an appropriate animal model to study severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the etiological agent responsible for COVID-19 pandemic disease, represents a significant hurdle in the process of understanding disease biology and evaluating therapeutic and preventive candidates. It is time for public health agencies to revisit regulation on transplantation of human pluripotent stem cells for the possibility of the development of a humanized mice model with a humanized lung.
4tclonmi
4tclonmi
2020-05-20
10.1080/21505594.2020.1763637
5
The RNA Virus Database
http://virus.zoo.ox.ac.uk/rnavirusdb; http://hivweb.sanbi.ac.za/rnavirusdb; http://bioinf.cs.auckland.ac.nz/rnavirusdb; http://tree.bio.ed.ac.uk/rnavirusdb.
4txctk7k
4txctk7k
2008-10-23
10.1093/nar/gkn729
1.5
Vaccinia virus F16 protein, a predicted catalytically inactive member of the prokaryotic serine recombinase superfamily, is targeted to nucleoli
Abstract The F16L gene of vaccinia virus (VACV) is conserved in all chordopoxviruses except avipoxviruses. The crocodile poxvirus F16 protein ortholog has highly significant similarity to prokaryotic serine recombinases and contains all amino acids that comprise the catalytic site. In contrast, F16 orthologs encoded by other poxviruses show only marginally significant similarity to serine recombinases, lack essential amino acids of the active site and are most likely inactive derivatives of serine recombinases. Nevertheless, the conservation of F16L in non-avian poxviruses suggested an important function. However, a VACV mutant with the F16L gene knocked out replicated normally in dividing and quiescent cells. The F16 protein was synthesized early after infection and detected in virus cores. When expressed in infected or uninfected cells, F16 accumulated in nucleoli depending on the level of expression and confluency of cells. Evidence was obtained that F16 forms multimers, which might regulate concentration-dependent intracellular localization.
4u5yt7b7
4u5yt7b7
2011-09-01
10.1016/j.virol.2011.06.017
2.5
Receptor Recognition by the Novel Coronavirus from Wuhan: an Analysis Based on Decade-Long Structural Studies of SARS Coronavirus
Recently, a novel coronavirus (2019-nCoV) has emerged from Wuhan, China, causing symptoms in humans similar to those caused by severe acute respiratory syndrome coronavirus (SARS-CoV). Since the SARS-CoV outbreak in 2002, extensive structural analyses have revealed key atomic-level interactions between the SARS-CoV spike protein receptor-binding domain (RBD) and its host receptor angiotensin-converting enzyme 2 (ACE2), which regulate both the cross-species and human-to-human transmissions of SARS-CoV. Here, we analyzed the potential receptor usage by 2019-nCoV, based on the rich knowledge about SARS-CoV and the newly released sequence of 2019-nCoV. First, the sequence of 2019-nCoV RBD, including its receptor-binding motif (RBM) that directly contacts ACE2, is similar to that of SARS-CoV, strongly suggesting that 2019-nCoV uses ACE2 as its receptor. Second, several critical residues in 2019-nCoV RBM (particularly Gln493) provide favorable interactions with human ACE2, consistent with 2019-nCoV's capacity for human cell infection. Third, several other critical residues in 2019-nCoV RBM (particularly Asn501) are compatible with, but not ideal for, binding human ACE2, suggesting that 2019-nCoV has acquired some capacity for human-to-human transmission. Last, while phylogenetic analysis indicates a bat origin of 2019-nCoV, 2019-nCoV also potentially recognizes ACE2 from a diversity of animal species (except mice and rats), implicating these animal species as possible intermediate hosts or animal models for 2019-nCoV infections. These analyses provide insights into the receptor usage, cell entry, host cell infectivity and animal origin of 2019-nCoV and may help epidemic surveillance and preventive measures against 2019-nCoV.IMPORTANCE The recent emergence of Wuhan coronavirus (2019-nCoV) puts the world on alert. 2019-nCoV is reminiscent of the SARS-CoV outbreak in 2002 to 2003. Our decade-long structural studies on the receptor recognition by SARS-CoV have identified key interactions between SARS-CoV spike protein and its host receptor angiotensin-converting enzyme 2 (ACE2), which regulate both the cross-species and human-to-human transmissions of SARS-CoV. One of the goals of SARS-CoV research was to build an atomic-level iterative framework of virus-receptor interactions to facilitate epidemic surveillance, predict species-specific receptor usage, and identify potential animal hosts and animal models of viruses. Based on the sequence of 2019-nCoV spike protein, we apply this predictive framework to provide novel insights into the receptor usage and likely host range of 2019-nCoV. This study provides a robust test of this reiterative framework, providing the basic, translational, and public health research communities with predictive insights that may help study and battle this novel 2019-nCoV.
4ulei2uh
4ulei2uh
2020
3.5
Replication of SARS-CoV-2 in human respiratory epithelium.
Currently, there are four seasonal coronaviruses associated with relatively mild respiratory tract disease in humans. However, there are also a plethora of animal coronaviruses, which have the potential to cross the species border. This regularly results in the emergence of new viruses in humans. In 2002 SARS-CoV emerged, to rapidly disappear in May 2003. In 2012 MERS-CoV was identified as a possible threat to humans, but its pandemic potential so far is minimal, as the human-to-human transmission is ineffective. The end of 2019 brought us information about the SARS-CoV-2 emergence, and the virus rapidly spread in 2020 causing an unprecedented pandemic.At present, the studies on the virus are carried out using a surrogate system based on the immortalized simian Vero E6 cell line. This model is convenient for diagnostics, but it has serious limitations and does not allow for the understanding of virus biology and evolution.Here we show that fully differentiated human airway epithelium cultures constitute an excellent model to study the infection with the novel human coronavirus SARS-CoV-2. We observed an efficient replication of the virus in the tissue, with the maximal replication at 2 days post-infection. The virus replicated in ciliated cells and was released apically.IMPORTANCE SARS-CoV-2 emerged by the end of 2019 to rapidly spread in 2020. At present, it is of utmost importance to understand the virus biology and to rapidly assess the potential of existing drugs and develop new active compounds. While some animal models for such studies are under development, most of the research is carried out in the Vero E6 cells. Here, we propose fully differentiated human airway epithelium cultures as a model for studies on the SARS-CoV-2.
4v42ezk8
4v42ezk8
2020-05-20
10.1128/jvi.00957-20
4
Blocking antibodies against SARS-CoV-2 RBD isolated from a phage display antibody library using a competitive biopanning strategy
The infection of the novel coronavirus SARS-CoV-2 have caused more than 150,000 deaths, but no vaccine or specific therapeutic antibody is currently available. SARS-CoV-2 relies on its spike protein, in particular the receptor binding domain (RBD), to bind human cell receptor angiotensin-converting enzyme 2 (ACE2) for viral entry, and thus targeting RBD holds the promise for preventing SARS-CoV-2 infection. In this work, a competitive biopanning strategy of a phage display antibody library was applied to screen blocking antibodies against RBD. High-affinity antibodies were enriched after the first round using a standard panning process in which RBD-His recombinant protein was immobilized as a bait. At the next two rounds, immobilized ACE2-Fc and free RBD-His proteins were mixed with the enriched phage antibodies. Antibodies binding to RBD at epitopes different from ACE2-binding site were captured by the immobilized ACE2-Fc, forming a “sandwich” complex. Only antibodies competed with ACE2 for recognizing RBD at the same or similar epitopes can bind to the free RBD-His in the supernatant and be subsequently separated by the Ni-NTA magnetic beads. Top 1 lead from the competitive biopanning of a synthetic antibody library, Lib AB1, was produced as the full-length IgG1 format. It was proved to competitively block the binding of RBD to ACE2 protein, and potently inhibit SARS-CoV-2 pseudovirus infection of ACE2-overexpressing Hela cells with IC50 values of 12nM. Nevertheless, top 1 lead from the standard biopanning of Lib AB1, can only bind to RBD in vitro but not have the blocking or neutralization activity. Our strategy can efficiently isolate the blocking antibodies of RBD, and it would speed up the discovery of neutralizing antibodies against SARS-CoV-2.
4w6caxwu
4w6caxwu
2020-04-20
10.1101/2020.04.19.049643
3.5
Development and characterisation of neutralising monoclonal antibody to the SARS-coronavirus
Abstract There is a global need to elucidate protective antigens expressed by the SARS-coronavirus (SARS-CoV). Monoclonal antibody reagents that recognise specific antigens on SARS-CoV are needed urgently. In this report, the development and immunochemical characterisation of a panel of murine monoclonal antibodies (mAbs) against the SARS-CoV is presented, based upon their specificity, binding requirements, and biological activity. Initial screening by ELISA, using highly purified virus as the coating antigen, resulted in the selection of 103mAbs to the SARS virus. Subsequent screening steps reduced this panel to seventeen IgG mAbs. A single mAb, F26G15, is specific for the nucleoprotein as seen in Western immunoblot while five other mAbs react with the Spike protein. Two of these Spike-specific mAbs demonstrate the ability to neutralise SARS-CoV in vitro while another four Western immunoblot-negative mAbs also neutralise the virus. The utility of these mAbs for diagnostic development is demonstrated. Antibody from convalescent SARS patients, but not normal human serum, is also shown to specifically compete off binding of mAbs to whole SARS-CoV. These studies highlight the importance of using standardised assays and reagents. These mAbs will be useful for the development of diagnostic tests, studies of SARS-CoV pathogenesis and vaccine development.
4wn40ivq
4wn40ivq
2004-09-01
10.1016/j.jviromet.2004.04.009
2.5
Disulfiram can inhibit MERS and SARS coronavirus papain-like proteases via different modes
Abstract Severe acute respiratory syndrome coronavirus (SARS-CoV) emerged in southern China in late 2002 and caused a global outbreak with a fatality rate around 10% in 2003. Ten years later, a second highly pathogenic human CoV, MERS-CoV, emerged in the Middle East and has spread to other countries in Europe, North Africa, North America and Asia. As of November 2017, MERS-CoV had infected at least 2102 people with a fatality rate of about 35% globally, and hence there is an urgent need to identify antiviral drugs that are active against MERS-CoV. Here we show that a clinically available alcohol-aversive drug, disulfiram, can inhibit the papain-like proteases (PLpros) of MERS-CoV and SARS-CoV. Our findings suggest that disulfiram acts as an allosteric inhibitor of MERS-CoV PLpro but as a competitive (or mixed) inhibitor of SARS-CoV PLpro. The phenomenon of slow-binding inhibition and the irrecoverability of enzyme activity after removing unbound disulfiram indicate covalent inactivation of SARS-CoV PLpro by disulfiram, while synergistic inhibition of MERS-CoV PLpro by disulfiram and 6-thioguanine or mycophenolic acid implies the potential for combination treatments using these three clinically available drugs.
4yecwdlo
4yecwdlo
2018-02-28
10.1016/j.antiviral.2017.12.015
2
Network-based drug repurposing for novel coronavirus 2019-nCoV/SARS-CoV-2
Human coronaviruses (HCoVs), including severe acute respiratory syndrome coronavirus (SARS-CoV) and 2019 novel coronavirus (2019-nCoV, also known as SARS-CoV-2), lead global epidemics with high morbidity and mortality. However, there are currently no effective drugs targeting 2019-nCoV/SARS-CoV-2. Drug repurposing, representing as an effective drug discovery strategy from existing drugs, could shorten the time and reduce the cost compared to de novo drug discovery. In this study, we present an integrative, antiviral drug repurposing methodology implementing a systems pharmacology-based network medicine platform, quantifying the interplay between the HCoV–host interactome and drug targets in the human protein–protein interaction network. Phylogenetic analyses of 15 HCoV whole genomes reveal that 2019-nCoV/SARS-CoV-2 shares the highest nucleotide sequence identity with SARS-CoV (79.7%). Specifically, the envelope and nucleocapsid proteins of 2019-nCoV/SARS-CoV-2 are two evolutionarily conserved regions, having the sequence identities of 96% and 89.6%, respectively, compared to SARS-CoV. Using network proximity analyses of drug targets and HCoV–host interactions in the human interactome, we prioritize 16 potential anti-HCoV repurposable drugs (e.g., melatonin, mercaptopurine, and sirolimus) that are further validated by enrichment analyses of drug-gene signatures and HCoV-induced transcriptomics data in human cell lines. We further identify three potential drug combinations (e.g., sirolimus plus dactinomycin, mercaptopurine plus melatonin, and toremifene plus emodin) captured by the “Complementary Exposure” pattern: the targets of the drugs both hit the HCoV–host subnetwork, but target separate neighborhoods in the human interactome network. In summary, this study offers powerful network-based methodologies for rapid identification of candidate repurposable drugs and potential drug combinations targeting 2019-nCoV/SARS-CoV-2.
4yuw7jo3
4yuw7jo3
2020-03-16
10.1038/s41421-020-0153-3
1
Current status of potential therapeutic candidates for the COVID-19 crisis
Abstract As of April 15, 2020, the ongoing coronavirus disease 2019 (COVID-2019) pandemic has swept through 213 countries and infected more than 1,870,000 individuals, posing an unprecedented threat to international health and the economy. There is currently no specific treatment available for patients with COVID-19 infection. The lessons learned from past management of respiratory viral infections have provided insights into treating COVID-19. Numerous potential therapies, including supportive intervention, immunomodulatory agents, antiviral therapy, and convalescent plasma transfusion, have been tentatively applied in clinical settings. A number of these therapies have provided substantially curative benefits in treating patients with COVID-19 infection. Furthermore, intensive research and clinical trials are underway to assess the efficacy of existing drugs and identify potential therapeutic targets to develop new drugs for treating COVID-19. Herein, we summarize the current potential therapeutic approaches for diseases related to COVID-19 infection and introduce their mechanisms of action, safety, and effectiveness.
4zmqplz0
4zmqplz0
2020-04-22
10.1016/j.bbi.2020.04.046
2.5
SARS-CoV-2 in the ocular surface of COVID-19 patients
The 2019 novel coronavirus disease (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has spread globally, while the routes of transmission of this virus are still controversial. We enrolled 33 patients, without any ocular manifestation, with their ocular surface swabs collected for virus detection. RNA was detected strong positive in samples of both eyes from two patients. Therefore, SARS-CoV-2 may exist in the normal ocular surface of COVID-19 patients, suggesting that this virus might be spread through conjunctival contact.
50jgbtnr
50jgbtnr
2020-04-26
10.1186/s40662-020-00189-0
3
A Tool to Early Predict Severe 2019-Novel Coronavirus Pneumonia (COVID-19) : A Multicenter Study using the Risk Nomogram in Wuhan and Guangdong, China
Background Severe cases of coronavirus disease 2019 (COVID-19) rapidly develop acute respiratory distress leading to respiratory failure, with high short-term mortality rates. At present, there is no reliable risk stratification tool for non-severe COVID-19 patients at admission. We aimed to construct an effective model for early identifying cases at high risk of progression to severe COVID-19. Methods SARS-CoV-2 infected patients from one center in Wuhan city and two centers in Guangzhou city, China were included retrospectively. All patients with non-severe COVID-19 during hospitalization were followed for more than 15 days after admission. Patients who deteriorated to severe or critical COVID-19 and patients who kept non-severe state were assigned to the severe and non-severe group, respectively. We compared the demographic, clinical, and laboratory data between severe and non-severe group. Based on baseline data, least absolute shrinkage and selection operator (LASSO) algorithm and logistic regression model were used to construct a nomogram for risk prediction in the train cohort. The predictive accuracy and discriminative ability of nomogram were evaluated by area under the curve (AUC) and calibration curve. Decision curve analysis (DCA) and clinical impact curve analysis (CICA) were conducted to evaluate the clinical applicability of our nomogram. Findings The train cohort consisted of 189 patients, while the two independent validation cohorts consisted of 165 and 18 patients. Among all cases, 72 (19.35%) patients developed severe COVID-19 and 107 (28.76%) patients had one of the following basic disease, including hypertension, diabetes, coronary heart disease, chronic respiratory disease, tuberculosis disease. We found one demographic and six serological indicators (age, serum lactate dehydrogenase, C-reactive protein, the coefficient of variation of red blood cell distribution width (RDW), blood urea nitrogen, albumin, direct bilirubin) are associated with severe COVID-19. Based on these features, we generated the nomogram, which has remarkably high diagnostic accuracy in distinguishing individuals who exacerbated to severe COVID-19 from non-severe COVID-19 (AUC 0.912 [95% CI 0.846-0.978]) in the train cohort with a sensitivity of 85.71 % and specificity of 87.58% ; 0.853 [0.790-0.916] in validation cohort with a sensitivity of 77.5 % and specificity of 78.4%. The calibration curve for probability of severe COVID-19 showed optimal agreement between prediction by nomogram and actual observation. DCA and CICA further indicated that our nomogram conferred significantly high clinical net benefit. Interpretation Our nomogram could help clinicians to early identify patients who will exacerbate to severe COVID-19. And this risk stratification tool will enable better centralized management and early treatment of severe patients, and optimal use of medical resources via patient prioritization and thus significantly reduce mortality rates. The RDW plays an important role in predicting severe COVID-19, implying that the role of RBC in severe disease is underestimated.
51b7hss1
51b7hss1
2020-03-20
10.1101/2020.03.17.20037515
1.5
From SARS coronavirus to novel animal and human coronaviruses.
In 2003, severe acute respiratory syndrome coronavirus (SARS-CoV) caused one of the most devastating epidemics known to the developed world. There were two important lessons from this epidemic. Firstly, coronaviruses, in addition to influenza viruses, can cause severe and rapidly spreading human infections. Secondly, bats can serve as the origin and natural animal reservoir of deadly human viruses. Since then, researchers around the world, especially those in Asia where SARS-CoV was first identified, have turned their focus to find novel coronaviruses infecting humans, bats, and other animals. Two human coronaviruses, HCoV-HKU1 and HCoV-NL63, were identified shortly after the SARS-CoV epidemic as common causes of human respiratory tract infections. In 2012, a novel human coronavirus, now called Middle East respiratory syndrome coronavirus (MERS-CoV), has emerged in the Middle East to cause fatal human infections in three continents. MERS-CoV human infection is similar to SARS-CoV in having a high fatality rate and the ability to spread from person to person which resulted in secondary cases among close contacts including healthcare workers without travel history to the Middle East. Both viruses also have close relationships with bat coronaviruses. New cases of MERS-CoV infection in humans continue to occur with the origins of the virus still unknown in many cases. A multifaceted approach is necessary to control this evolving MERS-CoV outbreak. Source identification requires detailed epidemiological studies of the infected patients and enhanced surveillance of MERS-CoV or similar coronaviruses in humans and animals. Early diagnosis of infected patients and appropriate infection control measures will limit the spread in hospitals, while social distancing strategies may be necessary to control the outbreak in communities if it remained uncontrolled as in the SARS epidemic.
52kqp9yw
52kqp9yw
2013
10.3978/j.issn.2072-1439.2013.06.02
4
Phagocytic cells contribute to the antibody-mediated elimination of pulmonary-infected SARS coronavirus
Abstract While the 2002–2003 outbreak of severe acute respiratory syndrome (SARS) resulted in 774 deaths, patients who were affected with mild pulmonary symptoms successfully recovered. The objective of the present work was to identify, using SARS coronavirus (SARS-CoV) mouse infection models, immune factors responsible for clearing of the virus. The elimination of pulmonary SARS-CoV infection required the activation of B cells by CD4+ T cells. Furthermore, passive immunization (post-infection) with homologous (murine) anti-SARS-CoV antiserum showed greater elimination efficacy against SARS-CoV than that with heterologous (rabbit) antiserum, despite the use of equivalent titers of neutralizing antibodies. This distinction was mediated by mouse phagocytic cells (monocyte-derived infiltrating macrophages and partially alveolar macrophages, but not neutrophils), as demonstrated both by adoptive transfer from donors and by immunological depletion of selected cell types. These results indicate that the cooperation of anti-SARS-CoV antibodies and phagocytic cells plays an important role in the elimination of SARS-CoV.
52vzwax8
52vzwax8
2014-04-30
10.1016/j.virol.2014.02.005
2
Forecasting the Worldwide Spread of COVID-19 based on Logistic Model and SEIR Model
Background: With the outbreak of coronavirus disease 2019 (COVID-19), a sudden case increase in late February 2020 led to deep concern globally. Italy, South Korea, Iran, France, Germany, Spain, the US and Japan are probably the countries with the most severe outbreaks. Collecting epidemiological data and predicting epidemic trends are important for the development and measurement of public intervention strategies. Epidemic prediction results yielded by different mathematical models are inconsistent; therefore, we sought to compare different models and their prediction results to generate objective conclusions. Methods: We used the number of cases reported from January 23 to March 20, 2020, to estimate the possible spread size and peak time of COVID-19, especially in 8 high-risk countries. The logistic growth model, basic SEIR model and adjusted SEIR model were adopted for prediction. Given that different model inputs may infer different model outputs, we implemented three model predictions with three scenarios of epidemic development. Results: When comparing all 8 countries short-term prediction results and peak predictions, the differences among the models were relatively large. The logistic growth model estimated a smaller epidemic size than the basic SERI model did; however, once we added parameters that considered the effects of public health interventions and control measures, the adjusted SERI model results demonstrated a considerably rapid deceleration of epidemic development. Our results demonstrated that contact rate, quarantine scale, and the initial quarantine time and length are important factors in controlling epidemic size and length. Conclusions: We demonstrated a comparative assessment of the predictions of the COVID-19 outbreak in eight high-risk countries using multiple methods. By forecasting epidemic size and peak time as well as simulating the effects of public health interventions, the intent of this paper is to help clarify the transmission dynamics of COVID-19 and recommend operation suggestions to slow down the epidemic. It is suggested that the quick detection of cases, sufficient implementation of quarantine and public self-protection behaviors are critical to slow down the epidemic.
52zjm9jt
52zjm9jt
2020-03-30
10.1101/2020.03.26.20044289
1.5
Potent and selective inhibition of SARS coronavirus replication by aurintricarboxylic acid
Abstract The severe acute respiratory syndrome virus (SARS) is a coronavirus that instigated regional epidemics in Canada and several Asian countries in 2003. The newly identified SARS coronavirus (SARS-CoV) can be transmitted among humans and cause severe or even fatal illnesses. As preventive vaccine development takes years to complete and adverse reactions have been reported to some veterinary coronaviral vaccines, anti-viral compounds must be relentlessly pursued. In this study, we analyzed the effect of aurintricarboxylic acid (ATA) on SARS-CoV replication in cell culture, and found that ATA could drastically inhibit SARS-CoV replication, with viral production being 1000-fold less than that in the untreated control. Importantly, when compared with IFNs α and β, viral production was inhibited by more than 1000-fold as compared with the untreated control. In addition, when compared with IFNs α and β, ATA was approximately 10 times more potent than IFN α and 100 times more than interferon β at their highest concentrations reported in the literature previously. Our data indicated that ATA should be considered as a candidate anti-SARS compound for future clinical evaluation.
53l0yw16
53l0yw16
2004-08-06
10.1016/j.bbrc.2004.06.076
0.5
Isolation of porcine epidemic diarrhea virus in porcine cell cultures and experimental infection of pigs of different ages
Abstract This paper describes the isolation of porcine epidemic diarrhea (PED) virus in Vero and porcine cell cultures, and the influence of age on disease in experimental infection. PED virus was isolated from the small intestine of piglets inoculated with PED samples and cultured in Vero, porcine bladder and kidney cells propagated in collagen-coated tissue culture plates in maintenance medium (MM) containing trypsin. In porcine bladder and kidney cell cultures inoculated with isolated PED virus, cytopathic effects (CPE) including cell fusion were detected. Specific brilliant fluorescence was observed in the cytoplasm of these cells. Two- and 7-day old, and 2-, 4-, 8- and 12-week old specific pathogen-free (SPF) pigs were orally inoculated with PED virus isolated from an outbreak. All 2- and 7-day old pigs inoculated developed severe watery diarrhea from post-inoculation day (PID) 1 and died between PID 3 and 4. Although three of five 2-week old pigs developed diarrhea on PID 1–4, they eventually recovered. In the 4-week old group, three of five pigs had mild diarrhea for 1–2 days. None of the 8- and 12-week old pigs showed any clinical signs. Antibodies against PED virus were detected in all surviving pigs by virus neutralization (VN) test and immunofluorescence assay (IFA). Therefore, there is an age-dependent resistance to pathogenic PED virus infection in pigs.
542qbbgp
542qbbgp
2000-03-15
10.1016/s0378-1135(99)00199-6
3.5
“Amantadine disrupts lysosomal gene expression; a hypothesis for COVID19 treatment “
Abstract SARS-coronavirus 2 is the causal agent of the COVID-19 outbreak. SARS-Cov-2 entry into a cell is dependent upon binding of the viral spike (S) protein to cellular receptor and on cleavage of the spike protein by the host cell proteases such as Cathepsin L and Cathepsin B. CTSL/B are crucial elements of lysosomal pathway and both enzymes are almost exclusively located in the lysosomes. CTSL disruption offers potential for CoVID-19 therapies. The mechanisms of disruption include: decreasing expression of CTSL, direct inhibition of CTSL activity and affecting the conditions of CTSL environment (increase pH in the lysosomes). We have conducted a high throughput drug screen gene expression analysis to identify compounds that would downregulate the expression of CTSL/CTSB. One of the top significant results shown to downregulate the expression of the CTSL gene is amantadine (10uM). Amantadine was approved by the US Food and Drug Administration in 1968 as a prophylactic agent for influenza and later for Parkinson's disease. It is available as a generic drug. Amantadine in addition to downregulating CTSL appears to further disrupt lysosomal pathway, hence, interfering with the capacity of the virus to replicate. It acts as a lysosomotropic agent altering the CTSL functional environment. We hypothesize that amantadine could decrease the viral load in SARS-CoV-2 positive patients and as such it may serve as a potent therapeutic decreasing the replication and infectivity of the virus likely leading to better clinical outcomes. Clinical studies will be needed to examine the therapeutic utility of amantadine in COVID-19 infection.
56yey6ka
56yey6ka
2020-04-30
10.1016/j.ijantimicag.2020.106004
4.5
Vulnerabilities of the SARS-CoV-2 virus to proteotoxicity – opportunity for repurposed chemotherapy of COVID-19 infection
There is an urgent requirement for improved treatments of COVID-19 disease. A strategy for chemotherapy is to increase levels of endogenous reactive metabolites - such as reactive oxygen species and arginine-directed glycating agent, methylglyoxal - for selective toxicity to SARS-CoV-2. Sequence analysis of functional domains in the SARS-CoV-2 proteome showed 0.8-fold depletion of cysteine residues and 4.9-fold enrichment of arginine residues, suggesting methylglyoxal modification may inactivate the virus. We discovered the peptide motif for MG modification: 3 – 5-fold enrichment of cationic residues preceding the target arginine. There was 5-fold enrichment of methylglyoxal modification sites in the SARS-CoV-2 proteome, compared to the human host - indicating selective toxicity of methylglyoxal to the virus. We found antitumor drugs, doxorubicin and paclitaxel, increase cellular methylglyoxal to virucidal levels. Taken together, these findings reveal a proteomic vulnerability of SARS-CoV-2 to methylglyoxal modification and provide a rationale for repurposing doxorubicin and paclitaxel for COVID-19 treatment.
581tchjw
581tchjw
2020-04-09
10.1101/2020.04.07.029488
3
Replication of SARS-CoV-2 in human respiratory epithelium
Currently, there are four seasonal coronaviruses associated with relatively mild respiratory tract disease in humans. However, there are also a plethora of animal coronaviruses, which have the potential to cross the species border. This regularly results in the emergence of new viruses in humans. In 2002 SARS-CoV emerged, to rapidly disappear in May 2003. In 2012 MERS-CoV was identified as a possible threat to humans, but its pandemic potential so far is minimal, as the human-to-human transmission is ineffective. The end of 2019 brought us information about the SARS-CoV-2 emergence, and the virus rapidly spread in 2020 causing an unprecedented pandemic.At present, the studies on the virus are carried out using a surrogate system based on the immortalized simian Vero E6 cell line. This model is convenient for diagnostics, but it has serious limitations and does not allow for the understanding of virus biology and evolution.Here we show that fully differentiated human airway epithelium cultures constitute an excellent model to study the infection with the novel human coronavirus SARS-CoV-2. We observed an efficient replication of the virus in the tissue, with the maximal replication at 2 days post-infection. The virus replicated in ciliated cells and was released apically.IMPORTANCE SARS-CoV-2 emerged by the end of 2019 to rapidly spread in 2020. At present, it is of utmost importance to understand the virus biology and to rapidly assess the potential of existing drugs and develop new active compounds. While some animal models for such studies are under development, most of the research is carried out in the Vero E6 cells. Here, we propose fully differentiated human airway epithelium cultures as a model for studies on the SARS-CoV-2.
598n91gb
598n91gb
2020
4
Human monoclonal antibodies for prophylaxis and therapy of viral infections
5ba0alok
5ba0alok
2006
10.1007/978-0-387-31047-3_18
3.5
One Health and Emerging Infectious Diseases: Clinical Perspectives
To date, there has been little articulation of specific One Health clinical activities for veterinary and human health care providers regarding emerging infectious diseases, yet they could play a critical role. Under current clinical paradigms, both human and animal health professionals routinely diagnose and treat zoonotic infectious diseases in their patients, but tend to work in parallel with little cross-professional communication or coordination of care. For this to evolve toward a One Health model, both types of clinicians need to see how individual cases can be “sentinel events” indicating environmental risk for disease emergence, and develop mechanisms of rapid communication about these risks. Human and animal clinicians also need to take a more proactive and preventive approach to zoonotic diseases that includes the occupational health of animal workers in farms, laboratories, veterinary clinics, and other settings, as well as the recognition of increased risk among immunocompromised individuals in contact with animals. This requires training in One Health clinical competencies including the ability to diagnose and treat zoonotic diseases, implement preventive care interventions for individual patients, provide occupational health services for animal workers, recognize sentinel cases, report cases to public heath and clinical colleagues, and assess and help to intervene with environmental factors driving infectious disease risk in humans and animals. To provide an evidence base for such competency training, there is a need for development and testing of innovative protocols for One Health clinical collaborations.
5be1ab4w
5be1ab4w
2012-09-11
10.1007/82_2012_263
2.5
Increasing the translation of mouse models of MERS coronavirus pathogenesis through kinetic hematological analysis
Newly emerging viral pathogens pose a constant and unpredictable threat to human and animal health. Coronaviruses (CoVs) have a penchant for sudden emergence, as evidenced by severe acute respiratory syndrome coronavirus (SARS-CoV), Middle East respiratory syndrome CoV (MERS-CoV) and most recently, swine acute diarrhea syndrome coronavirus (SADS-CoV). Small animal models of emerging viral pathogenesis are crucial to better understand the virus and host factors driving disease progression. However, rodent models are often criticized for their limited translatability to humans. The complete blood count is the most ordered clinical test in the United States serving as the cornerstone of clinical medicine and differential diagnosis. We recently generated a mouse model for MERS-CoV pathogenesis through the humanization of the orthologous entry receptor dipeptidyl peptidase 4 (DPP4). To increase the translatability of this model, we validated and established the use of an automated veterinary hematology analyzer (VetScan HM5) at biosafety level 3 for analysis of peripheral blood. MERS-CoV lung titer peaked 2 days post infection concurrent with lymphopenia and neutrophilia in peripheral blood, two phenomena also observed in MERS-CoV infection of humans. The fluctuations in leukocyte populations measured by Vetscan HM5 were corroborated by standard flow cytometry, thus confirming the utility of this approach. Comparing a sublethal and lethal dose of MERS-CoV in mice, analysis of daily blood draws demonstrates a dose dependent modulation of leukocytes. Major leukocyte populations were modulated before weight loss was observed. Importantly, neutrophil counts on 1dpi were predictive of disease severity with a lethal dose of MERS-CoV highlighting the predictive value of hematology in this model. Taken together, the inclusion of hematological measures in mouse models of emerging viral pathogenesis increases their translatability and should elevate the preclinical evaluation of MERS-CoV therapeutics and vaccines to better mirror the complexity of the human condition.
5bp2bmy4
5bp2bmy4
2019-07-24
10.1371/journal.pone.0220126
2.5
Traditional Chinese medicine is a resource for drug discovery against 2019 novel coronavirus (SARS-CoV-2)
5cw1ycyh
5cw1ycyh
2020-03-31
10.1016/j.joim.2020.02.004
1
A guideline for homology modeling of the proteins from newly discovered betacoronavirus, 2019 novel coronavirus (2019-nCoV)
During an outbreak of respiratory diseases including atypical pneumonia in Wuhan, a previously unknown ß-coronavirus was detected in patients. The newly discovered coronavirus is similar to some ß-coronaviruses found in bats but different from previously known SARS-CoV and MERS-CoV. High sequence identities and similarities between 2019-nCoV and SARS-CoV were found. In this study, we searched the homologous templates of all nonstructural and structural proteins of 2019-nCoV. Among the nonstructural proteins, the leader protein (nsp1), the papain-like protease (nsp3), the nsp4, the 3C-like protease (nsp5), the nsp7, the nsp8, the nsp9, the nsp10, the RNA-directed RNA polymerase (nsp12), the helicase (nsp13), the guanine-N7 methyltransferase (nsp14), the uridylate-specific endoribonuclease (nsp15), the 2'-O-methyltransferase (nsp16), and the ORF7a protein could be built on the basis of homology templates. Among the structural proteins, the spike protein (S-protein), the envelope protein (E-protein), and the nucleocapsid protein (N-protein) can be constructed based on the crystal structures of the proteins from SARS-CoV. It is known that PL-Pro, 3CL-Pro, and RdRp are important targets for design antiviral drugs against 2019-nCoV. And S protein is a critical target candidate for inhibitor screening or vaccine design against 2019-nCoV because coronavirus replication is initiated by the binding of S protein to cell surface receptors. It is believed that these proteins should be useful for further structure-based virtual screening and related computer-aided drug development and vaccine design.
5duo9ffv
5duo9ffv
2020
4
SARS-coronavirus replication in human peripheral monocytes/macrophages
Abstract A novel coronavirus (CoV) has been described in association with cases of severe acute respiratory syndrome (SARS). The virus, SARS-CoV, differs from the previously described human coronaviruses, 229E and OC43. 229E was previously shown to productively infect human monocytes/macrophages, whereas OC43 poorly infected the cells. In this study, we examined whether SARS-CoV could productively infect purified monocytes/macrophages (PM) derived from human donor cells. Unlike 229E-infected cells, which produced viral titers of 103.5 to 106 TCID50/ml, SARS-CoV replicated poorly in PM, producing titers of 101.75 to 102 TCID50/ml. This finding was similar to results reported for OC43-infected cells, with titers ranging from 101.2 to 102.7 TCID50/ml. Of interest, SARS-CoV proteins were detected only in PM that did not produce significant amounts of interferon (IFN)-α, and in one such case, preliminary electron microscope studies demonstrated that SARS-CoV-like particles could enter the cells, possibly via phagocytosis. These results suggest that SARS-CoV, like human CoV OC43, poorly infects human PM, and production of IFN-α by these cells further limits the infection. Given the importance of monocytes/macrophages to the immune response, it is possible that their infection by SARS-CoV and alteration of this infection by IFN-α may be important to the course of the infection in humans.
5e5846m4
5e5846m4
2005-01-31
10.1016/j.virusres.2004.09.004
2.5
Experimental infection of Cynomolgus Macaques with highly pathogenic H5N1 influenza virus through the aerosol route
Several animal models are used to study influenza viruses. Intranasal inoculation of animals with a liquid inoculum is one of the main methods used to experimentally infect animals with influenza virus; however, this method does not reflect the natural infection with influenza virus by contact or aerosol route. Aerosol inhalation methods have been established with several influenza viruses for mouse and ferret models, but few studies have evaluated inoculation routes in a nonhuman primates (NHP) model. Here, we performed the experimental infection of NHPs with a highly pathogenic H5N1 influenza virus via the aerosol route and demonstrated that aerosol infection had no effect on clinical outcome, but caused broader infection throughout all of the lobes of the lung compared with a non-aerosolized approach. Aerosol infection therefore represents an option for inoculation of NHPs in future studies.
5e7xrd1y
5e7xrd1y
2018-03-19
10.1038/s41598-018-23022-0
1
The phenotypic changes of Î³Î´ T cells in COVID-19 patients
A novel pneumonia-associated respiratory syndrome named coronavirus disease-2019 (COVID-19), which caused by SARS-CoV-2 and broken in Wuhan, China in the end of 2019. Unfortunately, there is no specific antiviral agent or vaccine available to treat SARS-CoV-2 infections. Also, information regarding the immunological characteristics in COVID-19 patients remains limited. Here we collected the blood samples from 18 healthy donors (HD) and 38 COVID-19 patients to analyze changes in {gamma}{delta} T cells. In comparison to HD, the {gamma}{delta} T cells percentage was decreased. {gamma}{delta} T cells are able to immediately respond to SARS-CoV-2 infection and upregulate the activation marker CD25. In addition, the increased expression of CD4 in {gamma}{delta} T cells may serve as a biomarker for the assessment of SARS-CoV-2 infection.
5ekdfers
5ekdfers
2020-04-07
10.1101/2020.04.05.20046433
1
Pharmacoinformatics and molecular dynamics simulation studies reveal potential covalent and FDA-approved inhibitors of SARS-CoV-2 main protease 3CLpro
The SARS-CoV-2 was confirmed to cause the global pandemic of coronavirus disease 2019 (COVID-19). The 3-chymotrypsin-like protease (3CLpro), an essential enzyme for viral replication, is a valid target to combat SARS-CoV and MERS-CoV. In this work, we present a structure-based study to identify potential covalent inhibitors containing a variety of chemical warheads. The targeted Asinex Focused Covalent (AFCL) library was screened based on different reaction types and potential covalent inhibitors were identified. In addition, we screened FDA-approved protease inhibitors to find candidates to be repurposed against SARS-CoV-2 3CLpro. A number of compounds with significant covalent docking scores were identified. These compounds were able to establish a covalent bond (C-S) with the reactive thiol group of Cys145 and to form favorable interactions with residues lining the substrate-binding site. Moreover, paritaprevir and simeprevir from FDA-approved protease inhibitors were identified as potential inhibitors of SARS-CoV-2 3CLpro. The mechanism and dynamic stability of binding between the identified compounds and SARS-CoV-2 3CLpro were characterized by molecular dynamics (MD) simulations. The identified compounds are potential inhibitors worthy of further development as COVID-19 drugs. Importantly, the identified FDA-approved anti-hepatitis-C virus (HCV) drugs paritaprevir and simeprevir could be ready for clinical trials to treat infected patients and help curb COVID-19. Communicated by Ramaswamy H. Sarma.
5f5rqgiv
5f5rqgiv
2020
5
Identification of antiviral drug candidates against SARS-CoV-2 from FDA-approved drugs
COVID-19 is an emerging infectious disease and was recently declared as a pandemic by WHO. Currently, there is no vaccine or therapeutic available for this disease. Drug repositioning represents the only feasible option to address this global challenge and a panel of 48 FDA-approved drugs that have been pre-selected by an assay of SARS-CoV was screened to identify potential antiviral drug candidates against SARS-CoV-2 infection. We found a total of 24 drugs which exhibited antiviral efficacy (0.1 μM < IC50 < 10 μM) against SARS-CoV-2. In particular, two FDA-approved drugs - niclosamide and ciclesonide – were notable in some respects. These drugs will be tested in an appropriate animal model for their antiviral activities. In near future, these already FDA-approved drugs could be further developed following clinical trials in order to provide additional therapeutic options for patients with COVID-19.
5f95gve3
5f95gve3
2020-03-28
10.1101/2020.03.20.999730
0.5
[Inhibitors of RAS Might Be a Good Choice for the Therapy of COVID-19 Pneumonia].
The novel coronavirus 2019 (COVID-19) infected patients by binding human ACE2, leading to severe pneumonia and highly mortality rate in patients. At present, there is no definite and effective treatment for COVID-19. ACE2 plays an important role in the RAS, and the imbalance between ACE/Ang II/AT1R pathway and ACE2/Ang (1-7)/Mas receptor pathway in the RAS system will lead to multi-system inflammation. Increased ACE and Ang II are poor prognostic factors for severe pneumonia. Animal studies have shown that RAS inhibitors could effectively relieve symptoms of acute severe pneumonia and respiratory failure. The binding of COVID-19 and ACE2 resulted in the exhaustion of ACE2, and then ACE2/Ang (1-7)/Mas receptor pathway was inhibited. The balance of the RAS system was broken, and this would lead to the exacerbation of acute severe pneumonia. Therefore, we speculate that ACEI and AT1R inhibitors could be used in patients with COVID-19 pneumonia under the condition of controlling blood pressure, and might reduce the pulmonary inflammatory response and mortality.
5fbcjhqj
5fbcjhqj
2020-02-16
10.3760/cma.j.issn.1001-0939.2020.0014
1.5
Conditional ligands for Asian HLA variants facilitate the definition of CD8(+) T-cell responses in acute and chronic viral diseases
Conditional ligands have enabled the high-throughput production of human leukocyte antigen (HLA) libraries that present defined peptides. Immunomonitoring platforms typically concentrate on restriction elements associated with European ancestry, and such tools are scarce for Asian HLA variants. We report 30 novel irradiation-sensitive ligands, specifically targeting South East Asian populations, which provide 93, 63, and 79% coverage for HLA-A, -B, and -C, respectively. Unique ligands for all 16 HLA types were constructed to provide the desired soluble HLA product in sufficient yield. Peptide exchange was accomplished for all variants as demonstrated by an ELISA-based MHC stability assay. HLA tetramers with redirected specificity could detect antigen-specific CD8(+) T-cell responses against human cytomegalovirus, hepatitis B (HBV), dengue virus (DENV), and Epstein-Barr virus (EBV) infections. The potential of this population-centric HLA library was demonstrated with the characterization of seven novel T-cell epitopes from severe acute respiratory syndrome coronavirus, HBV, and DENV. Posthoc analysis revealed that the majority of responses would be more readily identified by our unbiased discovery approach than through the application of state-of-the-art epitope prediction. This flow cytometry-based technology therefore holds considerable promise for monitoring clinically relevant antigen-specific T-cell responses in populations of distinct ethnicity.
5fgbxwm3
5fgbxwm3
2012-12-26
10.1002/eji.201243088
3
SARS-CoV-2 invades host cells via a novel route: CD147-spike protein
Currently, COVID-19 caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been widely spread around the world; nevertheless, so far there exist no specific antiviral drugs for treatment of the disease, which poses great challenge to control and contain the virus. Here, we reported a research finding that SARS-CoV-2 invaded host cells via a novel route of CD147-spike protein (SP). SP bound to CD147, a receptor on the host cells, thereby mediating the viral invasion. Our further research confirmed this finding. First, in vitro antiviral tests indicated Meplazumab, an anti-CD147 humanized antibody, significantly inhibited the viruses from invading host cells, with an EC50 of 24.86 μg/mL and IC50 of 15.16 μg/mL. Second, we validated the interaction between CD147 and SP, with an affinity constant of 1.85×10−7M. Co-Immunoprecipitation and ELISA also confirmed the binding of the two proteins. Finally, the localization of CD147 and SP was observed in SARS-CoV-2 infected Vero E6 cells by immuno-electron microscope. Therefore, the discovery of the new route CD147-SP for SARS-CoV-2 invading host cells provides a critical target for development of specific antiviral drugs.
5hpbjkft
5hpbjkft
2020-03-14
10.1101/2020.03.14.988345
1
Surveillance to improve evidence for community control decisions during the COVID-19 pandemic – Opening the animal epidemic toolbox for public health
Abstract During the first few months of 2020, the COVID-19 pandemic has reached Europe. Health systems all over the world are trying to control the outbreak in the shortest possible time. Exotic disease outbreaks are not uncommon in animal health and randomised surveillance is frequently used as support for decision-making. This editorial discusses the possibilities of practicing One Health, by using methods from animal health to enhance surveillance for COVID-19 to provide an evidence base fort decision-making in communities and countries.
5j4nt2qs
5j4nt2qs
2020-03-27
10.1016/j.onehlt.2020.100130
1.5
A novel neutralizing monoclonal antibody targeting the N-terminal domain of the MERS-CoV spike protein
Middle East respiratory syndrome coronavirus (MERS-CoV) has caused fatal infections, some through hospital-acquired transmission, in affected regions since its emergence in 2012. Although the virus is not pandemic among humans, it poses a great threat to public health due to its zoonotic origin. Thus, both preventative and therapeutic countermeasures are urgently needed. In this study, we discovered a panel of neutralizing monoclonal antibodies (mAbs) against MERS-CoV, which mapped to a wide range of regions on the spike (S) protein of the virus. In addition to mAbs with neutralizing epitopes located on the receptor-binding domain, one mAb, 5F9, which binds to the N-terminal domain (NTD) of the MERS-CoV S1 subunit, showed efficient neutralizing activity against the wild-type MERS-CoV strain EMC/2012, with a half maximal inhibitory concentration of 0.2 μg/mL. We concluded that a novel neutralizing epitope for MERS-CoV also resides on the NTD of the S protein, indicating that the NTD might be important during the viral infection process. Our findings have significant implications for further vaccine design and for the development of prophylactic and therapeutic monoclonal immunotherapies against MERS-CoV infection.
5jau2gjn
5jau2gjn
2017-05-24
10.1038/emi.2017.18
3.5
In vitro inhibition of severe acute respiratory syndrome coronavirus by chloroquine
Abstract We report on chloroquine, a 4-amino-quinoline, as an effective inhibitor of the replication of the severe acute respiratory syndrome coronavirus (SARS-CoV) in vitro. Chloroquine is a clinically approved drug effective against malaria. We tested chloroquine phosphate for its antiviral potential against SARS-CoV-induced cytopathicity in Vero E6 cell culture. Results indicate that the IC50 of chloroquine for antiviral activity (8.8±1.2μM) was significantly lower than its cytostatic activity; CC50 (261.3±14.5μM), yielding a selectivity index of 30. The IC50 of chloroquine for inhibition of SARS-CoV in vitro approximates the plasma concentrations of chloroquine reached during treatment of acute malaria. Addition of chloroquine to infected cultures could be delayed for up to 5h postinfection, without an important drop in antiviral activity. Chloroquine, an old antimalarial drug, may be considered for immediate use in the prevention and treatment of SARS-CoV infections.
5lzzobl3
5lzzobl3
2004-10-08
10.1016/j.bbrc.2004.08.085
3
Chapter 11 Manufacturing Vaccines for an Emerging Viral Infection–Specific Issues Associated with the Development of a Prototype SARS Vaccine
Abstract The world was struck by surprise when a Severe Acute Respiratory Syndrome (SARS) epidemic started in 2003 in China. This disease had never been observed in man before; the SARS-Coronavirus causing the disease was unknown. With the uncertainty about the future impact of this epidemic, an important international collaboration started spontaneously sharing scientific knowledge and reagents. Resources became quickly available, and public and private efforts were undertaken to develop rapidly a vaccine. We will discuss here the importance of the international collaboration and the availability of funding. Moreover, we will review the most important and challenging steps during the industrial development of the SARS vaccine highlighting the difficulties in terms of safety working with such a highly pathogenic, unknown virus. We will emphasize the industrial perspectives on inactivation and decontamination experiments, the selection of the most promising vaccine candidate, the production process and the choice and use of animal models in such a pressing and difficult situation. Finally, we will briefly review the unique regulatory environment created during this period for the development of a SARS vaccine.
5ns1onkw
5ns1onkw
2009-12-31
10.1016/b978-0-12-369408-9.00011-1
0.5
Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open-label non-randomized clinical trial
Abstract Background Chloroquine and hydroxychloroquine have been found to be efficient on SARS-CoV-2, and reported to be efficient in Chinese COV-19 patients. We evaluate the role of hydroxychloroquine on respiratory viral loads. Patients and methods French Confirmed COVID-19 patients were included in a single arm protocol from early March to March 16th, to receive 600mg of hydroxychloroquine daily and their viral load in nasopharyngeal swabs was tested daily in a hospital setting. Depending on their clinical presentation, azithromycin was added to the treatment. Untreated patients from another center and cases refusing the protocol were included as negative controls. Presence and absence of virus at Day6-post inclusion was considered the end point. Results Six patients were asymptomatic, 22 had upper respiratory tract infection symptoms and eight had lower respiratory tract infection symptoms. Twenty cases were treated in this study and showed a significant reduction of the viral carriage at D6-post inclusion compared to controls, and much lower average carrying duration than reported of untreated patients in the literature. Azithromycin added to hydroxychloroquine was significantly more efficient for virus elimination. Conclusion Despite its small sample size our survey shows that hydroxychloroquine treatment is significantly associated with viral load reduction/disappearance in COVID-19 patients and its effect is reinforced by azithromycin.
5o9bbspc
5o9bbspc
2020-03-20
10.1016/j.ijantimicag.2020.105949
1.5
Clinical Characteristics of Hospitalized Patients with SARS-CoV-2 and Hepatitis B virus Co-infection
Background & Aims The coronavirus disease 2019 (COIVD-19) caused by SARS-CoV-2 has been characterized as a pandemic, which causes a serious public health challenge in the world. A very large group of patients infected by HBV has been reported worldwide, especially in China. In order to answer whether specific treatment strategy on the patients coinfected with HBV and SARS-CoV-2, it requires profound understanding of the clinical characteristics on those patients. However, the impacts of SARS-CoV-2 infection on HBV patients remain largely unknown. Approach & Results In this retrospective investigation, we included 123 COVID-19 patients admitted to Zhongnan Hospital of Wuhan University, Wuhan, China, from January 5 to March 7, 2020. All enrolled patients are the laboratory confirmed COVID-19 pneumonia cases according to the criteria reported previously. A total of 123 patients were analyzed for their Clinical records, laboratory results including the diagnosis of HBV infection and liver function. Among 123 confirmed COVID-19 patients, the mean age was 51 years old and 59.3% were females (73/123). Fifteen were previously HBV infected patients, 66.7% of them were males (10/15), patients with HBV infection appeared to have a higher incidence of liver cirrhosis and an increased level of total bilirubin. Seven (46.7%) patients with HBV infection were defined as severe cases, while the severity rate was 24.1% for the patients without HBV infection (26/108). The mortality of patients with HBV infection was 13.3% (2/15) compared to 2.8% (3/108) for the patients without HBV infection. Conclusions SARS-CoV-2 infection may cause liver function damage in COVID-19 cases and the patients with HBV infection are likely to have more severe disease outcome.
5pfusktn
5pfusktn
2020-03-27
10.1101/2020.03.23.20040733
1.5
Therapeutic efficacy of Pudilan Xiaoyan Oral Liquid (PDL) for COVID-19 in vitro and in vivo
5pt9jmyz
5pt9jmyz
2020-05-08
10.1038/s41392-020-0176-0
4.5
Relative antioxidant activities of quercetin and its structurally related substances and their effects on NF-κB/CRE/AP-1 signaling in murine macrophages
Reactive oxygen species (ROS) and reactive nitrogen species (RNS) produced by the oxidative burst in activated macrophages and neutrophils cause oxidative stressimplicated diseases. Quercetin is flavonoid that occurs naturally in plants and is widely used as a nutritional supplement due to its antioxidant and anti-inflammatory properties. In this study, we investigated antioxidant activities and mechanisms of action in zymosan-induced macrophages of quercetin and quercetin-related flavonoids such as quercitrin, isoquercitrin, quercetin 3-O-β-(2″-galloyl)-rhamnopyranoside (QGR) and quercetin 3-O-β-(2″-galloyl)-glucopyranoside (QGG) as well as gallic acid, a building moiety of QGR and QGG. QGR and QGG exhibited stronger antioxidant activities compared with quercetin, whereas quercitrin, isoquercitrin and gallic acid exhibited weak-tono antioxidant activities, assessed by 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging, superoxide production, superoxide scavenging, nitric oxide (NO) production, peroxynitrite (ONOO(−)) scavenging and myeloperoxidase (MPO) activity. Regarding mechanisms, the quercetincontaining flavonoids QGR and QGG differentially targeted compared with quercetin in the NF-κB signaling pathway that inhibited the DNA binding activity of the NF-κB complex without affecting the degradation and phosphorylation of IκBα and NF-κB phosphorylation. In addition, QGR and QGG inhibited CRE and activator protein (AP-1) transcriptional activity and JNK phosphorylation by inhibiting the cAMP/protein kinase A (PKA) and protein kinase C (PKC) signaling in a different manner than quercetin. Our results showed that although QGR and QGG exhibited stronger antioxidant activities than querce-tin in macrophages, their mechanisms of action in terms of the NF-κB, PKA and PKC signaling pathways were different.
5s10b9zy
5s10b9zy
2013-05-01
10.1007/s10059-013-0031-z
4
Thiopurine analogues inhibit papain-like protease of severe acute respiratory syndrome coronavirus
Abstract The papain-like protease of severe acute respiratory syndrome coronavirus (PLpro) (EC 3.4.22.46) is essential for the viral life cycle and therefore represents an important antiviral target. We have identified 6MP and 6TG as reversible and slow-binding inhibitors of SARS-CoV PLpro, which is the first report about small molecule reversible inhibitors of PLpro. The inhibition mechanism was investigated by kinetic measurements and computer docking. Both compounds are competitive, selective, and reversible inhibitors of the PLpro with K is values ∼10 to 20μM. A structure–function relationship study has identified the thiocarbonyl moiety of 6MP or 6TG as the active pharmacophore essential for these inhibitions, which has not been reported before. The inhibition is selective because these compounds do not exert significant inhibitory effects against other cysteine proteases, including SARS-CoV 3CLpro and several cathepsins. Thus, our results present the first potential chemical leads against SARS-CoV PLpro, which might be used as lead compounds for further optimization to enhance their potency against SARS-CoV. Both 6MP and 6TG are still used extensively in clinics, especially for children with acute lymphoblastic or myeloblastic leukemia. In light of the possible inhibition against subset of cysteine proteases, our study has emphasized the importance to study in depth these drug actions in vivo.
5szqfufh
5szqfufh
2008-04-15
10.1016/j.bcp.2008.01.005
0.5
A systematic review of lopinavir therapy for SARS coronavirus and MERS coronavirus—A possible reference for coronavirus disease‐19 treatment option
In the past few decades, coronaviruses have risen as a global threat to public health. Currently, the outbreak of coronavirus disease‐19 (COVID‐19) from Wuhan caused a worldwide panic. There are no specific antiviral therapies for COVID‐19. However, there are agents that were used during the severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS) epidemics. We could learn from SARS and MERS. Lopinavir (LPV) is an effective agent that inhibits the protease activity of coronavirus. In this review, we discuss the literature on the efficacy of LPV in vitro and in vivo, especially in patients with SARS and MERS, so that we might clarify the potential for the use of LPV in patients with COVID‐19.
5trqi9tp
5trqi9tp
2020-03-12
10.1002/jmv.25729
1.5
Neurotropism of SARS-CoV 2: Mechanisms and manifestations
5uhw5oam
5uhw5oam
2020-04-08
10.1016/j.jns.2020.116824
1.5
Human-Wildlife Contact and Emerging Infectious Diseases
The majority of all emerging pathogens in humans are zoonotic (nonhuman animal) in origin. Population, ecological, and behavioral changes that increase contact with wildlife exacerbate emergence of these pathogens. Anthropogenic modification of the physical environment has altered not only our risk of zoonotic infection from wildlife but also the likelihood of pathogen transmission from human to nonhuman animal populations. This is particularly the case for primates that share a number of common infections with humans. In this chapter, I use a series of case studies involving SARS, HIV, Nipah virus, Lyme disease, malaria, and Ebola to exemplify how various anthropogenic factors have facilitated pathogen transmission between human and nonhuman animal populations. The costs and benefits of primate-based ecotourism are also reviewed to better illustrate how human-wildlife contact can affect both populations. Responsible health monitoring of human-wildlife interactions is a necessary prerequisite for prevention of the transmission of future emerging infectious diseases.
5ule2x9w
5ule2x9w
2012-07-19
10.1007/978-94-007-4780-7_4
1
Repurposing approved drugs as inhibitors of SARS-CoV-2 S-protein from molecular modeling and virtual screening
Herein, molecular modeling techniques were used with the main goal to obtain candidates from a drug database as potential targets to be used against SARS-CoV-2. This novel coronavirus, responsible by the COVID-19 outbreak since the end of 2019, became a challenge since there is not vaccine for this disease. The first step in this investigation was to solvate the isolated S-protein in water for molecular dynamics (MD) simulation, being observed a transition from "up" to "down" conformation of receptor-binding domain (RBD) of the S-protein with angle of 54.3 and 43.0 degrees, respectively. The RBD region was more exposed to the solvent and to the possible drugs due to its enhanced surface area. From the equilibrated MD structure, virtual screening by docking calculations were performed using a library contained 9091 FDA approved drugs. Among them, 24 best-scored ligands (14 traditional herbal isolate and 10 approved drugs) with the binding energy below -8.1 kcal/mol were selected as potential candidates to inhibit the SARS-CoV-2 S-protein, preventing the human cell infection and their replication. For instance, the ivermectin drug (present in our list of promise candidates) was recently used successful to control viral replication in vitro. MD simulations were performed for the three best ligands@S-protein complexes and the binding energies were calculated using the MM/PBSA approach. Overall, it is highlighted an important strategy, some key residues, and chemical groups which may be considered on clinical trials for COVID-19 outbreak.
5vgfliv0
5vgfliv0
2020
4.5
Structural and molecular modelling studies reveal a new mechanism of action of chloroquine and hydroxychloroquine against SARS-CoV-2 infection
The recent emergence of the novel pathogenic SARS-coronavirus 2 (SARS-CoV-2) is responsible for a worldwide pandemic. Given the global health emergency, drug repositioning is the most reliable option to design an efficient therapy for infected patients without delay. The first step of the viral replication cycle [i.e. attachment to the surface of respiratory cells, mediated by the spike (S) viral protein] offers several potential therapeutic targets. The S protein uses the angiotension-converting enzyme-2 (ACE-2) receptor for entry, but also sialic acids linked to host cell surface gangliosides. Using a combination of structural and molecular modelling approaches, this study showed that chloroquine (CLQ), one of the drugs currently under investigation for SARS-CoV-2 treatment, binds sialic acids and gangliosides with high affinity. A new type of ganglioside-binding domain at the tip of the N-terminal domain of the SARS-CoV-2 S protein was identified. This domain (111-158), which is fully conserved among clinical isolates worldwide, may improve attachment of the virus to lipid rafts and facilitate contact with the ACE-2 receptor. This study showed that, in the presence of CLQ [or its more active derivative, hydroxychloroquine (CLQ-OH)], the viral S protein is no longer able to bind gangliosides. The identification of this new mechanism of action of CLQ and CLQ-OH supports the use of these repositioned drugs to cure patients infected with SARS-CoV-2. The in-silico approaches used in this study might also be used to assess the efficiency of a broad range of repositioned and/or innovative drug candidates before clinical evaluation.
5wvm70p3
5wvm70p3
2020
3.5
Anti-RAS drugs and SARS-CoV-2 infection
• There is no enough evidence to indicate that ACEIs and ARBs result in ACE2 upregulation. • The level of ACE2 expression is not completely related with the risk of COVID-19 infection. • There is currently no evidence that ACEI/ARB increase risk for COVID-19 infection from clinical trials. • It is not recommended that COVID-19 patients with hypertension or normal hypertensive patients at risk for exposure to stop using ACEI/ARB or change to other antihypertensive drugs.
5y8cc5eb
5y8cc5eb
2020-04-28
10.1016/j.apsb.2020.04.013
3.5
Evaluation of the susceptibility of mice & hamsters to SARS-CoV-2 infection
5yc5vgdw
5yc5vgdw
2020
5
Therapeutic use of chloroquine and hydroxychloroquine in COVID-19 and other viral infections: A narrative review
Abstract The rapidly spreading Coronavirus Disease (COVID-19) pandemic, caused by the severe acute respiratory syndrome coronavirus (SARS-CoV-2), represents an unprecedented serious challenge to the global public health community. The extremely rapid international spread of the disease with significant morbidity and mortality made finding possible therapeutic interventions a global priority. While approved specific antiviral drugs against SARS-CoV-2 are still lacking, a large number of existing drugs are being explored as a possible treatment for COVID-19 infected patients. Recent publications have re-examined the use of Chloroquine (CQ) and/or Hydroxychloroquine (HCQ) as a potential therapeutic option for these patients. In an attempt to explore the evidence that supports their use in COVID-19 patients, we comprehensively reviewed the previous studies which used CQ or HCQ as an antiviral treatment. Both CQ and HCQ demonstrated promising in vitro results, however, such data have not yet been translated into meaningful in vivo studies. While few clinical trials have suggested some beneficial effects of CQ and HCQ in COVID-19 patients, most of the reported data are still preliminary. Given the current uncertainty, it is worth being mindful of the potential risks and strictly rational the use of these drugs in COVID-19 patients until further high quality randomized clinical trials are available to clarify their role in the treatment or prevention of COVID-19.
5yvjbr5q
5yvjbr5q
2020-05-06
10.1016/j.tmaid.2020.101735
3
Protection from infection with severe acute respiratory syndrome coronavirus in a Chinese hamster model by equine neutralizing F(ab')2.
To warrant potential clinical testing, the equine anti-severe acute respiratory syndrome coronavirus (SARS-CoV) F(ab')(2) requires evaluation in as many animal models as possible. In this study, we established a new animal model, the Chinese hamster, susceptible to SARS-CoV infection. SARS-CoV could propagate effectively and sustain high levels for 1 wk in animal lungs. All animals were protected from SARS-CoV infection in preventive settings. Further, when used therapeutically this antibody led to an approximately 4-log(10) decrease in viral burden in infected animal lungs. The pathological changes in lungs correlated closely with the dose of antibody administered. The excellent preventive and therapeutic roles of equine anti-SARS-CoV F(ab')(2) in several animal models, including the novel Chinese hamster model described in this study, have provided exciting data concerning its potential clinical study.
60516gav
60516gav
2007
3
The search for a COVID-19 animal model.
60xeqgrf
60xeqgrf
2020-05-29
10.1126/science.abc6141
5
Inflammatory bowel diseases and COVID-19: the invisible enemy
60yn4hg7
60yn4hg7
2020-04-16
10.1053/j.gastro.2020.04.032
2.5
Immunology of COVID-19: current state of the science
Abstract The coronavirus disease 2019 (COVID-19) pandemic, caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has affected millions of people worldwide, igniting an unprecedented effort from the scientific community to understand the biological underpinning of COVID19 pathophysiology. In this review, we summarize the current state of knowledge of innate and adaptive immune responses elicited by SARS-CoV-2 infection and the immunological pathways that likely contribute to disease severity and death. We also discuss the rationale and clinical outcome of current therapeutic strategies as well as prospective clinical trials to prevent or treat SARS-CoV-2 infection.
61fmul8c
61fmul8c
2020-05-06
10.1016/j.immuni.2020.05.002
3
THREE INSIGHTS ON PSYCHONEUROIMMUNOLOGY OF MOOD DISORDERS TO BE TAKEN FROM THE COVID-19 PANDEMIC
Abstract In the recent months, the world was taken by surprise by the outbreak of a coronavirus (SARS-CoV-2) pandemic (COVID-19). The COVID-19 pandemic is a unique opportunity to advance the understanding of the association of respiratory viruses with mood disorders and suicide. In this editorial, we explore three insights to the neuropsychoneuroimmunology of mood disorders that could be taken from the COVID-19 pandemic.
61gajzlr
61gajzlr
2020-04-22
10.1016/j.bbih.2020.100076
4.5
Analysis of SARS-CoV-2 RNA-dependent RNA polymerase as a potential therapeutic drug target using a computational approach
BACKGROUND: The Severe acute respiratory syndrome-related coronavirus 2 (SARS-CoV-2) outbreak originating in Wuhan, China, has raised global health concerns and the pandemic has now been reported on all inhabited continents. Hitherto, no antiviral drug is available to combat this viral outbreak. METHODS: Keeping in mind the urgency of the situation, the current study was designed to devise new strategies for drug discovery and/or repositioning against SARS-CoV-2. In the current study, RNA-dependent RNA polymerase (RdRp), which regulates viral replication, is proposed as a potential therapeutic target to inhibit viral infection. RESULTS: Evolutionary studies of whole-genome sequences of SARS-CoV-2 represent high similarity (> 90%) with other SARS viruses. Targeting the RdRp active sites, ASP760 and ASP761, by antiviral drugs could be a potential therapeutic option for inhibition of coronavirus RdRp, and thus viral replication. Target-based virtual screening and molecular docking results show that the antiviral Galidesivir and its structurally similar compounds have shown promise against SARS-CoV-2. CONCLUSIONS: The anti-polymerase drugs predicted here—CID123624208 and CID11687749—may be considered for in vitro and in vivo clinical trials.
61nwk2sg
61nwk2sg
2020-07-07
10.1186/s12967-020-02439-0
5
COVID-19 pandemic: Impact of lockdown, contact and non-contact transmissions on infection dynamics
COVID-19 coronavirus pandemic has virtually locked down the entire world of human population, and through its rapid and unstoppable spread COVID-19 has essentially compartmentalised the population merely into susceptible, exposed, infected and recovered classes. Adapting the classical epidemic modelling framework, two distinct routes of COVID-19 transmission are incorporated into a model: (a) direct person-to-person contact transmission, and (b) indirect airborne and fomites-driven transmission. The indirect non-contact transmission route needs to explored in models of COVID-19 spread, because evidences show that this route of transmission is entirely viable with hugely uncertain level of relative contribution. This theoretical study based on model simulations demonstrates the following: (1) Not incorporating indirect transmission route in the model leads to underestimation of the basic reproduction number, and hence will impact on the COVID-19 mitigation decisions; (2) Lockdown measures can suppress the primary infection peak, but will lead to a secondary peak whose relative strength and time of occurrence depend on the success and duration of the lockdown measures; (3) To make lockdown effective, a considerable level of reduction in both contact and non-contact transmission rates over a long period is required; (4) To bring down the infection cases below any hypothetical health-care capacity, reduction of non-contact transmission rate is key, and hence active measures should be taken to reduce non-contact transmission (e.g., extensive uses of areal and aerosol disinfectant in public spaces to improve contaminated surfaces and air); (5) Any premature withdrawal of lockdown following the sign of a brief retracement in the infection cases can backfire, and can lead to a quicker, sharper and higher secondary peak, due to reactivation of the two transmission routes. Based on these results, this study recommends that any exit policy from lockdown, should take into account the level of transmission reduction in both routes, the absolute scale of which will vary among countries depending on their health-service capacity, but should be computed using accurate time-series data on infection cases and transmission rates.
61ta81iy
61ta81iy
2020-04-07
10.1101/2020.04.04.20050328
1.5
The anti-viral facet of anti-rheumatic drugs: Lessons from COVID-19
The outbreak of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has posed the world at a pandemic risk. Coronavirus-19 disease (COVID-19) is an infectious disease caused by SARS-CoV-2, which causes pneumonia, requires intensive care unit hospitalization in about 10% of cases and can lead to a fatal outcome. Several efforts are currently made to find a treatment for COVID-19 patients. So far, several anti-viral and immunosuppressive or immunomodulating drugs have demonstrated some efficacy on COVID-19 both in vitro and in animal models as well as in cases series. In COVID-19 patients a pro-inflammatory status with high levels of interleukin (IL)-1B, IL-1 receptor (R)A and tumor necrosis factor (TNF)-&#945; has been demonstrated. Moreover, high levels of IL-6 and TNF-&#945; have been observed in patients requiring intensive-care-unit hospitalization. This provided rationale for the use of anti-rheumatic drugs as potential treatments for this severe viral infection. Other agents, such as hydroxychloroquine and chloroquine might have a direct anti-viral effect. The anti-viral aspect of immunosuppressants towards a variety of viruses has been known since long time and it is herein discussed in the view of searching for a potential treatment for SARS-CoV-2 infection.
63gq2wu1
63gq2wu1
2020
3
Simeprevir suppresses SARS-CoV-2 replication and synergizes with remdesivir
The recent outbreak of coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus, is a global threat to human health. By in vitro screening and biochemical characterization, we identified the hepatitis C virus (HCV) protease inhibitor simeprevir as an especially promising repurposable drug for treating COVID-19. We also revealed that simeprevir synergizes with the RNA-dependent RNA polymerase (RdRP) inhibitor remdesivir to suppress the replication of SARS-CoV-2 in vitro. Our results provide preclinical rationale for the combination treatment of simeprevir and remdesivir for the pharmacological management of COVID-19 patients. One Sentence Summary Discovery of simeprevir as a potent suppressor of SARS-CoV-2 viral replication that synergizes remdesivir.
6470qlu1
6470qlu1
2020-05-26
10.1101/2020.05.26.116020
5
Structure analysis of the receptor binding of 2019-nCoV
Abstract 2019-nCoV is a newly identified coronavirus with high similarity to SARS-CoV. We performed a structural analysis of the receptor binding domain (RBD) of spike glycoprotein responsible for entry of coronaviruses into host cells. The RBDs from the two viruses share 72% identity in amino acid sequences, and molecular simulation reveals highly similar ternary structures. However, 2019-nCoV has a distinct loop with flexible glycyl residues replacing rigid prolyl residues in SARS-CoV. Molecular modeling revealed that 2019-nCoV RBD has a stronger interaction with angiotensin converting enzyme 2 (ACE2). A unique phenylalanine F486 in the flexible loop likely plays a major role because its penetration into a deep hydrophobic pocket in ACE2. ACE2 is widely expressed with conserved primary structures throughout the animal kingdom from fish, amphibians, reptiles, birds, to mammals. Structural analysis suggests that ACE2 from these animals can potentially bind RBD of 2019-nCoV, making them all possible natural hosts for the virus. 2019-nCoV is thought to be transmitted through respiratory droplets. However, since ACE2 is predominantly expressed in intestines, testis, and kidney, fecal-oral and other routes of transmission are also possible. Finally, antibodies and small molecular inhibitors that can block the interaction of ACE2 with RBD should be developed to combat the virus.
647zcjgu
647zcjgu
2020-02-17
10.1016/j.bbrc.2020.02.071
1
Identification of neutralizing human monoclonal antibodies from Italian Covid-19 convalescent patients
In the absence of approved drugs or vaccines, there is a pressing need to develop tools for therapy and prevention of Covid-19. Human monoclonal antibodies have very good probability of being safe and effective tools for therapy and prevention of SARS-CoV-2 infection and disease. Here we describe the screening of PBMCs from seven people who survived Covid-19 infection to isolate human monoclonal antibodies against SARS-CoV-2. Over 1,100 memory B cells were single-cell sorted using the stabilized prefusion form of the spike protein and incubated for two weeks to allow natural production of antibodies. Supernatants from each cell were tested by ELISA for spike protein binding, and positive antibodies were further tested for neutralization of spike binding to receptor(s) on Vero E6 cells and for virus neutralization in vitro. From the 1,167 memory B specific for SARS-CoV-2, we recovered 318 B lymphocytes expressing human monoclonals recognizing the spike protein and 74 of these were able to inhibit the binding of the spike protein to the receptor. Finally, 17 mAbs were able to neutralize the virus when assessed for neutralization in vitro. Lead candidates to progress into the drug development pipeline will be selected from the panel of neutralizing antibodies identified with the procedure described in this study. One Sentence Summary Neutralizing human monoclonal antibodies isolated from Covid-19 convalescent patients for therapeutic and prophylactic interventions.
64y43o0y
64y43o0y
2020-05-09
10.1101/2020.05.05.078154
3
Receptor-binding domain of SARS-CoV spike protein induces long-term protective immunity in an animal model
Development of effective vaccines against severe acute respiratory syndrome (SARS) coronavirus (SARS-CoV) is still a priority in prevention of re-emergence of SARS. Our previous studies have shown that the receptor-binding domain (RBD) of SARS-CoV spike (S) protein elicits highly potent neutralizing antibody responses in the immunized animals. But it is unknown whether RBD can also induce protective immunity in an animal model, a key aspect for vaccine development. In this study, BALB/c mice were vaccinated intramuscularly (i.m.) with 10 μg of RBD-Fc (RBD fused with human IgG1 Fc) and boosted twice at 3-week intervals and one more time at 12th month. Humoral immune responses of vaccinated mice were investigated for up to 12 months at a 1-month interval and the neutralizing titers of produced antibodies were reported at months 0, 3, 6 and 12 post-vaccination. Mice were challenged with the homologous strain of SARS-CoV 5 days after the last boost, and sacrificed 5 days after the challenge. Mouse lung tissues were collected for detection of viral load, virus replication and histopathological effects. Our results showed that RBD-Fc vaccination induced high titer of S-specific antibodies with long-term and potent SARS-CoV neutralizing activity. Four of five vaccinated mice were protected from subsequent SARS-CoV challenge because no significant virus replication, and no obvious histopathological changes were found in the lung tissues of the vaccinated mice challenged with SARS-CoV. Only one vaccinated mouse had mild alveolar damage in the lung tissues. In contrast, high copies of SARS-CoV RNA and virus replication were detected, and pathological changes were observed in the lung tissues of the control mice. In conclusion, our findings suggest that RBD, which can induce protective antibodies to SARS-CoV, may be further developed as a safe and effective SARS subunit vaccine.
651uz4ev
651uz4ev
2007-04-12
10.1016/j.vaccine.2006.10.031
1.5
On predicting the novel COVID-19 human infections by using Infectious Disease modelling method in the Indian State of Tamil Nadu during 2020
Since the introduction of the novel Corona Virus (The COVID 19) to the Chinese city Wuhan in the Hubei province during the late December 2019, the effectiveness of the deadly disease, its human infection, spreading severity and the mortality rate of the infection has been an issue of debate. The outbreak of the virus along the time has become a massive threat to the global public health security and has been declared as a pandemic. Accounting the radical number of increases in the infected cases and the death due to COVID 19 infections around the globe, there is a need to predict the infections among the people by making proper optimization and using various Infectious Disease modelling (IDM) methods, in order to challenge the outcome. In comparison with previous diseases like SARS and Ebola viruses, the new corona virus (COVID 19) infections are infectious during the incubation period. In addition to that, naturally produced droplets from humans (e.g. droplets produced by breathing, talking, sneezing, coughing) and Person-to-person contact transmission are reported to be the foremost ways of transmission of novel corona virus. By considering the above two factors, a modified SEIR (Susceptibility Exposure Infection Recovery) method have been used for predicting the spread of the infections in the state of Tamil Nadu which is located in the southern part of India. Further, we have utilized the current surveillance data from Health and Family Welfare Department, Government of Tamil Nadu to accurately predict the spreading trend of the infection on a state level.
660ul4fb
660ul4fb
2020-04-07
10.1101/2020.04.05.20054593
1
Nelfinavir inhibits replication of severe acute respiratory syndrome coronavirus 2 in vitro
In December 2019, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged in Wuhan, Hubei Province, China. No specific treatment has been established against coronavirus disease-2019 (COVID-19) so far. Therefore, it is urgently needed to identify effective antiviral agents for the treatment of this disease, and several approved drugs such as lopinavir have been evaluated. Here, we report that nelfinavir, an HIV-1 protease inhibitor, potently inhibits replication of SARS-CoV-2. The effective concentrations for 50% and 90% inhibition (EC50 and EC90) of nelfinavir were 1.13 µM and 1.76 µM respectively, the lowest of the nine HIV-1 protease inhibitors including lopinavir. The trough and peak serum concentrations of nelfinavir were three to six times higher than EC50 of this drug. These results suggest that nelfinavir is a potential candidate drug for the treatment of COVID-19 and should be assessed in patients with COVID-19.
662pfa61
662pfa61
2020-04-08
10.1101/2020.04.06.026476
1
Truncated human angiotensin converting enzyme 2; a potential inhibitor of SARS-CoV-2 spike glycoprotein and potent COVID-19 therapeutic agent
The current pandemic of Covid-19 caused by SARS-CoV-2 is continued to spread globally and no potential drug or vaccine against it is available. Spike (S) glycoprotein is the structural protein of SARS-CoV-2 located on the envelope surface, involve in interaction with angiotensin converting enzyme 2 (ACE2), a cell surface receptor, followed by entry into the host cell. Thereby, blocking the S glycoprotein through potential inhibitor may interfere its interaction with ACE2 and impede its entry into the host cell. Here, we present a truncated version of human ACE2 (tACE2), comprising the N terminus region of the intact ACE2 from amino acid position 21-119, involved in binding with receptor binding domain (RBD) of SARS-CoV-2. We analyzed the in-silico potential of tACE2 to compete with intact ACE2 for binding with RBD. The protein-protein docking and molecular dynamic simulation showed that tACE2 has higher binding affinity for RBD and form more stabilized complex with RBD than the intact ACE2. Furthermore, prediction of tACE2 soluble expression in E. coli makes it a suitable candidate to be targeted for Covid-19 therapeutics. This is the first MD simulation based findings to provide a high affinity protein inhibitor for SARS-CoV-2 S glycoprotein, an important target for drug designing against this unprecedented challenge. Communicated by Ramaswamy H. Sarma
66qle52a
66qle52a
2020-05-20
10.1080/07391102.2020.1768150
4
Lack of Antiviral Activity of Darunavir against SARS-CoV-2
Given the high need and the absence of specific antivirals for treatment of COVID-19 (the disease caused by severe acute respiratory syndrome-associated coronavirus-2 [SARS-CoV-2]), human immunodeficiency virus (HIV) protease inhibitors are being considered as therapeutic alternatives. Prezcobix/Rezolsta is a fixed-dose combination of 800 mg of the HIV protease inhibitor darunavir (DRV) and 150 mg cobicistat, a CYP3A4 inhibitor, which is indicated in combination with other antiretroviral agents for the treatment of HIV infection. There are currently no definitive data on the safety and efficacy of DRV/cobicistat for treatment of COVID-19. The in vitro antiviral activity of darunavir against a clinical isolate from a patient infected with SARS-CoV-2 was assessed. DRV showed no activity against SARS-CoV-2 at clinically relevant concentrations (EC50 >100 μM). Remdesivir, used as a positive control, showed potent antiviral activity (EC50 = 0.38 μM). Overall, the data do not support the use of DRV for treatment of COVID-19.
679qfp2s
679qfp2s
2020-04-08
10.1101/2020.04.03.20052548
1.5
COVID-19, an emerging coronavirus infection: advances and prospects in designing and developing vaccines, immunotherapeutics, and therapeutics
The novel coronavirus infection (COVID-19 or Coronavirus disease 2019) that emerged from Wuhan, Hubei province of China has spread to many countries worldwide. Efforts have been made to develop vaccines against human coronavirus (CoV) infections such as MERS and SARS in the past decades. However, to date, no licensed antiviral treatment or vaccine exists for MERS and SARS. Most of the efforts for developing CoV vaccines and drugs target the spike glycoprotein or S protein, the major inducer of neutralizing antibodies. Although a few candidates have shown efficacy in in vitro studies, not many have progressed to randomized animal or human trials, hence may have limited use to counter COVID-19 infection. This article highlights ongoing advances in designing vaccines and therapeutics to counter COVID-19 while also focusing on such experiences and advances as made with earlier SARS- and MERS-CoVs, which together could enable efforts to halt this emerging virus infection.
68sbqdi3
68sbqdi3
2020-03-18
10.1080/21645515.2020.1735227
0.5
Candidate drugs against SARS-CoV-2 and COVID-19
Outbreak and pandemic of coronavirus SARS-CoV-2 in 2019/2020 will challenge global health for the future. Because a vaccine against the virus will not be available in the near future, we herein try to offer a pharmacological strategy to combat the virus. There exists a number of candidate drugs that may inhibit infection with and replication of SARS-CoV-2. Such drugs comprise inhibitors of TMPRSS2 serine protease and inhibitors of angiotensin-converting enzyme 2 (ACE2). Blockade of ACE2, the host cell receptor for the S protein of SARS-CoV-2 and inhibition of TMPRSS2, which is required for S protein priming may prevent cell entry of SARS-CoV-2. Further, chloroquine and hydroxychloroquine, and off-label antiviral drugs, such as the nucleotide analogue remdesivir, HIV protease inhibitors lopinavir and ritonavir, broad-spectrum antiviral drugs arbidol and favipiravir as well as antiviral phytochemicals available to date may limit spread of SARS-CoV-2 and morbidity and mortality of COVID-19 pandemic.
68wbeol7
68wbeol7
2020
3
Ontology-based systematic classification and analysis of coronaviruses, hosts, and host-coronavirus interactions towards deep understanding of COVID-19
Given the existing COVID-19 pandemic worldwide, it is critical to systematically study the interactions between hosts and coronaviruses including SARS-Cov, MERS-Cov, and SARS-CoV-2 (cause of COVID-19). We first created four host-pathogen interaction (HPI)-Outcome postulates, and generated a HPI-Outcome model as the basis for understanding host-coronavirus interactions (HCI) and their relations with the disease outcomes. We hypothesized that ontology can be used as an integrative platform to classify and analyze HCI and disease outcomes. Accordingly, we annotated and categorized different coronaviruses, hosts, and phenotypes using ontologies and identified their relations. Various COVID-19 phenotypes are hypothesized to be caused by the backend HCI mechanisms. To further identify the causal HCI-outcome relations, we collected 35 experimentally-verified HCI protein-protein interactions (PPIs), and applied literature mining to identify additional host PPIs in response to coronavirus infections. The results were formulated in a logical ontology representation for integrative HCI-outcome understanding. Using known PPIs as baits, we also developed and applied a domain-inferred prediction method to predict new PPIs and identified their pathological targets on multiple organs. Overall, our proposed ontology-based integrative framework combined with computational predictions can be used to support fundamental understanding of the intricate interactions between human patients and coronaviruses (including SARS-CoV-2) and their association with various disease outcomes.
6a4ds69d
6a4ds69d
2020-05-31
4.5
Limitations of Animal Studies for Predicting Toxicity in Clinical Trials: Part 2: Potential Alternatives to the Use of Animals in Preclinical Trials
Dramatically rising costs in drug development are in large part because of the high failure rates in clinical phase trials. The poor correlation of animal studies to human toxicity and efficacy have led many developers to question the value of requiring animal studies in determining which drugs should enter in-human trials. Part 1 of this 2-part series examined some of the data regarding the lack of concordance between animal toxicity studies and human trials, as well as some of the potential reasons behind it. This second part of the series focuses on some alternatives to animal trials (hereafter referred to as animal research) as well as current regulatory discussions and developments regarding such alternatives.
6aouw8sb
6aouw8sb
2020-04-27
10.1016/j.jacbts.2020.03.010
2
Demand for Nonhuman Primate Resources in the Age of Biodefense
The demand for nonhuman primates will undoubtedly increase to meet biomedical needs in this current age of biodefense. The availability of funding has increased the research on select agents and has created a requirement to validate results in relevant primate models. This review provides a description of current and potential biological threats that are likely to require nonhuman primates for the development of vaccines and therapeutics. Primates have been an invaluable resource in the dissection of viral disease pathogenesis as well as in testing vaccine efficacy. DNA vaccine approaches have been studied successfully for Ebola, Lassa, and anthrax in nonhuman primate models. Nonhuman primate research with monkeypox has provided insight into the role of cytokines in limiting disease severity. Biodefense research that has focused on select agents of bacterial origin has also benefited from nonhuman primate studies. Rhesus macaques have traditionally been the model of choice for anthrax research and have yielded successful findings in vaccine development. In plague research, African green monkeys have contributed to vaccine development. However, the disadvantages of current vaccines will undoubtedly require the generation of new vaccines, thus increasing the need for nonhuman primate research. Unfortunately, the current biosafety level (BSL)-3 and BSL-4 facilities equipped to perform this research are limited, which may ultimately impede progress in this era of biodefense.
6c1rnou3
6c1rnou3
2005-01-01
10.1093/ilar.46.1.15
1.5
Recent progress and challenges in drug development against COVID-19 coronavirus (SARS-CoV-2) - an update on the status
Abstract Coronaviruses are a large group of viruses known to cause illnesses that vary between the common cold and more severe diseases to include severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS). A novel coronavirus was identified in December 2019 in Wuhan city, Hubei province, China. This virus represents a new strain that has not been previously identified in humans. The virus is now known as the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and the resulting disease is called coronavirus disease 2019 (COVID-19). The World Health Organization (WHO) declared the novel coronavirus outbreak a global pandemic in March 2020. Despite rigorous global containment and quarantine efforts, the incidence of COVID-19 continues to rise, with more than 1,948,617 laboratory-confirmed cases and over 121,846 deaths worldwide. Currently, no specific medication is recommended to treat COVID-19 patients. However, governments and pharmaceutical companies are struggling to quickly find an effective drug to defeat the coronavirus. In the current review, we summarize the existing state of knowledge about COVID-19, available medications, and treatment options. Favilavir is an antiviral drug that is approved in Japan for common influenza treatment and is now approved to treat symptoms of COVID-19 in China. Moreover, Chloroquine and hydroxychloroquine, drugs used to treat malaria and arthritis, respectively, were recommended by the National Health Commission of the People's Republic of China for treatment of COVID-19. Presently, chloroquine and hydroxychloroquine are under investigation by the US Food and Drug Administration (FDA) as a treatment for COVID-19. The first COVID-19 vaccine is not expected to be ready for clinical trials before the end of the year.
6dq8xx7c
6dq8xx7c
2020-04-19
10.1016/j.meegid.2020.104327
2
Coronavirus Susceptibility to the Antiviral Remdesivir (GS-5734) Is Mediated by the Viral Polymerase and the Proofreading Exoribonuclease
Emerging coronaviruses (CoVs) cause severe disease in humans, but no approved therapeutics are available. The CoV nsp14 exoribonuclease (ExoN) has complicated development of antiviral nucleosides due to its proofreading activity. We recently reported that the nucleoside analogue GS-5734 (remdesivir) potently inhibits human and zoonotic CoVs in vitro and in a severe acute respiratory syndrome coronavirus (SARS-CoV) mouse model. However, studies with GS-5734 have not reported resistance associated with GS-5734, nor do we understand the action of GS-5734 in wild-type (WT) proofreading CoVs. Here, we show that GS-5734 inhibits murine hepatitis virus (MHV) with similar 50% effective concentration values (EC(50)) as SARS-CoV and Middle East respiratory syndrome coronavirus (MERS-CoV). Passage of WT MHV in the presence of the GS-5734 parent nucleoside selected two mutations in the nsp12 polymerase at residues conserved across all CoVs that conferred up to 5.6-fold resistance to GS-5734, as determined by EC(50). The resistant viruses were unable to compete with WT in direct coinfection passage in the absence of GS-5734. Introduction of the MHV resistance mutations into SARS-CoV resulted in the same in vitro resistance phenotype and attenuated SARS-CoV pathogenesis in a mouse model. Finally, we demonstrate that an MHV mutant lacking ExoN proofreading was significantly more sensitive to GS-5734. Combined, the results indicate that GS-5734 interferes with the nsp12 polymerase even in the setting of intact ExoN proofreading activity and that resistance can be overcome with increased, nontoxic concentrations of GS-5734, further supporting the development of GS-5734 as a broad-spectrum therapeutic to protect against contemporary and emerging CoVs.
6dqy7tzc
6dqy7tzc
2018-03-06
10.1128/mbio.00221-18
2
Should RT-PCR be considered a gold standard in the diagnosis of Covid-19?
To face the new Covid-19 pandemic, the need for early and accurate diagnosis of the disease among suspected cases quickly became obvious for effective management, and for better control of the spread of the disease in the population. Since the beginning of this disease epidemic caused by the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), reverse transcriptase polymerase chain reaction (RT-PCR) has routinely been used to confirm diagnosis. However, several authors have pointed out the poor performance of this technique, particularly in terms of sensitivity.1,2 This article is protected by copyright. All rights reserved.
6e9i4su7
6e9i4su7
2020
3
Renin-angiotensin-aldosterone system and COVID-19 infection
Abstract With the multiplication of COVID-19 severe acute respiratory syndrome cases due to SARS COV2, some concerns about angiotensin-converting enzyme 1 (ACE1) inhibitors (ACEi) and angiotensin II type 1 receptor blockers (ARB) have emerged. Because the ACE2 (angiotensin-converting enzyme 2) enzyme is the receptor that allows SARS COV2 entry into cells, the fear was that pre-existing treatment with ACEi or ARB might increase the risk of developing severe or fatal severe acute respiratory syndrome in case of COVID-19 infection. The present article discusses these concerns. ACE2 is a membrane-bound enzyme (carboxypeptidase) that contributes to the inactivation of angiotensin II and therefore physiologically counters angiotensin II effects. ACEis do not inhibit ACE2. Although ARBs have been shown to upregulate ACE2 tissue expression in experimental animals, evidence was not always consistent in human studies. Moreover, to date there is no evidence that ACEi or ARB administration facilitates SARS COV2 cell entry by increasing ACE2 tissue expression in either animal or human studies. Finally, some studies support the hypothesis that elevated ACE2 membrane expression and tissue activity by administration of ARB and/or infusion of soluble ACE2 could confer protective properties against inflammatory tissue damage in COVID-19 infection. In summary, based on the currently available evidence and as advocated by many medical societies, ACEi or ARB should not be discontinued because of concerns with COVID-19 infection, except when the hemodynamic situation is precarious and case-by-case adjustment is required.
6eggfavx
6eggfavx
2020-04-21
10.1016/j.ando.2020.04.005
2
Modeling Tempo of COVID-19 Pandemic in India and Significance of Lockdown
A very special type of pneumonic disease that generated the COVID-19 pandemic was first identified in Wuhan, China in December 2019 and is spreading all over the world. The ongoing outbreak presents a challenge for data scientists to model COVID-19, when the epidemiological characteristics of the COVID-19 are yet to be fully explained. The uncertainty around the COVID-19 with no vaccine and effective medicine available until today create additional pressure on the epidemiologists and policy makers. In such a crucial situation, it is very important to predict infected cases to support prevention of the disease and aid in the preparation of healthcare service. In this paper, we have tried to understand the spreading capability of COVID-19 in India taking into account of the lockdown period. The numbers of confirmed cases are increased in India and states in the past few weeks. A differential equation based simple model has been used to understand the pattern of COVID-19 in India and some states. Our findings suggest that the physical distancing and lockdown strategies implemented in India are successfully reducing the spread and that the tempo of pandemic growth has slowed in recent days.
6f3up1h0
6f3up1h0
2020-05-16
10.1101/2020.05.15.20103325
3
Susceptibility to SARS coronavirus S protein-driven infection correlates with expression of angiotensin converting enzyme 2 and infection can be blocked by soluble receptor
Abstract The angiotensin converting enzyme 2 (ACE2) has been identified as a receptor for the severe acute respiratory syndrome associated coronavirus (SARS-CoV). Here we show that ACE2 expression on cell lines correlates with susceptibility to SARS-CoV S-driven infection, suggesting that ACE2 is a major receptor for SARS-CoV. The soluble ectodomain of ACE2 specifically abrogated S-mediated infection and might therefore be exploited for the generation of inhibitors. Deletion of a major portion of the cytoplasmic domain of ACE2 had no effect on S-driven infection, indicating that this domain is not important for receptor function. Our results point to a central role of ACE2 in SARS-CoV infection and suggest a minor contribution of the cytoplasmic domain to receptor function.
6fq07ifm
6fq07ifm
2004-07-09
10.1016/j.bbrc.2004.05.114
2.5
Meplazumab treats COVID-19 pneumonia: an open-labelled, concurrent controlled add-on clinical trial
Background: SARS-CoV-2 is a novel human coronavirus, there is no specific antiviral drugs. It has been proved that host-cell-expressed CD147 could bind spike protein of SARS-CoV-2 and involve in host cell invasion. Antibody against CD147 could block the infection of SARS-CoV-2. We aimed to assess the efficacy and safety of meplazumab, a humanized anti-CD147 antibody, as add-on therapy in patients with COVID-19 pneumonia. Methods: All patients received recommended strategy from Diagnosis and Treatment for 2019 Novel Coronavirus Diseases released by National Health Commission of China. Eligible patients were add-on administered 10 mg meplazumab intravenously at days 1, 2, and 5. Patients hospitalized in the same period were observed as concurrent control. The endpoints include virological clearance rate, case severity, chest radiographic, and laboratory test. This trial was approved by the Ethics Committee of Institution at the Tangdu hospital, and registered with ClinicalTrials.gov, NCT 04275245. Findings:17 patients were enrolled and assigned to meplazumab group between Feb 3, 2020 and Feb 10, 2020. 11 hospitalized patients served as concurrent control. Baseline characteristics were generally balanced across two groups. Compared to control group, meplazumab treatment significantly improved the discharged (p=0.006) and case severity (p=0.021) in critical and severe patients. The time to virus negative in meplazumab group was reduced than that in control group (median 3, 95%CI[1.5-4.5] vs. 13, [6.5-19.5]; p=0.014, HR=0.37, 95%CI[0.155-0.833]). The percentages of patients recovered to the normal lymphocyte count and CRP concentration were also increased remarkably and rapidly in meplazumab group. No adverse effect was found in meplazumab-treated patients. Interpretation:Meplazumab efficiently improved the recovery of patients with SARS-CoV-2 pneumonia with a favorable safety profile. Our results support to carry out a large-scale investigation of meplazumab as a treatment for COVID-19 pneumonia. Funding:National Science and Technology Major Project.
6g34qwer
6g34qwer
2020-03-24
10.1101/2020.03.21.20040691
1.5
A SARS-CoV-2 serological assay to determine the presence of blocking antibodies that compete for human ACE2 binding
As SARS-CoV-2 continues to spread around the world, there is an urgent need for new assay formats to characterize the humoral response to infection. Convalescent serum is being used for treatment and for isolation of patient-derived antibodies. However, currently there is not a simple means to estimate serum bulk neutralizing capability. Here we present an efficient competitive serological assay that can simultaneously determine an individual’s seropositivity against the SARS-CoV-2 Spike protein and estimate the neutralizing capacity of anti-Spike antibodies to block interaction with the human angiotensin converting enzyme 2 (ACE2) required for viral entry. In this ELISA-based assay, we present natively-folded viral Spike protein receptor binding domain (RBD)-containing antigens via avidin-biotin interactions. Sera are then supplemented with soluble ACE2-Fc to compete for RBD-binding serum antibodies, and antibody binding quantified. Comparison of signal from untreated serum and ACE2-Fc-treated serum reveals the presence of antibodies that compete with ACE2 for RBD binding, as evidenced by loss of signal with ACE2-Fc treatment. In our test cohort of nine convalescent SARS-CoV-2 patients, we found all patients had developed anti-RBD antibodies targeting the epitope responsible for ACE2 engagement. This assay provides a simple and high-throughput method to screen patient sera for potentially neutralizing anti-Spike antibodies to enable identification of candidate sera for therapeutic use.
6gshvem8
6gshvem8
2020-05-29
10.1101/2020.05.27.20114652
4.5
Prise en charge des cancers du sein pendant la pandémie de COVID 19 : le CNGOF se mobilise
6hyrcq7y
6hyrcq7y
2020-04-18
10.1016/j.gofs.2020.04.009
3.5
Development of a Dose‐Response Model for SARS Coronavirus
In order to develop a dose‐response model for SARS coronavirus (SARS‐CoV), the pooled data sets for infection of transgenic mice susceptible to SARS‐CoV and infection of mice with murine hepatitis virus strain 1, which may be a clinically relevant model of SARS, were fit to beta‐Poisson and exponential models with the maximum likelihood method. The exponential model (k= 4.1 × l0(2)) could describe the dose‐response relationship of the pooled data sets. The beta‐Poisson model did not provide a statistically significant improvement in fit. With the exponential model, the infectivity of SARS‐CoV was calculated and compared with those of other coronaviruses. The does of SARS‐CoV corresponding to 10% and 50% responses (illness) were estimated at 43 and 280 PFU, respectively. Its estimated infectivity was comparable to that of HCoV‐229E, known as an agent of human common cold, and also similar to those of some animal coronaviruses belonging to the same genetic group. Moreover, the exponential model was applied to the analysis of the epidemiological data of SARS outbreak that occurred at an apartment complex in Hong Kong in 2003. The estimated dose of SARS‐CoV for apartment residents during the outbreak, which was back‐calculated from the reported number of cases, ranged from 16 to 160 PFU/person, depending on the floor. The exponential model developed here is the sole dose‐response model for SARS‐CoV at the present and would enable us to understand the possibility for reemergence of SARS.
6izmhty0
6izmhty0
2010-05-20
10.1111/j.1539-6924.2010.01427.x
2
Cinanserin is an inhibitor of the 3C-like proteinase of severe acute respiratory syndrome coronavirus and strongly reduces virus replication in vitro.
The 3C-like proteinase (3CLpro) of severe acute respiratory syndrome-associated coronavirus (SARS-CoV) is one of the most promising targets for anti-SARS-CoV drugs due to its crucial role in the viral life cycle. In this study, a database containing structural information of more than 8,000 existing drugs was virtually screened by a docking approach to identify potential binding molecules of SARS-CoV 3CLpro. As a target for screening, both a homology model and the crystallographic structure of the binding pocket of the enzyme were used. Cinanserin (SQ 10,643), a well-characterized serotonin antagonist that has undergone preliminary clinical testing in humans in the 1960s, showed a high score in the screening and was chosen for further experimental evaluation. Binding of both cinanserin and its hydrochloride to bacterially expressed 3CLpro of SARS-CoV and the related human coronavirus 229E (HCoV-229E) was demonstrated by surface plasmon resonance technology. The catalytic activity of both enzymes was inhibited with 50% inhibitory concentration (IC50) values of 5 microM, as tested with a fluorogenic substrate. The antiviral activity of cinanserin was further evaluated in tissue culture assays, namely, a replicon system based on HCoV-229E and quantitative test assays with infectious SARS-CoV and HCoV-229E. All assays revealed a strong inhibition of coronavirus replication at nontoxic drug concentrations. The level of virus RNA and infectious particles was reduced by up to 4 log units, with IC50 values ranging from 19 to 34 microM. These findings demonstrate that the old drug cinanserin is an inhibitor of SARS-CoV replication, acting most likely via inhibition of the 3CL proteinase.
6kiiluon
6kiiluon
2005
3
Rapid Detection of Novel Coronavirus (COVID-19) by Reverse Transcription-Loop-Mediated Isothermal Amplification
Novel Corona virus (COVID-19 or 2019-nCoV) is an emerging global health concern that requires a rapid diagnostic test. Quantitative reverse transcription PCR (qRT-PCR) is currently the standard for COVID-19 detection; however, Reverse Transcription Loop-Mediated Isothermal Amplification (RT-LAMP) may allow for faster and cheaper field based testing at point-of-risk. The objective of this study was to develop a rapid screening diagnostic test that could be completed in under 30 minutes. Simulated patient samples were generated by spiking serum, urine, saliva, oropharyngeal swabs, and nasopharyngeal swabs with a portion of the COVID-19 nucleic sequence. The samples were tested using RT-LAMP as well as by conventional qRT-PCR. Specificity of the RT-LAMP was evaluated by also testing against other related coronaviruses. RT-LAMP specifically detected COVID-19 in simulated patient samples. This test was performed in under 30 minutes. This approach could be used for monitoring of exposed individuals or potentially aid with screening efforts in the field and potential ports of entry.
6kpgt70s
6kpgt70s
2020-02-24
10.1101/2020.02.19.20025155
1
Enhancement of the infectivity of SARS-CoV in BALB/c mice by IMP dehydrogenase inhibitors, including ribavirin
Abstract Because of the conflicting data concerning the SARS-CoV inhibitory efficacy of ribavirin, an inosine monophosphate (IMP) dehydrogenase inhibitor, studies were done to evaluate the efficacy of ribavirin and other IMP dehydrogenase inhibitors (5-ethynyl-1-β-d-ribofuranosylimidazole-4-carboxamide (EICAR), mizoribine, and mycophenolic acid) in preventing viral replication in the lungs of BALB/c mice, a replication model for severe acute respiratory syndrome (SARS) infections (Subbarao, K., McAuliffe, J., Vogel, L., Fahle, G., Fischer, S., Tatti, K., Packard, M., Shieh, W.J., Zaki, S., Murphy, B., 2004. Prior infection and passive transfer of neutralizing antibody prevent replication of severe acute respiratory syndrome coronavirus (SARS-CoV) in the respiratory tract of mice. J. Virol. 78, 3572–3577). Ribavirin given at 75mg/kg 4h prior to virus exposure and then given twice daily for 3 days beginning at day 0 was found to increase virus lung titers and extend the length of time that virus could be detected in the lungs of mice. Other IMP dehydrogenase inhibitors administered near maximum tolerated doses using the same dosing regimen as for ribavirin were found to slightly enhance virus replication in the lungs. In addition, ribavirin treatment seemed also to promote the production of pro-inflammatory cytokines 4 days after cessation of treatment, although after 3 days of treatment ribavirin inhibited pro-inflammatory cytokine production in infected mice, significantly reducing the levels of the cytokines IL-1α, interleukin-5 (IL-5), monocyte chemotactic protein-1 (MCP-1), and granulocyte-macrophage colony stimulating factor (GM-CSF). These findings suggest that ribavirin may actually contribute to the pathogenesis of SARS-CoV by prolonging and/or enhancing viral replication in the lungs. By not inhibiting viral replication in the lungs of infected mice, ribavirin treatment may have provided a continual source of stimulation for the inflammatory response thought to contribute to the pathogenesis of the infection. Our data do not support the use of ribavirin or other IMP dehydrogenase inhibitors for treating SARS infections in humans.
6l87y6jg
6l87y6jg
2006-08-31
10.1016/j.antiviral.2006.03.001
4
NIAID resources for developing new therapies for severe viral infections
Abstract Severe viral infections, including hemorrhagic fever and encephalitis, occur throughout the world, but are most prevalent in developing areas that are most vulnerable to infectious diseases. Some of these can also infect related species as illustrated by the threatened extinction of gorillas by Ebola infection in west and central Africa. There are no safe and effective treatments available for these serious infections. In addition to the logistical difficulties inherent in developing a drug for infections that are sporadic and occur mainly in the third world, there is the overwhelming barrier of no hope for return on investment to encourage the pharmaceutical industry to address these unmet medical needs. Therefore, the National Institute of Allergy and infectious Disease (NIAID) has developed and supported a variety of programs and resources to provide assistance and lower the barrier for those who undertake these difficult challenges. The primary programs relevant to the development of therapies for severe viral infections are described and three case studies illustrate how they have been used. In addition, contact information for accessing these resources is supplied.
6lh4jsor
6lh4jsor
2008-04-30
10.1016/j.antiviral.2007.10.006
1.5
In silico studies on therapeutic agents for COVID-19: Drug repurposing approach
Abstract Aims The severe acute respiratory syndrome coronavirus 2, better known as COVID-19 has become the current health concern to the entire world. Initially appeared in Wuhan, China around December 2019, it had spread to almost 187 countries due to its high contagious nature. Precautionary measures remain the sole obliging tactic to cease the person to person transmissions till any effective method of treatment or vaccine is developed. Amidst the pandemic, research and development of new molecule is labour-intensive and tedious process. Drug repurposing is the concept of identifying therapeutically potent molecule from the library of pre-existing molecules. Materials and methods In the present study, 61 molecules that are already being used in clinics or under clinical scrutiny as antiviral agents are surveyed via docking study. Docking study was performed using Maestro interface (Schrödinger Suite, LLC, NY). Key findings Out of these 61 molecules, 37 molecules were found to interact with >2 protein structures of COVID-19. The docking results indicate that amongst the reported molecules, HIV protease inhibitors and RNA-dependent RNA polymerase inhibitors showed promising features of binding to COVID-19 enzyme. Along with these, Methisazone an inhibitor of protein synthesis, CGP42112A an angiotensin AT2 receptor agonist and ABT450 an inhibitor of the non-structural protein 3-4A might become convenient treatment option as well against COVID-19. Significance The drug repurposing approach provide an insight about the therapeutics that might be helpful in treating corona virus disease.
6mqg4nb5
6mqg4nb5
2020-07-01
10.1016/j.lfs.2020.117652
3.5
Structural and Functional Basis of SARS-CoV-2 Entry by Using Human ACE2
The recent emergence of a novel coronavirus (SARS-CoV-2) in China has caused significant public health concerns. Recently, ACE2 was reported as an entry receptor for SARS-CoV-2. In this study, we present the crystal structure of the C-terminal domain of SARS-CoV-2 (SARS-CoV-2-CTD) spike (S) protein in complex with human ACE2 (hACE2), which reveals a hACE2-binding mode similar overall to that observed for SARS-CoV. However, atomic details at the binding interface demonstrate that key residue substitutions in SARS-CoV-2-CTD slightly strengthen the interaction and lead to higher affinity for receptor binding than SARS-RBD. Additionally, a panel of murine monoclonal antibodies (mAbs) and polyclonal antibodies (pAbs) against SARS-CoV-S1/receptor-binding domain (RBD) were unable to interact with the SARS-CoV-2 S protein, indicating notable differences in antigenicity between SARS-CoV and SARS-CoV-2. These findings shed light on the viral pathogenesis and provide important structural information regarding development of therapeutic countermeasures against the emerging virus.
6nd9fmz3
6nd9fmz3
2020-04-09
10.1016/j.cell.2020.03.045
2
Broad Host Range of SARS-CoV-2 Predicted by Comparative and Structural Analysis of ACE2 in Vertebrates
The novel coronavirus SARS-CoV-2 is the cause of Coronavirus Disease-2019 (COVID-19). The main receptor of SARS-CoV-2, angiotensin I converting enzyme 2 (ACE2), is now undergoing extensive scrutiny to understand the routes of transmission and sensitivity in different species. Here, we utilized a unique dataset of 410 vertebrates, including 252 mammals, to study cross-species conservation of ACE2 and its likelihood to function as a SARS-CoV-2 receptor. We designed a five-category ranking score based on the conservation properties of 25 amino acids important for the binding between receptor and virus, classifying all species from very high to very low. Only mammals fell into the medium to very high categories, and only catarrhine primates in the very high category, suggesting that they are at high risk for SARS-CoV-2 infection. We employed a protein structural analysis to qualitatively assess whether amino acid changes at variable residues would be likely to disrupt ACE2/SARS-CoV-2 binding, and found the number of predicted unfavorable changes significantly correlated with the binding score. Extending this analysis to human population data, we found only rare (<0.1%) variants in 10/25 binding sites. In addition, we observed evidence of positive selection in ACE2 in multiple species, including bats. Utilized appropriately, our results may lead to the identification of intermediate host species for SARS-CoV-2, justify the selection of animal models of COVID-19, and assist the conservation of animals both in native habitats and in human care.
6ne76rh1
6ne76rh1
2020-04-18
10.1101/2020.04.16.045302
2
Structure Basis for Inhibition of SARS-CoV-2 by the Feline Drug GC376
The pandemic of SARS-CoV-2 coronavirus disease-2019 (COVID-19) caused by SARS-COV-2 continues to ravage many countries in the world. Mpro is an indispensable protein for viral translation in SARS-CoV-2 and a potential target in high-specificity anti-SARS-CoV-2 drug screening. In this study, to explore potential drugs for treating COVID-19, we elucidated the structure of SARS-CoV-2 Mpro and explored the interaction between Mpro and GC376, an antiviral drug used to treat a range of coronaviruses in Feline via inhibiting Mpro. The availability and safety of GC376 were proved by biochemical and cell experiments in vitro. We determined the structure of an important protein, Mpro, in SARS-CoV-2, and revealed the interaction of GC376 with the viral substrate and inhibition of the catalytic site of SARS-CoV-2 Mpro.
6nh28ntv
6nh28ntv
2020-06-08
10.1101/2020.06.07.138677
5
Cholesterol-modifying drugs in COVID-19
Infection with SARS-CoV-2 is more likely to lead to poor outcomes in the elderly and those with cardiovascular disease, obesity or metabolic syndrome. Here we consider mechanisms by which dyslipidemia and the use of cholesterol-modifying drugs could influence the virus-host relationship. Cholesterol is essential for the assembly, replication and infectivity of enveloped virus particles; we highlight several cholesterol-modifying drugs with the potential to alter the SARS-CoV-2 life cycle that could be tested in in vitro and in vivo models. Although cholesterol is an essential component of immune cell membranes, excess levels can dysregulate protective immunity and promote exaggerated pulmonary and systemic inflammatory responses. Statins block the production of multiple sterols, oxysterols and isoprenoids, resulting in a pleotropic range of context-dependent effects on virus infectivity, immunity and inflammation. We highlight antiviral, immunomodulatory and anti-inflammatory effects of cholesterol-modifying drugs that merit further consideration in the management of SARS-CoV-2 infection.
6p7ve23b
6p7ve23b
2020-06-18
10.1093/oxfimm/iqaa001
5
The search for a structural basis for therapeutic intervention against the SARS coronavirus
The 2003 outbreak of severe acute respiratory syndrome (SARS), caused by a previously unknown coronavirus called SARS‐CoV, had profound social and economic impacts worldwide. Since then, structure–function studies of SARS‐CoV proteins have provided a wealth of information that increases our understanding of the underlying mechanisms of SARS. While no effective therapy is currently available, considerable efforts have been made to develop vaccines and drugs to prevent SARS‐CoV infection. In this review, some of the notable achievements made by SARS structural biology projects worldwide are examined and strategies for therapeutic intervention are discussed based on available SARS‐CoV protein structures. To date, 12 structures have been determined by X‐ray crystallography or NMR from the 28 proteins encoded by SARS‐CoV. One key protein, the SARS‐CoV main protease (M (pro)), has been the focus of considerable structure‐based drug discovery efforts. This article highlights the importance of structural biology and shows that structures for drug design can be rapidly determined in the event of an emerging infectious disease.
6q9h5rpb
6q9h5rpb
2008-01-10
10.1107/s0108767307054426
2
Establishment of an African green monkey model for COVID-19
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is responsible for an unprecedented global pandemic of COVID-19. Animal models are urgently needed to study the pathogenesis of COVID-19 and to screen candidate vaccines and treatments. Nonhuman primates (NHP) are considered the gold standard model for many infectious pathogens as they usually best reflect the human condition. Here, we show that African green monkeys support a high level of SARS-CoV-2 replication and develop pronounced respiratory disease that may be more substantial than reported for other NHP species including cynomolgus and rhesus macaques. In addition, SARS-CoV-2 was detected in mucosal samples of all animals including feces of several animals as late as 15 days after virus exposure. Importantly, we show that virus replication and respiratory disease can be produced in African green monkeys using a much lower and more natural dose of SARS-CoV-2 than has been employed in other NHP studies.
6qavhrob
6qavhrob
2020-05-17
10.1101/2020.05.17.100289
4
SARS-CoV-2 SPIKE PROTEIN: an optimal immunological target for vaccines
COVID-19 has rapidly spread all over the world, progressing into a pandemic. This situation has urgently impelled many companies and public research institutes to concentrate their efforts on research for effective therapeutics. Here, we outline the strategies and targets currently adopted in developing a vaccine against SARS-CoV-2. Based on previous evidence and experience with SARS and MERS, the primary focus has been the Spike protein, considered as the ideal target for COVID-19 immunotherapies.
6rqmc89u
6rqmc89u
2020-06-03
10.1186/s12967-020-02392-y
4
Potential therapeutic targets for combating SARS-CoV-2: Drug repurposing, clinical trials and recent advancements
The present pandemic of SARS-CoV-2 has been a tough task for the whole world to deal with. With the absence of specific drugs or vaccines against SARS-CoV-2, the situation is very difficult to control. Apart from the absence of specific therapies, the lack of knowledge about potential therapeutic targets and individual perception is adding to the complications. The present review describes the novel SARS-CoV-2 structure, surface proteins, asymptomatic and symptomatic transmission in addition to the genotype and phenotype of SARS-CoV-2 along with genetic strains and similarity between SARS, MERS and SARS-CoV-2. Therapeutic strategies such as inhibition of the endocytic pathway and suppressing RNA polymerase activity by metal ions, which could be quite beneficial for controlling COVID-19, are outlined. The drug repurposing for SARS-CoV-2 is discussed in detail along with therapeutic classes such as antivirals, antibiotics, and amino quinolones and their probable role in suppressing SARS-CoV-2 with reference to case studies. The ongoing clinical trials both with respect to drug repurposing and vaccines are summarized along with a brief description. The recent advancements and future perspective of ongoing research for therapy and detection of SARS-CoV-2 are provided. The review, in brief, summarizes epidemiology, therapy and the current scenario for combating SARS-CoV-2.
6sdutr03
6sdutr03
2020-06-01
10.1016/j.lfs.2020.117883
4.5
Coronavirus as silent killer: recent advancement to pathogenesis, therapeutic strategy and future perspectives
The present outbreak associated with corona virus [CoVs] in China which is believed to be one of the massive eruptions towards mankind in 2019–2020. In the present scenario CoVs has been transmitted to the European and American regions through the travellers from wide spread countries like China and Japan. The viral disease is spreading through the contact in any form by the infected persons or patients and creating huge risk of mortality. CoVs are a single positive-sense RNA virus; mutation rates are higher than DNA viruses and indicate a more effective survival adaption mechanism. Human CoVs can cause common cold and influenza-like illness and a variety of severe acute respiratory disease such as pneumonia. Early in infection, CoVs infects epithelial cells, macrophages, T-cells, dendritic cells and also can affect the development and implantation of pro-inflammatory cytokines and chemokines. It mainly produces the melanoma differentiation associated with protein-5, retinoic acid inducible gene-1 and endosomal toll-like receptor 3. How CoVs affects the function of the immune system is still unclear due to lack of this knowledge. No Food and Drug Administration approved treatment is available till date. In this review, we are tried to explore the epidemiology, pathogenesis and current treatment of CoVs infection. The promising therapeutics molecules against CoVs and future prospective have been also discussed which will be helpful for researchers to find out the new molecules for the treatment of CoVs disease.
6tcho8u0
6tcho8u0
2020-04-20
10.1007/s13337-020-00580-4
4.5
Gastro-entérites virales des animaux domestiques et zoonoses
SUMMARY Etiologic investigations of infectious diarrhea were long limited to bacteria and protozoa. The advent of electron microscopy and molecular biology showed that diarrhea could also be caused by viruses, both in humans and in other animals. In 1969, electron microcopy was used to show, for the first time, the responsibility of a virus in a case of calf diarrhea. This “ reo-like virus ” was subsequently identified as a rotavirus, and was shown only four years later to be responsible for severe diarrhea in young children. Noroviruses, and particularly the human virus Norwalk, were subsequently discovered, followed by coronavirus, sapovirus, pestivirus, astrovirus, enteric adenoviruses, torovirus, and picobirnavirus. Some of viruses found in animals, and particularly rotaviruses, can also infect humans. Rotaviruses have been identified in numerous animal species and are generally host-specific, but zoonotic transmission has been suggested by cross-infection (especially in experimental models), by genetic studies showing a close relationship between certain human and animal rotaviruses, and by the discovery of new animal genotypes during epidemiological surveillance of human rotaviroses. Some animal strains of norovirus, sapovirus, picobirnavirus and astrovirus are genetically related to human strains, but their human transmission has not been demonstrated.
6tyda5p4
6tyda5p4
2010-11-30
10.1016/s0001-4079(19)32174-0
1.5
Interactions of coronaviruses with ACE2, angiotensin II, and RAS inhibitors—lessons from available evidence and insights into COVID-19
The rapid spread of a novel coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has led to an ongoing pandemic of coronavirus disease 2019 (COVID-19). Recently, angiotensin-converting enzyme 2 (ACE2) has been shown to be a functional receptor for SARS-CoV-2 to enter host target cells. Given that angiotensin receptor blockers (ARBs) and an ACE inhibitor (ACEI) upregulated ACE2 expression in animal studies, the concern might arise regarding whether ARBs and ACEIs would increase the morbidity and mortality of COVID-19. On the other hand, animal data suggested a potential protective effect of ARBs against COVID-19 pneumonia because an ARB prevented the aggravation of acute lung injury in mice infected with SARS-CoV, which is closely related to SARS-CoV-2. Importantly, however, there is no clinical or experimental evidence supporting that ARBs and ACEIs either augment the susceptibility to SARS-CoV-2 or aggravate the severity and outcomes of COVID-19 at present. Until further data are available, it is recommended that ARB and ACEI medications be continued for the treatment of patients with cardiovascular disease and hypertension, especially those at high risk, according to guideline-directed medical therapy based on the currently available evidence.
6u623i0w
6u623i0w
2020-04-27
10.1038/s41440-020-0455-8
3
The SARS-CoV-2 receptor, ACE-2, is expressed on many different cell types: implications for ACE-inhibitor- and angiotensin II receptor blocker-based cardiovascular therapies
SARS-CoV-2 is characterized by a spike protein allowing viral binding to the angiotensin-converting enzyme (ACE)-2, which acts as a viral receptor and is expressed on the surface of several pulmonary and extra-pulmonary cell types, including cardiac, renal, intestinal and endothelial cells. There is evidence that also endothelial cells are infected by SARS-COV-2, with subsequent occurrence of systemic vasculitis, thromboembolism and disseminated intravascular coagulation. Those effects, together with the “cytokine storm” are involved in a worse prognosis. In clinical practice, angiotensin-converting enzyme inhibitors (ACE-Is) and angiotensin II receptor blockers (ARBs) are extensively used for the treatment of hypertension and other cardiovascular diseases. In in vivo studies, ACE-Is and ARBs seem to paradoxically increase ACE-2 expression, which could favour SARS-CoV-2 infection of host’s cells and tissues. By contrast, in patients treated with ACE-Is and ARBs, ACE-2 shows a downregulation at the mRNA and protein levels in kidney and cardiac tissues. Yet, it has been claimed that both ARBs and ACE-Is could result potentially useful in the clinical course of SARS-CoV-2-infected patients. As detected in China and as the Italian epidemiological situation confirms, the most prevalent comorbidities in deceased patients with COVID-19 are hypertension, diabetes and cardiovascular diseases. Older COVID-19-affected patients with cardiovascular comorbidities exhibit a more severe clinical course and a worse prognosis, with many of them being also treated with ARBs or ACE-Is. Another confounding factor is cigarette smoking, which has been reported to increase ACE-2 expression in both experimental models and humans. Sex also plays a role, with chromosome X harbouring the gene coding for ACE-2, which is one of the possible explanations of why mortality in female patients is lower. Viral entry also depends on TMPRSS2 protease activity, an androgen dependent enzyme. Despite the relevance of experimental animal studies, to comprehensively address the question of the potential hazards or benefits of ACE-Is and ARBs on the clinical course of COVID-19-affected patients treated by these anti-hypertensive drugs, we will need randomized human studies. We claim the need of adequately powered, prospective studies aimed at answering the following questions of paramount importance for cardiovascular, internal and emergency medicine: Do ACE-Is and ARBs exert similar or different effects on infection or disease course? Are such effects dangerous, neutral or even useful in older, COVID-19-affected patients? Do they act on multiple cell types? Since ACE-Is and ARBs have different molecular targets, the clinical course of SARS-CoV-2 infection could be also different in patients treated by one or the other of these two drug classes. At present, insufficient detailed data from trials have been made available.
6w13xo2a
6w13xo2a
2020-05-19
10.1007/s11739-020-02364-6
4
Molecular mechanism of SARS-CoV-2 components caused ARDS in murine model
COVID-19 has become a major challenge to global health, and until now, no efficient antiviral agents have been developed. The SARS-CoV-2 infection is characterized by pulmonary and systemic inflammation in severe patients, and acute respiratory distress syndrome (ARDS) caused respiratory failure contributes to most mortalities. There is an urgent need for developing effective drugs and vaccines against SARS-CoV-2 and COVID-19 caused ARDS. However, most researchers cannot perform SARS-CoV-2 related researches due to lacking P3 or P4 facility. We developed a non-infectious, highly safety, time-saving SARS-CoV-2 components induced murine model to study the SARS-CoV-2 caused ARDS and cytokine storm syndrome (CSS). We also investigated mAbs and inhibitors which potentially neutralize the pro-inflammatory phenotype of COVID-19, and found that anti-IL-1α, anti-IL-6, anti-TNFα, anti-GM-CSF mAbs, p38 inhibitor, and JAK inhibitor partially relieved CSS. Besides, anti-IL-6, anti-TNFα, anti-GM-CSF mAbs and inhibitors of p38, ERK, and MPO somewhat reduced neutrophilic alveolitis in the lung. In all, we established the murine model mimic of COVID-19, opening a biosafety and less time-consuming avenue for clarifying the mechanism of ARDS and CSS in COVID-19 and developing the therapeutic drugs.
6x2hhuj6
6x2hhuj6
2020-07-02
10.1101/2020.06.07.119032
4
Middle East respiratory syndrome: An emerging coronavirus infection tracked by the crowd
Abstract In 2012 in Jordan, infection by a novel coronavirus (CoV) caused the first known cases of Middle East respiratory syndrome (MERS). MERS-CoV sequences have since been found in a bat and the virus appears to be enzootic among dromedary camels across the Arabian Peninsula and in parts of Africa. The majority of human cases have occurred in the Kingdom of Saudi Arabia (KSA). In humans, the etiologic agent, MERS-CoV, has been detected in severe, mild and influenza-like illness and in those without any obvious signs or symptoms of disease. MERS is often a lower respiratory tract disease associated with fever, cough, breathing difficulties, pneumonia that can progress to acute respiratory distress syndrome, multiorgan failure and death among more than a third of those infected. Severe disease is usually found in older males and comorbidities are frequently present in cases of MERS. Compared to SARS, MERS progresses more rapidly to respiratory failure and acute kidney injury, is more often observed as severe disease in patients with underlying illnesses and is more often fatal. MERS-CoV has a broader tropism than SARS-CoV, rapidly triggers cellular damage, employs a different receptor and induces a delayed proinflammatory response in cells. Most human cases have been linked to lapses in infection prevention and control in healthcare settings, with a fifth of virus detections reported among healthcare workers. This review sets out what is currently known about MERS and the MERS-CoV, summarises the new phenomenon of crowd-sourced epidemiology and lists some of the many questions that remain unanswered, nearly three years after the first reported case.
6xyipioz
6xyipioz
2015-04-16
10.1016/j.virusres.2015.01.021
0.5
Atazanavir inhibits SARS-CoV-2 replication and pro-inflammatory cytokine production
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is already responsible for far more deaths than previous pathogenic coronaviruses (CoVs) from 2002 and 2012. The identification of clinically approved drugs to be repurposed to combat 2019 CoV disease (COVID-19) would allow the rapid implementation of potentially life-saving procedures. The major protease (Mpro) of SARS-CoV-2 is considered a promising target, based on previous results from related CoVs with lopinavir (LPV), an HIV protease inhibitor. However, limited evidence exists for other clinically approved antiretroviral protease inhibitors, such as atazanavir (ATV). ATV is of high interest because of its bioavailability within the respiratory tract. Our results show that ATV could dock in the active site of SARS-CoV-2 Mpro, with greater strength than LPV. ATV blocked Mpro activity. We confirmed that ATV inhibits SARS-CoV-2 replication, alone or in combination with ritonavir (RTV) in Vero cells, human pulmonary epithelial cell line and primary monocytes, impairing virus-induced enhancement of IL-6 and TNF-α levels. Together, our data strongly suggest that ATV and ATV/RTV should be considered among the candidate repurposed drugs undergoing clinical trials in the fight against COVID-19.
6zk0ioep
6zk0ioep
2020-04-06
10.1101/2020.04.04.020925
1
Animal-to-Human SARS-associated Coronavirus Transmission?
71o6oig8
71o6oig8
2004-05-16
10.3201/eid1005.040022
1.5
Systematic Comparison of Two Animal-to-Human Transmitted Human Coronaviruses: SARS-CoV-2 and SARS-CoV
After the outbreak of the severe acute respiratory syndrome (SARS) in the world in 2003, human coronaviruses (HCoVs) have been reported as pathogens that cause severe symptoms in respiratory tract infections. Recently, a new emerged HCoV isolated from the respiratory epithelium of unexplained pneumonia patients in the Wuhan seafood market caused a major disease outbreak and has been named the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). This virus causes acute lung symptoms, leading to a condition that has been named as “coronavirus disease 2019” (COVID-19). The emergence of SARS-CoV-2 and of SARS-CoV caused widespread fear and concern and has threatened global health security. There are some similarities and differences in the epidemiology and clinical features between these two viruses and diseases that are caused by these viruses. The goal of this work is to systematically review and compare between SARS-CoV and SARS-CoV-2 in the context of their virus incubation, originations, diagnosis and treatment methods, genomic and proteomic sequences, and pathogenic mechanisms.
73a7uvyz
73a7uvyz
2020-02-22
10.3390/v12020244
0.5
Key residues of the receptor binding motif in the spike protein of SARS-CoV-2 that interact with ACE2 and neutralizing antibodies
Coronavirus disease 2019 (COVID-19), caused by the novel human coronavirus SARS-CoV-2, is currently a major threat to public health worldwide. The viral spike protein binds the host receptor angiotensin-converting enzyme 2 (ACE2) via the receptor-binding domain (RBD), and thus is believed to be a major target to block viral entry. Both SARS-CoV-2 and SARS-CoV share this mechanism. Here we functionally analyzed the key amino acid residues located within receptor binding motif of RBD that may interact with human ACE2 and available neutralizing antibodies. The in vivo experiments showed that immunization with either the SARS-CoV RBD or SARS-CoV-2 RBD was able to induce strong clade-specific neutralizing antibodies in mice; however, the cross-neutralizing activity was much weaker, indicating that there are distinct antigenic features in the RBDs of the two viruses. This finding was confirmed with the available neutralizing monoclonal antibodies against SARS-CoV or SARS-CoV-2. It is worth noting that a newly developed SARS-CoV-2 human antibody, HA001, was able to neutralize SARS-CoV-2, but failed to recognize SARS-CoV. Moreover, the potential epitope residues of HA001 were identified as A475 and F486 in the SARS-CoV-2 RBD, representing new binding sites for neutralizing antibodies. Overall, our study has revealed the presence of different key epitopes between SARS-CoV and SARS-CoV-2, which indicates the necessity to develop new prophylactic vaccine and antibody drugs for specific control of the COVID-19 pandemic although the available agents obtained from the SARS-CoV study are unneglectable.
73inqtb9
73inqtb9
2020
5
Repurposing approved drugs as inhibitors of SARS-CoV-2 S-protein from molecular modeling and virtual screening
Herein, molecular modeling techniques were used with the main goal to obtain candidates from a drug database as potential targets to be used against SARS-CoV-2. This novel coronavirus, responsible by the COVID-19 outbreak since the end of 2019, became a challenge since there is not vaccine for this disease. The first step in this investigation was to solvate the isolated S-protein in water for molecular dynamics (MD) simulation, being observed a transition from “up” to “down” conformation of receptor-binding domain (RBD) of the S-protein with angle of 54.3 and 43.0 degrees, respectively. The RBD region was more exposed to the solvent and to the possible drugs due to its enhanced surface area. From the equilibrated MD structure, virtual screening by docking calculations were performed using a library contained 9091 FDA approved drugs. Among them, 24 best-scored ligands (14 traditional herbal isolate and 10 approved drugs) with the binding energy below –8.1 kcal/mol were selected as potential candidates to inhibit the SARS-CoV-2 S-protein, preventing the human cell infection and their replication. For instance, the ivermectin drug (present in our list of promise candidates) was recently used successful to control viral replication in vitro. MD simulations were performed for the three best ligands@S-protein complexes and the binding energies were calculated using the MM/PBSA approach. Overall, it is highlighted an important strategy, some key residues, and chemical groups which may be considered on clinical trials for COVID-19 outbreak.
74xvvwrw
74xvvwrw
2020-06-02
10.1080/07391102.2020.1772885
4
Shell disorder analysis predicts greater resilience of the SARS-CoV-2 (COVID-19) outside the body and in body fluids
Abstract The coronavirus (CoV) family consists of viruses that infects a variety of animals including humans with various levels of respiratory and fecal-oral transmission levels depending on the behavior of the viruses' natural hosts and optimal viral fitness. A model to classify and predict the levels of respective respiratory and fecal-oral transmission potentials of the various viruses was built before the outbreak of MERS-CoV using AI and empirically-based molecular tools to predict the disorder level of proteins. Using the percentages of intrinsic disorder (PID) of the nucleocapsid (N) and membrane (M) proteins of CoV, the model easily clustered the viruses into three groups with the SARS-CoV (M PID = 8%, N PID = 50%) falling into Category B, in which viruses have intermediate levels of both respiratory and fecal-oral transmission potentials. Later, MERS-CoV (M PID = 9%, N PID = 44%) was found to be in Category C, which consists of viruses with lower respiratory transmission potential but with higher fecal-oral transmission capabilities. Based on the peculiarities of disorder distribution, the SARS-CoV-2 (M PID = 6%, N PID = 48%) has to be placed in Category B. Our data show however, that the SARS-CoV-2 is very strange with one of the hardest protective outer shell, (M PID = 6%) among coronaviruses. This means that it might be expected to be highly resilient in saliva or other body fluids and outside the body. An infected body is likelier to shed greater numbers of viral particles since the latter is more resistant to antimicrobial enzymes in body fluids. These particles are also likelier to remain active longer. These factors could account for the greater contagiousness of the SARS-CoV-2 and have implications for efforts to prevent its spread.
75u57fw1
75u57fw1
2020-07-31
10.1016/j.micpath.2020.104177
1
HIV protease inhibitor nelfinavir inhibits replication of SARS-associated coronavirus
Abstract A novel coronavirus has been identified as an etiological agent of severe acute respiratory syndrome (SARS). To rapidly identify anti-SARS drugs available for clinical use, we screened a set of compounds that included antiviral drugs already in wide use. Here we report that the HIV-1 protease inhibitor, nelfinavir, strongly inhibited replication of the SARS coronavirus (SARS-CoV). Nelfinavir inhibited the cytopathic effect induced by SARS-CoV infection. Expression of viral antigens was much lower in infected cells treated with nelfinavir than in untreated infected cells. Quantitative RT-PCR analysis showed that nelfinavir could decrease the production of virions from Vero cells. Experiments with various timings of drug addition revealed that nelfinavir exerted its effect not at the entry step, but at the post-entry step of SARS-CoV infection. Our results suggest that nelfinavir should be examined clinically for the treatment of SARS and has potential as a good lead compound for designing anti-SARS drugs.
77cylm1o
77cylm1o
2004-06-04
10.1016/j.bbrc.2004.04.083
2.5
Defining Protective Epitopes for COVID‐19 Vaccination Models
Recent papers in the Journal provide tangible avenues for COVID‐19 vaccine production as immunoreactive epitopes are brought to the forefront in these and many other emerging studies.(1,2) The development of a consistent predictable animal model of COVID‐19 infection is evidently also a welcome event for preliminary antiviral and vaccine assessments and surely brings us to another level of progression.(3) This article is protected by copyright. All rights reserved.
77mw0dws
77mw0dws
2020-04-14
10.1002/jmv.25876
4
A “One-Health” approach for diagnosis and molecular characterization of SARS-CoV-2 in Italy
Abstract The current pandemic is caused by a novel coronavirus (CoV) called SARS-CoV-2 (species Severe acute respiratory syndrome-related coronavirus, subgenus Sarbecovirus, genus Betacoronavirus, family Coronaviridae). In Italy, up to the 2nd of April 2020, overall 139,422 confirmed cases and 17,669 deaths have been notified, while 26,491 people have recovered. Besides the overloading of hospitals, another issue to face was the capacity to perform thousands of tests per day. In this perspective, to support the National Health Care System and to minimize the impact of this rapidly spreading virus, the Italian Ministry of Health involved the Istituti Zooprofilattici Sperimentali (IZSs), Veterinary Public Health Institutes, in the diagnosis of SARS-CoV-2 by testing human samples. IZSAM, is currently testing more than 600 samples per day and WGS from positive samples. Sequence analysis of these samples suggested that outbreaks in Abruzzo region may be related to outbreaks of northern Italy and northern Europe, these latter as for the presence of mutations in the N protein. CoVs, and related diseases, are well known to veterinarians since decades. The experience that veterinarians operating within the Public health system gained in the control and characterization of previous health issues of livestock and poultry including avian flu, bluetongue, foot and mouth disease, responsible for huge economic losses, is certainly of great help to minimize the impact of this global crisis.
7897zxdm
7897zxdm
2020-04-19
10.1016/j.onehlt.2020.100135
2
The protective effect of recombinant Lactococcus lactis oral vaccine on a Clostridium difficile-infected animal model
BACKGROUND: Oral immunization with vaccines may be an effective strategy for prevention of Clostridium difficile infection (CDI). However, application of previously developed vaccines for preventing CDI has been limited due to various reasons. Here, we developed a recombinant Lactococcus lactis oral vaccine and evaluated its effect on a C. difficile-infected animal model established in golden hamsters in attempt to provide an alternative strategy for CDI prevention. METHODS: Recombinant L. lactis vaccine was developed using the pTRKH2 plasmid, a high-copy-number Escherichia coli-L. shuttle vector: 1) L. lactis expressing secreted proteins was constructed with recombinant pTRKH2 (secreted-protein plasmid) carrying the Usp45 signal peptide (SPUsp45), nontoxic adjuvanted tetanus toxin fragment C (TETC), and 14 of the 38 C-terminal repeats (14CDTA) of nontoxic C. difficile toxin A (TcdA); and 2) L. lactis expressing secreted and membrane proteins was constructed with recombinant pTRKH2 (membrane-anchored plasmid) carrying SPUsp45, TETC, 14CDTA, and the cell wall-anchored sequence of protein M6 (cwaM6). Then, 32 male Syrian golden hamsters were randomly divided into 4 groups (n = 8 each) for gavage of normal saline (blank control) and L. lactis carrying the empty shuttle vector, secreted-protein plasmid, and membrane-anchored plasmid, respectively. After 1-week gavage of clindamycin, the animals were administered with C. difficile spore suspension. General symptoms and intestinal pathological changes of the animals were examined by naked eye and microscopy, respectively. Protein levels of anti-TcdA IgG/IgA antibodies in intestinal tissue and fluid were analyzed by enzyme-linked immunosorbent assay (ELISA). A cell culture cytotoxicity neutralization assay was done by TcdA treatment with or without anti-TcdA serum pre-incubation or treatment. Apoptosis of intestinal epithelial cells was examined by flow cytometry (FL) assay. Expression of mucosal inflammatory cytokines in the animals was detected by polymer chain reaction (PCR) assay. RESULTS: After the C. difficile challenge, the animals of control group had severe diarrhea symptoms on day 1 and all died on day 4, indicating that the CDI animal model was established in hamster. Of the 3 immunization groups, secreted-protein and membrane-anchored plasmid groups had significantly lower mortalities, body weight decreases, and pathological scores, with higher survival rate/time than the empty plasmid group (P < 0.05). The tilter of IgG antibody directed against TcdA was significantly higher in serum and intestinal fluid of secreted-protein and membrane-anchored plasmid groups than in the empty plasmid group (P < 0.05) while the corresponding titer of IgA antibody directed against TcdA had no substantial differences (P > 0.05). The anti-TcdA serum of membrane-anchored plasmid group neutralized the cytotoxicity of 200 ng/ml TcdA with the best protective effect achieved by anti-TcdA serum pre-incubation. The incidences of TcdA-induced death and apoptosis of intestinal epithelial cells were significantly reduced by cell pre-incubation or treatment with anti-TcdA serum of membrane-anchored plasmid group (P < 0.05). MCP-1, ICAM-1, IL-6, and Gro-1 mRNA expression levels were the lowest in cecum tissue of the membrane-anchored groups compared to the other groups. CONCLUSION: Recombinant L. lactis live vaccine is effective for preventing CDI in the hamster model, thus providing an alternative for immunization of C. difficile-associated diseases.
7899iaku
7899iaku
2013-07-17
10.1186/1471-230x-13-117
4.5
Repositioning of 8565 Existing Drugs for COVID-19
The coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has infected over 7.1 million people and led to over 0.4 million deaths. Currently, there is no specific anti-SARS-CoV-2 medication. New drug discovery typically takes more than 10 years. Drug repositioning becomes one of the most feasible approaches for combating COVID-19. This work curates the largest available experimental data set for SARS-CoV-2 or SARS-CoV 3CL (main) protease inhibitors. On the basis of this data set, we develop validated machine learning models with relatively low root-mean-square error to screen 1553 FDA-approved drugs as well as another 7012 investigational or off-market drugs in DrugBank. We found that many existing drugs might be potentially potent to SARS-CoV-2. The druggability of many potent SARS-CoV-2 3CL protease inhibitors is analyzed. This work offers a foundation for further experimental studies of COVID-19 drug repositioning.
78vo1jkc
78vo1jkc
2020
5
No evidence of SARS-CoV-2 in semen of males recovering from COVID-19
Abstract Objective To describe detection of SARS-CoV-2 in seminal fluid of patients recovering from COVID-19 and describe the expression profile of ACE2 and TMPRSS2 within the testicle. Design observational, cross-sectional study Setting Tertiary referral center Patients Thirty-four adult Chinese males diagnosed with COVID-19 through confirmatory quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR) from pharyngeal swab samples Intervention None Main Outcome Measures Identification of SARS-CoV-2 on qRT-PCR of single ejaculated semen samples. Semen quality was not assessed. Expression patterns of ACE2 and TMPRSS2 in the human testis are explored through previously published single-cell transcriptome datasets. Results Six patients (19%) demonstrated scrotal discomfort concerning for viral orchitis around the time of COVID-19 confirmation. SARS-CoV-2 was not detected in semen after a median of 31 days (IQR: 29-36 days) from COVID-19 diagnosis. Single-cell transcriptome analysis demonstrates sparse expression of ACE2 and TMPRSS2, with almost no overlapping gene expression. Conclusions SARS-CoV-2 was not detected in the semen of patients recovering from COVID-19 one month after COVID-19 diagnosis. ACE2-mediated viral entry of SARS-CoV-2 into target host cells is unlikely to occur within the human testicle based on ACE2 and TMPRSS2 expression. The long-term effects of SARS-CoV-2 on male reproductive function remain unknown.
78w5fafs
78w5fafs
2020-04-17
10.1016/j.fertnstert.2020.04.024
3
SARS-CoV Infection Was from at Least Two Origins in the Taiwan Area
OBJECTIVE: Severe acute respiratory syndrome (SARS) is caused by a new coronavirus. Genomic sequence analysis will provide the molecular epidemiology and help to develop vaccines. METHODS: We developed a rapid method to amplify and sequence the whole SARS-CoV genome from clinical specimens. The technique employed one-step multiplex RT-PCR to amplify the whole SARS-CoV genome, and then nested PCR was performed to amplify a 2-kb region separately. The PCR products were sequenced. RESULTS: We sequenced the genomes of SARS-CoV from 3 clinical specimens obtained in Taiwan. The sequences were similar to those reported by other groups, except that 17 single nucleotide variations and two 2-nucleotide deletions, and a 1-nucleotide deletion were found. All the variations in the clinical specimens did not alter the amino acid sequence. Of these 17 sequenced variants, two loci (positions 26203 and 27812) were segregated together as a specific genotype-T:T or C:C. Phylogenetic analysis showed two major clusters of SARS patients in Taiwan. CONCLUSION: We developed a very economical and rapid method to sequence the whole genome of SARS-CoV, which can avoid cultural influence. From our results, SARS patients in Taiwan may be infected from two different origins.
79uxm3bg
79uxm3bg
2005-03-24
10.1159/000081739
2
A screen of the NIH Clinical Collection small molecule library identifies potential anti-coronavirus drugs
Abstract With the recent emergence of Middle East Respiratory Syndrome coronavirus in humans and the outbreak of devastating porcine epidemic diarrhea coronavirus in swine, therapeutic intervention is urgently needed. However, anti-coronavirus drugs currently are not available. In an effort to assist rapid development of anti-coronavirus drugs, here we screened the NIH Clinical Collection in cell culture using a luciferase reporter-expressing recombinant murine coronavirus. Of the 727 compounds screened, 84 were found to have a significant anti-coronavirus effect. Further experiments revealed that 51 compounds blocked virus entry while 19 others inhibited viral replication. Additional validation studies with the top 3 inhibitors (hexachlorophene, nitazoxanide and homoharringtonine) demonstrated robust anti-coronavirus activities (a reduction of 6 to 8log10 in virus titer) with an IC50 ranging from 11nM to 1.2μM. Furthermore, homoharringtonine and hexachlorophene exhibited broad antiviral activity against diverse species of human and animal coronaviruses. Since the NIH Clinical Collection consists of compounds that have already been through clinical trials, these small molecule inhibitors have a great potential for rapid development as anti-coronavirus drugs.
79v0hdi9
79v0hdi9
2015-02-28
10.1016/j.antiviral.2014.11.010
2
COVID-19 and chronological aging: senolytics and other anti-aging drugs for the treatment or prevention of corona virus infection?
COVID-19, also known as SARS-CoV-2, is a new emerging zoonotic corona virus of the SARS (Severe Acute Respiratory Syndrome) and the MERS (Middle East Respiratory Syndrome) family. COVID-19 originated in China and spread world-wide, resulting in the pandemic of 2020. For some reason, COVID-19 shows a considerably higher mortality rate in patients with advanced chronological age. This begs the question as to whether there is a functional association between COVID-19 infection and the process of chronological aging. Two host receptors have been proposed for COVID-19. One is CD26 and the other is ACE-2 (angiotensin-converting enzyme 2). Interestingly, both CD26 and the angiotensin system show associations with senescence. Similarly, two proposed therapeutics for the treatment of COVID-19 infection are Azithromycin and Quercetin, both drugs with significant senolytic activity. Also, Chloroquine-related compounds inhibit the induction of the well-known senescence marker, Beta-galactosidase. Other anti-aging drugs should also be considered, such as Rapamycin and Doxycycline, as they behave as inhibitors of protein synthesis, blocking both SASP and viral replication. Therefore, we wish to speculate that the fight against COVID-19 disease should involve testing the hypothesis that senolytics and other anti-aging drugs may have a prominent role in preventing the transmission of the virus, as well as aid in its treatment. Thus, we propose that new clinical trials may be warranted, as several senolytic and anti-aging therapeutics are existing FDA-approved drugs, with excellent safety profiles, and would be readily available for drug repurposing efforts. As Azithromycin and Doxycycline are both commonly used antibiotics that inhibit viral replication and IL-6 production, we may want to consider this general class of antibiotics that functionally inhibits cellular protein synthesis as a side-effect, for the treatment and prevention of COVID-19 disease.
79xhb2bf
79xhb2bf
2020-03-30
10.18632/aging.103001
3
Mapping the Immunodominance Landscape of SARS-CoV-2 Spike Protein for the Design of Vaccines against COVID-19
The ongoing coronavirus disease 2019 (COVID-19) pandemic is a serious threat to global public health, and imposes severe burdens on the entire human society. The severe acute respiratory syndrome (SARS) coronavirus-2 (SARS-CoV-2) can cause severe respiratory illness and death. Currently, there are no specific antiviral drugs that can treat COVID-19. Several vaccines against SARS-CoV-2 are being actively developed by research groups around the world. The surface S (spike) protein and the highly expressed internal N (nucleocapsid) protein of SARS-CoV-2 are widely considered as promising candidates for vaccines. In order to guide the design of an effective vaccine, we need experimental data on these potential epitope candidates. In this study, we mapped the immunodominant (ID) sites of S protein using sera samples collected from recently discharged COVID-19 patients. The SARS-CoV-2 S protein-specific antibody levels in the sera of recovered COVID-19 patients were strongly correlated with the neutralising antibody titres. We used epitope mapping to determine the landscape of ID sites of S protein, which identified nine linearized B cell ID sites. Four out of the nine ID sites were found in the receptor-binding domain (RBD). Further analysis showed that these ID sites are potential high-affinity SARS-CoV-2 antibody binding sites. Peptides containing two out of the nine sites were tested as vaccine candidates against SARS-CoV-2 in a mouse model. We detected epitope-specific antibodies and SARS-CoV-2-neutralising activity in the immunised mice. This study for the first time provides human serological data for the design of vaccines against COVID-19.
79yna07e
79yna07e
2020-04-27
10.1101/2020.04.23.056853
2
From SARS to MERS, Thrusting Coronaviruses into the Spotlight
Coronaviruses (CoVs) have formerly been regarded as relatively harmless respiratory pathogens to humans. However, two outbreaks of severe respiratory tract infection, caused by the severe acute respiratory syndrome coronavirus (SARS-CoV) and the Middle East respiratory syndrome coronavirus (MERS-CoV), as a result of zoonotic CoVs crossing the species barrier, caused high pathogenicity and mortality rates in human populations. This brought CoVs global attention and highlighted the importance of controlling infectious pathogens at international borders. In this review, we focus on our current understanding of the epidemiology, pathogenesis, prevention, and treatment of SARS-CoV and MERS-CoV, as well as provides details on the pivotal structure and function of the spike proteins (S proteins) on the surface of each of these viruses. For building up more suitable animal models, we compare the current animal models recapitulating pathogenesis and summarize the potential role of host receptors contributing to diverse host affinity in various species. We outline the research still needed to fully elucidate the pathogenic mechanism of these viruses, to construct reproducible animal models, and ultimately develop countermeasures to conquer not only SARS-CoV and MERS-CoV, but also these emerging coronaviral diseases.
7aj3fx5u
7aj3fx5u
2019-01-14
10.3390/v11010059
1
Necessitating repeated chest CT in COVID-19 pneumonia
7aotufm0
7aotufm0
2020-03-27
10.1016/j.jfma.2020.03.006
1.5
Analysis of a SARS-CoV-2 infected individual reveals development of potent neutralizing antibodies to distinct epitopes with limited somatic mutation
Abstract Antibody responses develop following SARS-CoV-2 infection, but little is known about their epitope specificities, clonality, binding affinities, epitopes and neutralizing activity. We isolated B cells specific for the SARS-CoV-2 envelope glycoprotein spike (S) from a COVID-19-infected subject twenty-one days after the onset of clinical disease. Forty-five S-specific monoclonal antibodies were generated. They had undergone minimal somatic mutation, with limited clonal expansion and three bound the receptor binding domain (RBD). Two antibodies neutralized SARS-CoV-2. The most potent antibody bound the RBD and prevented binding to the ACE2 receptor, while the other bound outside the RBD. Thus, most anti-S antibodies that were generated in this patient during the first weeks of COVID-19 infection were non-neutralizing and target epitopes outside the RBD. Antibodies that disrupt the SARS-CoV-2 S-ACE2 interaction can potently neutralize the virus without undergoing extensive maturation. Such antibodies have potential preventive and/or therapeutic potential and can serve as templates for vaccine-design.
7ati571p
7ati571p
2020-06-08
10.1016/j.immuni.2020.06.001
4.5
Exploring the SARS-CoV-2 virus-host-drug interactome for drug repurposing
Coronavirus Disease-2019 (COVID-19) is an infectious disease caused by the SARS-CoV-2 virus. It was first identified in Wuhan, China, and has since spread causing a global pandemic. Various studies have been performed to understand the molecular mechanisms of viral infection for predicting drug repurposing candidates. However, such information is spread across many publications and it is very time-consuming to access, integrate, explore, and exploit. We developed CoVex, the first interactive online platform for SARS-CoV-2 and SARS-CoV-1 host interactome exploration and drug (target) identification. CoVex integrates 1) experimentally validated virus-human protein interactions, 2) human protein-protein interactions and 3) drug-target interactions. The web interface allows user-friendly visual exploration of the virus-host interactome and implements systems medicine algorithms for network-based prediction of drugs. Thus, CoVex is an important resource, not only to understand the molecular mechanisms involved in SARS-CoV-2 and SARS-CoV-1 pathogenicity, but also in clinical research for the identification and prioritization of candidate therapeutics. We apply CoVex to investigate recent hypotheses on a systems biology level and to systematically explore the molecular mechanisms driving the virus life cycle. Furthermore, we extract and discuss drug repurposing candidates involved in these mechanisms. CoVex renders COVID-19 drug research systems-medicine-ready by giving the scientific community direct access to network medicine algorithms integrating virus-host-drug interactions. It is available at https://exbio.wzw.tum.de/covex/.
7cjm2yp0
7cjm2yp0
2020-04-26
10.1038/s41467-020-17189-2
2
Herd-level risk factors associated with cow mortality in Swedish dairy herds
Abstract An increase in on-farm mortality (euthanasia and death) in dairy herds has been reported in several countries in the last decade. This does not only imply possible problems with animal welfare, but it also causes economic losses to the farmer. The objective of this study was to evaluate time trends in on-farm dairy cow mortality in Sweden and identify potential herd-level risk factors. Data were retrieved on all Swedish dairy herds enrolled in the milk recording scheme between 2002 and 2010. Herds with a herd size of <20 cows or a mortality rate (MR) of >40 dead or euthanized cows per 100 cow-years were excluded. Two different models were used: 1 multiple-year analysis, which included 6,898 herds during the period 2002 to 2010 and 1 single-year analysis including 4,252 herds for the year 2010, where other variables that were not present during the entire multiple year study were analyzed. The outcome variable was the number of euthanized and dead cows per year and season. A negative binomial regression model, adjusted for clustering within herd, was applied to both models. Fixed effects in the multiple-year analysis were breed, calving interval, herd size, milk yield, region, season, pasture period, and year. The fixed effects in the single-year analysis were breed, calving interval, conventional versus organic farming, herd size, housing system, milk yield, region, and season. The results demonstrated that MR gradually increased from 5.1 to 6.6 events per 100 cow-years during the study period. Swedish MR are consequently on par with, or even greater than, MR among dairy herds in other comparable countries. Higher mortality was associated with larger herd size, longer calving intervals, and herds that had Swedish Holstein as the predominant breed. Lower mortality was observed in herds with a higher herd average milk yield, during the fall and winter, and in organically managed herds. There were regional differences in mortality. An interaction between herd size and season was found in both models. Also, an interaction between housing system and milk yield was found in the single-year analysis. This first assessment of on-farm mortality in Swedish dairy herds confirmed that the MR has increased over the last few years. The study also identified some herd-level risk factors.
7d07su5r
7d07su5r
2012-08-31
10.3168/jds.2011-5085
1.5
A Comprehensive Review of Animal Models for Coronaviruses: SARS-CoV-2, SARS-CoV, and MERS-CoV
The recent outbreak of coronavirus disease (COVID-19) caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has already affected a large population of the world. SARS-CoV-2 belongs to the same family of severe acute respiratory syndrome coronavirus (SARS-CoV) and Middle East respiratory syndrome coronavirus (MERS-CoV). COVID-19 has a complex pathology involving severe acute respiratory infection, hyper-immune response, and coagulopathy. At present, there is no therapeutic drug or vaccine approved for the disease. There is an urgent need for an ideal animal model that can reflect clinical symptoms and underlying etiopathogenesis similar to COVID-19 patients which can be further used for evaluation of underlying mechanisms, potential vaccines, and therapeutic strategies. The current review provides a paramount insight into the available animal models of SARS-CoV-2, SARS-CoV, and MERS-CoV for the management of the diseases.
7dse0j98
7dse0j98
2020-06-30
10.1007/s12250-020-00252-z
5
Remdesivir, lopinavir, emetine, and homoharringtonine inhibit SARS-CoV-2 replication in vitro
An escalating pandemic by the novel SARS-CoV-2 virus is impacting global health and effective therapeutic options are urgently needed. We evaluated the in vitro antiviral effect of compounds that were previously reported to inhibit coronavirus replication and compounds that are currently under evaluation in clinical trials for SARS-CoV-2 patients. We report the antiviral effect of remdesivir, lopinavir, homorringtonine, and emetine against SARS-CoV-2 virus in Vero E6 cells with the estimated 50% effective concentration at 23.15 μM, 26.63 μM, 2.55 μM and 0.46 μM, respectively. Ribavirin or favipiravir that are currently evaluated under clinical trials showed no inhibition at 100 μM. Synergy between remdesivir and emetine was observed, and remdesivir at 6.25 μM in combination with emetine at 0.195 μM may achieve 64.9% inhibition in viral yield. Combinational therapy may help to reduce the effective concentration of compounds below the therapeutic plasma concentrations and provide better clinical benefits.
7e8zlt3t
7e8zlt3t
2020-06-30
10.1016/j.antiviral.2020.104786
1
Risk factors and consequences of anastomotic leakage after Ivor Lewis oesophagectomy†.
OBJECTIVES Oesophageal carcinoma (EC) remains an aggressive disease. Despite extensive changes in therapeutic modalities, surgical resection remains the first choice therapy for curable oesophageal cancer patients. Anastomotic sites are prone to serious complications such as leakage, fistula, bleeding and stricture. Leakage of the anastomosis (AL) remains one of the main causes of postoperative morbidity and mortality. The purpose of this study was to identify predictors associated with postoperative leakage after Ivor Lewis oesophagectomy and its consequences in a single centre. METHODS We performed a retrospective analysis of 412 Ivor Lewis oesophageal resections in a single institute between 2005 and 2014. Univariable and multivariable logistic regression have been used to identify predictors of AL and its impact on postoperative outcome and overall survival. Kaplan-Meier curve was used to analyse overall survival and log-rank analysis to determine odds ratio. RESULTS A total of 412 patients were evaluated. Mean age was 62 ± 11 years (77% male). Overall leak rate was 2.9%. In-hospital or 30-day mortality was 4.4%. Mean intensive care unit (ICU) stay was 1 day and mean hospital stay was 19 days. A history of renal failure, diabetes, higher American Society of Anaesthesiologists score and current cigarette and corticosteroid use were identified as predictors of AL on univariable analysis. Multivariable analysis identified active smoking [P = 0.05, odds ratio (OR) 4.34, 95% confidence interval (CI): 0.98-19.28] and active corticosteroid use (P < 0.001, OR 15.8, 95% CI: 3.25-76.7) as independent significant predictors. A history of diabetes tended to be associated with a higher leakage rate but failed to reach statistical significance. AL was associated with a longer ICU and hospital stay and a significantly higher mortality (42% in the AL group vs 3% in the control group, P < 0.0001). CONCLUSIONS Anastomotic leakage after oesophagectomy is a major cause of postoperative morbidity and mortality. Identifying risk factors preoperatively can contribute to the prevention of postoperative complications.
7elloeg9
7elloeg9
2016
10.1093/icvts/ivv276
3.5
Why Are Lopinavir and Ritonavir Effective against the Newly Emerged Coronavirus 2019? Atomistic Insights into the Inhibitory Mechanisms
[Image: see text] Since the emergence of a novel coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was first reported from Wuhan, China, neither a specific vaccine nor an antiviral drug against SARS-CoV-2 has become available. However, a combination of two HIV-1 protease inhibitors, lopinavir and ritonavir, has been found to be effective against SARS-CoV, and both drugs could bind well to the SARS-CoV 3C-like protease (SARS-CoV 3CL(pro)). In this work, molecular complexation between each inhibitor and SARS-CoV-2 3CL(pro) was studied using all-atom molecular dynamics simulations, free energy calculations, and pair interaction energy analyses based on MM/PB(GB)SA and FMO-MP2/PCM/6-31G* methods. Both anti-HIV drugs interacted well with the residues at the active site of SARS-CoV-2 3CL(pro). Ritonavir showed a somewhat higher number atomic contacts, a somewhat higher binding efficiency, and a somewhat higher number of key binding residues compared to lopinavir, which correspond with the slightly lower water accessibility at the 3CL(pro) active site. In addition, only ritonavir could interact with the oxyanion hole residues N142 and G143 via the formation of two hydrogen bonds. The interactions in terms of electrostatics, dispersion, and charge transfer played an important role in the drug binding. The obtained results demonstrated how repurposed anti-HIV drugs could be used to combat COVID-19.
7ew6lrvh
7ew6lrvh
2020-04-15
10.1021/acs.biochem.0c00160
2
An Update on Current Therapeutic Drugs Treating COVID-19
The current pandemic of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has presented unprecedented challenges to the healthcare systems in almost every country around the world. Currently, there are no proven effective vaccines or therapeutic agents against the virus. Current clinical management includes infection prevention and control measures and supportive care including supplemental oxygen and mechanical ventilatory support. Evolving research and clinical data regarding the virologic SARS-CoV-2 suggest a potential list of repurposed drugs with appropriate pharmacological effects and therapeutic efficacies in treating COVID-19 patients. In this review, we will update and summarize the most common and plausible drugs for the treatment of COVID-19 patients. These drugs and therapeutic agents include antiviral agents (remdesivir, hydroxychloroquine, chloroquine, lopinavir, umifenovir, favipiravir, and oseltamivir), and supporting agents (Ascorbic acid, Azithromycin, Corticosteroids, Nitric oxide, IL-6 antagonists), among others. We hope that this review will provide useful and most updated therapeutic drugs to prevent, control, and treat COVID-19 patients until the approval of vaccines and specific drugs targeting SARS-CoV-2.
7fdcu2f0
7fdcu2f0
2020-05-11
10.1007/s40495-020-00216-7
3
De novo 3D models of SARS-CoV-2 RNA elements and small-molecule-binding RNAs to guide drug discovery
The rapid spread of COVID-19 motivates development of antivirals targeting conserved molecular machinery of the SARS-CoV-2 virus. The SARS-CoV-2 genome includes conserved RNA elements that offer potential targets for RNA-targeting small-molecule drugs, but 3D structures of most of these elements have not been experimentally characterized. Here, we provide a dataset called ‘FARFAR2-SARS-CoV-2’, a collection of 3D coordinates modeled using Rosetta’s FARFAR2 algorithm, including de novo models for thirteen RNA elements in SARS-CoV-2 and homology models for a fourteenth. These elements comprise SL1, SL2, SL3, SL4, SL5, putative SL6 and SL7 in the extended 5′ UTR, as well as the entire extended 5′ UTR; the frameshifting element (FSE) from the SARS-CoV-2 ORF1a/b gene and a putative dimer of FSE; and the extended pseudoknot, hypervariable region, and the s2m of the 3′ UTR, as well as the entire 3′ UTR. For five of these elements (SL1, SL2, SL3, FSE, s2m), convergence of lowest predicted energy structures supports their accuracy in capturing low energy states that might be targeted for small molecule binding. To aid efforts to discover small molecule RNA binders guided by computational models, we provide a second benchmarking dataset called ‘FARFAR2-Apo-Riboswitch’, which consists of similarly prepared Rosetta-FARFAR2 models for RNA riboswitch aptamer regions that bind small molecules. Both datasets include up to 400 3D models for each RNA element, which may facilitate drug discovery approaches targeting dynamic ensembles of low-energy excited states of RNA molecules.
7gm92gau
7gm92gau
2020-04-15
10.1101/2020.04.14.041962
2.5
Predicting the Immunogenicity of T cell epitopes: From HIV to SARS-CoV-2
We describe a physics-based learning model for predicting the immunogenicity of Cytotoxic T Lymphocyte (CTL) epitopes derived from diverse pathogens, given a Human Leukocyte Antigen (HLA) genotype. The model was trained and tested on experimental data on the relative immunodominance of CTL epitopes in Human Immunodeficiency Virus infection. The method is more accurate than publicly available models. Our model predicts that only a fraction of SARS-CoV-2 epitopes that have been predicted to bind to HLA molecules is immunogenic. The immunogenic CTL epitopes across all SARS-CoV-2 proteins are predicted to provide broad population coverage, but the immunogenic epitopes in the SARS-CoV-2 spike protein alone are unlikely to do so. Our model predicts that several immunogenic SARS-CoV-2 CTL epitopes are identical to those contained in low-pathogenicity coronaviruses circulating in the population. Thus, we suggest that some level of CTL immunity against COVID-19 may be present in some individuals prior to SARS-CoV-2 infection.
7gpqlz25
7gpqlz25
2020-05-15
10.1101/2020.05.14.095885
4
A preliminary study on the reproductive toxicity of GS-5734 on male mice
The authors have withdrawn their manuscript given that some conclusions need more research and data support. In addition, they intend to improve the experimental design to make the research more rigorous. If you have any questions, please contact the corresponding author.
7gylvahd
7gylvahd
2020-04-30
10.1101/2020.04.21.050104
2.5
Inactivated SARS-CoV vaccine prepared from whole virus induces a high level of neutralizing antibodies in BALB/c mice.
We tested the ability of inactivated SARS-CoV vaccine to induce neutralizing antibodies in BALB/c mice. The inactivated vaccine was prepared by SARS-CoV virus propagation in Vero cells, with subsequent beta-propiolactone inactivation and Sepharose 4FF column chromatography purification. One hundred forty BALB/c female mice were divided into seven groups of 20 mice each. Of the seven groups, three groups were inoculated with 0.1, 1, and 3 microg of the vaccine without adjuvant while three other groups were inoculated at the same three dosages of vaccine with aluminum hydroxide as adjuvant, respectively. The remaining group was set up as a blank control. Each mouse was inoculated twice at an interval of 3 weeks. One week after the second immunization, mice sera were collected to detect serum neutralizing antibodies. An assay for determining neutralizing antibody titers was developed. The results can be summarized as follows: (1) higher dosages of vaccine induced higher levels of neutralizing antibody titer; (2) the level of neutralizing antibodies induced by the inoculation with aluminum hydroxide adjuvant was slightly higher than that without adjuvant, but the difference was not statistically significant.
7h2b1eku
7h2b1eku
2004
3
Antiviral Efficacies of FDA-Approved Drugs against SARS-CoV-2 Infection in Ferrets
Due to the urgent need of a therapeutic treatment for coronavirus (CoV) disease 2019 (COVID-19) patients, a number of FDA-approved/repurposed drugs have been suggested as antiviral candidates at clinics, without sufficient information. Furthermore, there have been extensive debates over antiviral candidates for their effectiveness and safety against severe acute respiratory syndrome CoV 2 (SARS-CoV-2), suggesting that rapid preclinical animal studies are required to identify potential antiviral candidates for human trials. To this end, the antiviral efficacies of lopinavir-ritonavir, hydroxychloroquine sulfate, and emtricitabine-tenofovir for SARS-CoV-2 infection were assessed in the ferret infection model. While the lopinavir-ritonavir-, hydroxychloroquine sulfate-, or emtricitabine-tenofovir-treated group exhibited lower overall clinical scores than the phosphate-buffered saline (PBS)-treated control group, the virus titers in nasal washes, stool specimens, and respiratory tissues were similar between all three antiviral-candidate-treated groups and the PBS-treated control group. Only the emtricitabine-tenofovir-treated group showed lower virus titers in nasal washes at 8 days postinfection (dpi) than the PBS-treated control group. To further explore the effect of immune suppression on viral infection and clinical outcome, ferrets were treated with azathioprine, an immunosuppressive drug. Compared to the PBS-treated control group, azathioprine-immunosuppressed ferrets exhibited a longer period of clinical illness, higher virus titers in nasal turbinate, delayed virus clearance, and significantly lower serum neutralization (SN) antibody titers. Taken together, all antiviral drugs tested marginally reduced the overall clinical scores of infected ferrets but did not significantly affect in vivo virus titers. Despite the potential discrepancy of drug efficacies between animals and humans, these preclinical ferret data should be highly informative to future therapeutic treatment of COVID-19 patients.IMPORTANCE The SARS-CoV-2 pandemic continues to spread worldwide, with rapidly increasing numbers of mortalities, placing increasing strain on health care systems. Despite serious public health concerns, no effective vaccines or therapeutics have been approved by regulatory agencies. In this study, we tested the FDA-approved drugs lopinavir-ritonavir, hydroxychloroquine sulfate, and emtricitabine-tenofovir against SARS-CoV-2 infection in a highly susceptible ferret infection model. While most of the drug treatments marginally reduced clinical symptoms, they did not reduce virus titers, with the exception of emtricitabine-tenofovir treatment, which led to diminished virus titers in nasal washes at 8 dpi. Further, the azathioprine-treated immunosuppressed ferrets showed delayed virus clearance and low SN titers, resulting in a prolonged infection. As several FDA-approved or repurposed drugs are being tested as antiviral candidates at clinics without sufficient information, rapid preclinical animal studies should proceed to identify therapeutic drug candidates with strong antiviral potential and high safety prior to a human efficacy trial.
7h3rrea7
7h3rrea7
2020
4
Preliminary identification of potential vaccine targets for the COVID-19 coronavirus (SARS-CoV-2) based on SARS-CoV immunological studies
The beginning of 2020 has seen the emergence of COVID-19 outbreak caused by a novel coronavirus, Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). There is an imminent need to better understand this new virus and to develop ways to control its spread. In this study, we sought to gain insights for vaccine design against SARS-CoV-2 by considering the high genetic similarity between SARS-CoV-2 and SARS-CoV, which caused the outbreak in 2003, and leveraging existing immunological studies of SARS-CoV. By screening the experimentally-determined SARS-CoV-derived B cell and T cell epitopes in the immunogenic structural proteins of SARS-CoV, we identified a set of B cell and T cell epitopes derived from the spike (S) and nucleocapsid (N) proteins that map identically to SARS-CoV-2 proteins. As no mutation has been observed in these identified epitopes among the available SARS-CoV-2 sequences (as of 9 February 2020), immune targeting of these epitopes may potentially offer protection against this novel virus. For the T cell epitopes, we performed a population coverage analysis of the associated MHC alleles and proposed a set of epitopes that is estimated to provide broad coverage globally, as well as in China. Our findings provide a screened set of epitopes that can help guide experimental efforts towards the development of vaccines against SARS-CoV-2.
7i52vltp
7i52vltp
2020-02-12
10.1101/2020.02.03.933226
1
COVID-19, immune system response, hyperinflammation and repurposing antirheumatic drugs
In the Wuhan Province of China, in December 2019, the novel coronavirus 2019 (COVID-19) has caused a severe involvement of the lower respiratory tract leading to an acute respiratory syndrome. Subsequently, coronavirus 2 (SARS-CoV-2) provoked a pandemic which is considered a life-threatening disease. The SARS-CoV-2, a family member of betacoronaviruses, possesses single-stranded positive-sense RNA with typical structural proteins, involving the envelope, membrane, nucleocapsid and spike proteins that are responsible for the viral infectivity, and nonstructural proteins. The effectual host immune response including innate and adaptive immunity against SARS-Cov-2 seems crucial to control and resolve the viral infection. However, the severity and outcome of the COVID-19 might be associated with the excessive production of proinflammatory cytokines “cytokine storm” leading to an acute respiratory distress syndrome. Regretfully, the exact pathophysiology and treatment, especially for the severe COVID-19, is still uncertain. The results of preliminary studies have shown that immune-modulatory or immune-suppressive treatments such as hydroxychloroquine, interleukin (IL)-6 and IL-1 antagonists, commonly used in rheumatology, might be considered as treatment choices for COVID-19, particularly in severe disease. In this review, to gain better information about appropriate anti-inflammatory treatments, mostly used in rheumatology for COVID-19, we have focused the attention on the structural features of SARS-CoV-2, the host immune response against SARS-CoV-2 and its association with the cytokine storm.
7ivw72l0
7ivw72l0
2020-04-21
10.3906/sag-2004-168
3.5
Utilization of Nucleic Acid Amplification Assays for the Detection of Respiratory Viruses
Viruses are major contributors to morbidity and mortality from acute respiratory infections in all age groups worldwide. Accurate identification of the etiologic agent of respiratory tract infections is important for proper patient management. Diagnosis can be problematic, because a range of potential pathogens can cause similar clinical symptoms. Nucleic acid amplification testing is emerging as the preferred method of diagnostic testing. Real-time technology and the ability to perform multiplex testing have facilitated this emergence. Commercial platforms for nucleic acid amplification testing of respiratory viruses include real-time polymerase chain reaction (PCR), nucleic acid sequence-based amplification, and loop-mediated isothermal amplification. Multiplex PCR with fluidic microarrays or DNA chips are the most recent diagnostic advance. These assays offer significant advantages in sensitivity over antigen detection methods and in most cases also over traditional culture methods. A limited number of assays, however, are commercially available, thus laboratory developed assays frequently are used. This article reviews the performance of commercially available assays and discusses issues relevant to the development of in-house assays.
7jfb4ttx
7jfb4ttx
2009-12-31
10.1016/j.cll.2009.07.008
1.5
Cross-reactive neutralization of SARS-CoV-2 by serum antibodies from recovered SARS patients and immunized animals
The current COVID-19 pandemic, caused by a novel coronavirus SARS-CoV-2, poses serious threats to public health and social stability, calling for urgent need for vaccines and therapeutics. SARS-CoV-2 is genetically close to SARS-CoV, thus it is important to define the between antigenic cross-reactivity and neutralization. In this study, we firstly analyzed 20 convalescent serum samples collected from SARS-CoV infected individuals during the 2003 SARS outbreak. All patient sera reacted strongly with the S1 subunit and receptor-binding domain (RBD) of SARS-CoV, cross-reacted with the S ectodomain, S1, RBD, and S2 proteins of SARS-CoV-2, and neutralized both SARS-CoV and SARS-CoV-2 S protein-driven infections. Multiple panels of antisera from mice and rabbits immunized with a full-length S and RBD immunogens of SARS-CoV were also characterized, verifying the cross-reactive neutralization against SARS-CoV-2. Interestingly, we found that a palm civet SARS-CoV-derived RBD elicited more potent cross-neutralizing responses in immunized animals than the RBD from a human SARS-CoV strain, informing a strategy to develop a universe vaccine against emerging CoVs. Summary Serum antibodies from SARS-CoV infected patients and immunized animals cross-neutralize SARS-CoV-2 suggests strategies for universe vaccines against emerging CoVs.
7jwhypgs
7jwhypgs
2020-04-21
10.1101/2020.04.20.052126
2
Alpha-ketoamides as broad-spectrum inhibitors of coronavirus and enterovirus replication
The main protease of coronaviruses and the 3C protease of enteroviruses share a similar active-site architecture and a unique requirement for glutamine in the P1 position of the substrate. Because of their unique specificity and essential role in viral polyprotein processing, these proteases are suitable targets for the development of antiviral drugs. In order to obtain near-equipotent, broad-spectrum antivirals against alphacoronaviruses, betacoronaviruses, and enteroviruses, we pursued structure-based design of peptidomimetic α-ketoamides as inhibitors of main and 3C proteases. Six crystal structures of protease:inhibitor complexes were determined as part of this study. Compounds synthesized were tested against the recombinant proteases as well as in viral replicons and virus-infected cell cultures; most of them were not cell-toxic. Optimization of the P2 substituent of the α-ketoamides proved crucial for achieving near-equipotency against the three virus genera. The best near-equipotent inhibitors, 11u (P2 = cyclopentylmethyl) and 11r (P2 = cyclohexylmethyl), display low-micromolar EC50 values against enteroviruses, alphacoronaviruses, and betacoronaviruses in cell cultures. In Huh7 cells, 11r exhibits three-digit picomolar activity against Middle East Respiratory Syndrome coronavirus.
7n8p9okf
7n8p9okf
2020-02-10
10.1101/2020.02.10.936898
0.5
Regulatory Aspects in the Development of Gene Therapies
Preclinical therapeutics development research is directed toward fulfilling two overlapping sets of goals. A set of scientific goals includes defining the best molecule or biologic construct for the task at hand, and proving the case for its development. The second set of goals addresses regulatory requirements necessary to introduce the agent into human subjects. In the case of “small molecule” drugs, in most cases the identity of the molecule and appropriate safety studies are straightforward. In contrast, the development of biologic agents, including gene therapies discussed here, presents distinct challenges. The nature of the “drug” may be an organism subject to mutation or selection of variants through recombination. Its properties may vary depending on the scale and method of its preparation, purification, and storage. How to test adequately for its safety prior to first introduction in humans may not be straightforward owing to intrinsic differences in response to the agent expected in humans as compared to animals.
7oew461e
7oew461e
2005
10.1007/978-1-59259-785-7_29
5
COVID-19-Related Stroke
The COVID-19 pandemic is associated with neurological symptoms and complications including stroke. There is hypercoagulability associated with COVID-19 that is likely a “sepsis-induced coagulopathy” and may predispose to stroke. The SARS-CoV-2 virus binds to angiotensin-converting enzyme 2 (ACE2) present on brain endothelial and smooth muscle cells. ACE2 is a key part of the renin angiotensin system (RAS) and a counterbalance to angiotensin-converting enzyme 1 (ACE1) and angiotensin II. Angiotensin II is proinflammatory, is vasoconstrictive, and promotes organ damage. Depletion of ACE2 by SARS-CoV-2 may tip the balance in favor of the “harmful” ACE1/angiotensin II axis and promote tissue injury including stroke. There is a rationale to continue to treat with tissue plasminogen activator for COVID-19-related stroke and low molecular weight heparinoids may reduce thrombosis and mortality in sepsis-induced coagulopathy.
7pxfzuq0
7pxfzuq0
2020-05-07
10.1007/s12975-020-00818-9
3
Could Chloroquine /Hydroxychloroquine Be Harmful in Coronavirus Disease 2019 (COVID-19) Treatment?
7q1sudgj
7q1sudgj
2020-03-24
10.1093/cid/ciaa321
3
A SARS-CoV-2 protein interaction map reveals targets for drug repurposing
A newly described coronavirus named severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which is the causative agent of coronavirus disease 2019 (COVID-19), has infected over 2.3 million people, led to the death of more than 160,000 individuals and caused worldwide social and economic disruption1,2. There are no antiviral drugs with proven clinical efficacy for the treatment of COVID-19, nor are there any vaccines that prevent infection with SARS-CoV-2, and efforts to develop drugs and vaccines are hampered by the limited knowledge of the molecular details of how SARS-CoV-2 infects cells. Here we cloned, tagged and expressed 26 of the 29 SARS-CoV-2 proteins in human cells and identified the human proteins that physically associated with each of the SARS-CoV-2 proteins using affinity-purification mass spectrometry, identifying 332 high-confidence protein-protein interactions between SARS-CoV-2 and human proteins. Among these, we identify 66 druggable human proteins or host factors targeted by 69 compounds (of which, 29 drugs are approved by the US Food and Drug Administration, 12 are in clinical trials and 28 are preclinical compounds). We screened a subset of these in multiple viral assays and found two sets of pharmacological agents that displayed antiviral activity: inhibitors of mRNA translation and predicted regulators of the sigma-1 and sigma-2 receptors. Further studies of these host-factor-targeting agents, including their combination with drugs that directly target viral enzymes, could lead to a therapeutic regimen to treat COVID-19.
7qd8z5e7
7qd8z5e7
2020
3.5
The search for a COVID-19 animal model
7st552bd
7st552bd
2020
5
Current studies of convalescent plasma therapy for COVID-19 may underestimate risk of antibody-dependent enhancement
7t9jr2qk
7t9jr2qk
2020-04-28
10.1016/j.jcv.2020.104388
2
Relevance of SARS-CoV-2 in food safety and food hygiene: potential preventive measures, suggestions and nanotechnological approaches
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is easily transmitted from person to person, which has fueled the ongoing pandemic. Governments in different countries have taken drastic actions such as complete lockdown. However, little attention has been paid to food safety and its potential linkage with the coronavirus disease (COVID-19) pandemic. SARS-CoV-2 spread from staff to food products or food surfaces is conceivable. At least, instead of consuming unpackaged or uncovered foods, consumption of boiled or canned foods processed at high temperatures should be preferred. Before consumption, consumers should clean the surface of canned foods. In addition to recommending or enforcing simple precautions, such as using masks, governments must conduct mandatory SARS-CoV-2 tests regularly and intermittently for personnel who handle food materials or supporting materials (e.g., plastic pouches). Local markets, such as those in Wuhan, which sell live animals and exotic foods for consumption, are a concern. Trade of exotic or wild animals, unhygienic marketplace conditions, and not cooking at high temperatures ought to be prohibited. The consumption of vitamins, minerals, and other food-derived compounds such as omega fatty acids is a prudent way to improve the performance of the immune system. In addition, nano-encapsulated materials with controlled release properties may be useful in protecting food products and packaging from SARS-CoV-2 contamination.
7ugz6z9s
7ugz6z9s
2020-06-11
10.1007/s13337-020-00611-0
4.5
The Essential Facts of Wuhan Novel Coronavirus Outbreak in China and Epitope-based Vaccine Designing against COVID-19
Wuhan Novel Coronavirus disease (COVID-19) outbreak has become a global outbreak which has raised the concern of scientific community to design and discover a definitive cure against this deadly virus which has caused deaths of numerous infected people upon infection and spreading. To date, no antiviral therapy or vaccine is available which can effectively combat the infection caused by this virus. This study was conducted to design possible epitope-based subunit vaccines against the SARS-CoV-2 virus using the approaches of reverse vaccinology and immunoinformatics. Upon continual computational experimentation three possible vaccine constructs were designed and one vaccine construct was selected as the best vaccine based on molecular docking study which is supposed to effectively act against SARS-CoV-2. Later, molecular dynamics simulation and in silico codon adaptation experiments were carried out in order to check biological stability and find effective mass production strategy of the selected vaccine. Hopefully, this study will contribute to uphold the present efforts of the researches to secure a definitive treatment against this lethal virus.
7vrm081c
7vrm081c
2020-02-11
10.1101/2020.02.05.935072
1.5
The in vitro antiviral activity of the anti-hepatitis C virus (HCV) drugs daclatasvir and sofosbuvir against SARS-CoV-2
The infection by the Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes major public health concern and economic burden. Although clinically approved drugs have been repurposed to treat individuals with 2019 Coronavirus disease (COVID-19), the lack of safety studies and limited efficiency as well jeopardize clinical benefits. Daclatasvir and sofosbuvir (SFV) are clinically approved direct-acting antivirals (DAA) against hepatitis C virus (HCV), with satisfactory safety profile. In the HCV replicative cycle, daclatasvir and SFV target the viral enzymes NS5A and NS5B, respectively. NS5A is endowed with pleotropic activities, which overlap with several proteins from SARS-CoV-2. HCV NS5B and SARS-CoV-2 nsp12 are RNA polymerases that share homology in the nucleotide uptake channel. These characteristics of the HCV and SARS-CoV-2 motivated us to further study the activity of daclatasvir and SFV against the new coronavirus. Daclatasvir consistently inhibited the production of infectious SARS-CoV-2 virus particles in Vero cells, in the hepatoma cell line HuH-7 and in type II pneumocytes (Calu-3), with potencies of 0.8, 0.6 and 1.1 μM, respectively. Daclatasvir targeted early events during SARS-CoV-2 replication cycle and prevented the induction of IL-6 and TNF-α, inflammatory mediators associated with the cytokine storm typical of SARS-CoV-2 infection. Sofosbuvir, although inactive in Vero cells, displayed EC50 values of 6.2 and 9.5 μM in HuH-7 and Calu-3 cells, respectively. Our data point to additional antiviral candidates, in especial daclatasvir, among drugs overlooked for COVID-19, that could immediately enter clinical trials.
7w19xxlq
7w19xxlq
2020-06-16
10.1101/2020.06.15.153411
5
The FDA-approved drug ivermectin inhibits the replication of SARS-CoV-2 in vitro
Although several clinical trials are now underway to test possible therapies, the worldwide response to the COVID-19 outbreak has been largely limited to monitoring/containment. We report here that Ivermectin, an FDA-approved anti-parasitic previously shown to have broad-spectrum anti-viral activity in vitro, is an inhibitor of the causative virus (SARS-CoV-2), with a single addition to Vero-hSLAM cells 2 h post infection with SARS-CoV-2 able to effect ~5000-fold reduction in viral RNA at 48 h. Ivermectin therefore warrants further investigation for possible benefits in humans.
7xh761g9
7xh761g9
2020
4.5
Potential RNA-dependent RNA polymerase inhibitors as prospective therapeutics against SARS-CoV-2.
Introduction. The emergence of SARS-CoV-2 has taken humanity off guard. Following an outbreak of SARS-CoV in 2002, and MERS-CoV about 10 years later, SARS-CoV-2 is the third coronavirus in less than 20 years to cross the species barrier and start spreading by human-to-human transmission. It is the most infectious of the three, currently causing the COVID-19 pandemic. No treatment has been approved for COVID-19. We previously proposed targets that can serve as binding sites for antiviral drugs for multiple coronaviruses, and here we set out to find current drugs that can be repurposed as COVID-19 therapeutics.Aim. To identify drugs against COVID-19, we performed an in silico virtual screen with the US Food and Drug Administration (FDA)-approved drugs targeting the RNA-dependent RNA polymerase (RdRP), a critical enzyme for coronavirus replication.Methodology. Initially, no RdRP structure of SARS-CoV-2 was available. We performed basic sequence and structural analysis to determine if RdRP from SARS-CoV was a suitable replacement. We performed molecular dynamics simulations to generate multiple starting conformations that were used for the in silico virtual screen. During this work, a structure of RdRP from SARS-CoV-2 became available and was also included in the in silico virtual screen.Results. The virtual screen identified several drugs predicted to bind in the conserved RNA tunnel of RdRP, where many of the proposed targets were located. Among these candidates, quinupristin is particularly interesting because it is expected to bind across the RNA tunnel, blocking access from both sides and suggesting that it has the potential to arrest viral replication by preventing viral RNA synthesis. Quinupristin is an antibiotic that has been in clinical use for two decades and is known to cause relatively minor side effects.Conclusion. Quinupristin represents a potential anti-SARS-CoV-2 therapeutic. At present, we have no evidence that this drug is effective against SARS-CoV-2 but expect that the biomedical community will expeditiously follow up on our in silico findings.
7xp3szhz
7xp3szhz
2020-05-29
10.1099/jmm.0.001203
4
Antibody repertoire induced by SARS-CoV-2 spike protein immunogens
Multiple vaccine candidates against SARS-CoV-2 based on viral spike protein are under development. However, there is limited information on the quality of antibody response generated following vaccination by these vaccine modalities. To better understand antibody response induced by spike protein-based vaccines, we immunized rabbits with various SARS-CoV-2 spike protein antigens: S-ectodomain (S1+S2) (aa 16-1213), which lacks the cytoplasmic and transmembrane domains (CT-TM), the S1 domain (aa 16-685), the receptor-binding domain (RBD) (aa 319-541), and the S2 domain (aa 686-1213 as control). Antibody response was analyzed by ELISA, Surface Plasmon Resonance (SPR) against different Spike proteins in native conformation, and a pseudovirion neutralization assay to measure the quality and function of the antibodies elicited by the different Spike antigens. All three antigens (S1+S2 ectodomain, S1 domain, and RBD) generated strong neutralizing antibodies against SARS-CoV-2. Vaccination induced antibody repertoire was analyzed by SARS-CoV-2 spike Genome Fragment Phage Display Libraries (SARS-CoV-2 GFPDL), which identified immunodominant epitopes in the S1, S1-RBD and S2 domains. Furthermore, these analyses demonstrated that surprisingly the RBD immunogen elicited a higher antibody titer with 5-fold higher affinity antibodies to native spike antigens compared with other spike antigens. These findings may help guide rational vaccine design and facilitate development and evaluation of effective therapeutics and vaccines against COVID-19 disease. One Sentence Summary SARS-CoV-2 Spike induced immune response
7zr1118b
7zr1118b
2020-05-13
10.1101/2020.05.12.091918
3
What to expect from antibody assays of SARS-CoV-2?
83kz2v3p
83kz2v3p
2020-06-26
10.1093/jalm/jfaa100
5
Identify potent SARS-CoV-2 main protease inhibitors via accelerated free energy perturbation-based virtual screening of existing drugs
Coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has become a global crisis. There is no therapeutic treatment specific for COVID-19. It is highly desirable to identify potential antiviral agents against SARS-CoV-2 from existing drugs available for other diseases and, thus, repurpose them for treatment of COVID-19. In general, a drug repurposing effort for treatment of a new disease, such as COVID-19, usually starts from a virtual screening of existing drugs, followed by experimental validation, but the actual hit rate is generally rather low with traditional computational methods. Here we report a new virtual screening approach with accelerated free energy perturbation-based absolute binding free energy (FEP-ABFE) predictions and its use in identifying drugs targeting SARS-CoV-2 main protease (Mpro). The accurate FEP-ABFE predictions were based on the use of a new restraint energy distribution (RED) function designed to accelerate the FEP-ABFE calculations and make the practical FEP-ABFE-based virtual screening of the existing drug library possible for the first time. As a result, out of twenty-five drugs predicted, fifteen were confirmed as potent inhibitors of SARS-CoV-2 Mpro. The most potent one is dipyridamole (Ki=0.04 μM) which has showed promising therapeutic effects in subsequently conducted clinical studies for treatment of patients with COVID-19. Additionally, hydroxychloroquine (Ki=0.36 μM) and chloroquine (Ki=0.56 μM) were also found to potently inhibit SARS-CoV-2 Mpro for the first time. We anticipate that the FEP-ABFE prediction-based virtual screening approach will be useful in many other drug repurposing or discovery efforts. Significance Statement Drug repurposing effort for treatment of a new disease, such as COVID-19, usually starts from a virtual screening of existing drugs, followed by experimental validation, but the actual hit rate is generally rather low with traditional computational methods. It has been demonstrated that a new virtual screening approach with accelerated free energy perturbation-based absolute binding free energy (FEP-ABFE) predictions can reach an unprecedently high hit rate, leading to successful identification of 16 potent inhibitors of SARS-CoV-2 main protease (Mpro) from computationally selected 25 drugs under a threshold of Ki = 4 μM. The outcomes of this study are valuable for not only drug repurposing to treat COVID-19, but also demonstrating the promising potential of the FEP-ABFE prediction-based virtual screening approach.
855dbj30
855dbj30
2020-05-28
10.1101/2020.03.23.004580
1.5
Receptor Recognition by the Novel Coronavirus from Wuhan: an Analysis Based on Decade-Long Structural Studies of SARS Coronavirus
Recently, a novel coronavirus (2019-nCoV) has emerged from Wuhan, China, causing symptoms in humans similar to those caused by severe acute respiratory syndrome coronavirus (SARS-CoV). Since the SARS-CoV outbreak in 2002, extensive structural analyses have revealed key atomic-level interactions between the SARS-CoV spike protein receptor-binding domain (RBD) and its host receptor angiotensin-converting enzyme 2 (ACE2), which regulate both the cross-species and human-to-human transmissions of SARS-CoV. Here, we analyzed the potential receptor usage by 2019-nCoV, based on the rich knowledge about SARS-CoV and the newly released sequence of 2019-nCoV. First, the sequence of 2019-nCoV RBD, including its receptor-binding motif (RBM) that directly contacts ACE2, is similar to that of SARS-CoV, strongly suggesting that 2019-nCoV uses ACE2 as its receptor. Second, several critical residues in 2019-nCoV RBM (particularly Gln493) provide favorable interactions with human ACE2, consistent with 2019-nCoV’s capacity for human cell infection. Third, several other critical residues in 2019-nCoV RBM (particularly Asn501) are compatible with, but not ideal for, binding human ACE2, suggesting that 2019-nCoV has acquired some capacity for human-to-human transmission. Last, while phylogenetic analysis indicates a bat origin of 2019-nCoV, 2019-nCoV also potentially recognizes ACE2 from a diversity of animal species (except mice and rats), implicating these animal species as possible intermediate hosts or animal models for 2019-nCoV infections. These analyses provide insights into the receptor usage, cell entry, host cell infectivity and animal origin of 2019-nCoV and may help epidemic surveillance and preventive measures against 2019-nCoV. IMPORTANCE The recent emergence of Wuhan coronavirus (2019-nCoV) puts the world on alert. 2019-nCoV is reminiscent of the SARS-CoV outbreak in 2002 to 2003. Our decade-long structural studies on the receptor recognition by SARS-CoV have identified key interactions between SARS-CoV spike protein and its host receptor angiotensin-converting enzyme 2 (ACE2), which regulate both the cross-species and human-to-human transmissions of SARS-CoV. One of the goals of SARS-CoV research was to build an atomic-level iterative framework of virus-receptor interactions to facilitate epidemic surveillance, predict species-specific receptor usage, and identify potential animal hosts and animal models of viruses. Based on the sequence of 2019-nCoV spike protein, we apply this predictive framework to provide novel insights into the receptor usage and likely host range of 2019-nCoV. This study provides a robust test of this reiterative framework, providing the basic, translational, and public health research communities with predictive insights that may help study and battle this novel 2019-nCoV.
85acs4lk
85acs4lk
2020-03-17
10.1128/jvi.00127-20
2
EARLY DETECTION OF COVID-19
Since SARS-Cov-2 epidemic appeared in Wuhan China, it became challenge for health authorities to counter Covid-19 epidemic. Early evaluation of suspects, screening for Covid-19 and management posed challenge to health authorities especially in developing countries which were not ready to cope with it. Early mild symptoms appeared during course of disease provide a chance to early detect Covid-19. We use retrospective methodology to collect available data on early sign and symptoms of Covid-19 through accessing World Health Organization (WHO) webpages, New England Journal of Medicine (NEJM), Nature Journal, Journal of American Medical Association (JAMA) network, British Medical Journal (BJM), Lancet and other world renowned journal publications to establish a relationship of early symptoms for detection of Covid-19. Data of 2707 Covid-19 laboratory confirmed cases was collected and analyzed for early signs. Available data was categorized into physical and blood biomarkers. This categorized data was assessed for scoring early detection of Covid-19 by scoring Hashmi-Asif Covid-19 formula. Each characteristic was given a score in Hashmi-Asif Covid-19 chart with maximum score of 28. Scoring 16 on chart means Covid-19 will fully develop in near future. Correlation of each sign and symptoms with development of Covid-19 in formula showed significant correlation assessed by Pearson correlation and Spearman Correlation coefficient (rho) showed significant correlation of development of Covid-19 with fever 64.11% (P=0.001), cough 65% and dry mucus 19.67% equally sensitive (P=0.000), leukopenia 19.06% (P=0.006), lymphopenia 52.93% (P=0.005), thrombopenia 19.1% (P=0.013), elevated Aspartate aminotransferase 12.79% (P=0.007) and elevated Alanine aminotransferase 11.34% (P=0.006). Chart can sense Covid-19 progression 72-96 hours earlier compared to usual course of disease and detection by standard method. Chart for early detection provides early quarantine decision to reduce disease spread and give ample time for intervening disease progression to reduce morbidity time due to Covid-19
86muphtv
86muphtv
2020-04-07
10.1101/2020.04.04.20053363
1.5
HTCC as a highly effective polymeric inhibitor of SARS-CoV-2 and MERS-CoV
The beginning of 2020 brought us information about the novel coronavirus emerging in China. Rapid research resulted in the characterization of the pathogen, which appeared to be a member of the SARS-like cluster, commonly seen in bats. Despite the global and local efforts, the virus escaped the healthcare measures and rapidly spread in China and later globally, officially causing a pandemic and global crisis in March 2020. At present, different scenarios are being written to contain the virus, but the development of novel anticoronavirals for all highly pathogenic coronaviruses remains the major challenge. Here, we describe the antiviral activity of previously developed by us HTCC compound (N-(2-hydroxypropyl)-3-trimethylammonium chitosan chloride), which may be used as potential inhibitor of currently circulating highly pathogenic coronaviruses – SARS-CoV-2 and MERS-CoV.
86stuueg
86stuueg
2020-03-31
10.1101/2020.03.29.014183
4.5
Chloroquine paradox may cause more damage than help fight COVID-19
Novel coronavirus disease 2019 (COVID-19) pandemic is the most recent health care crisis without specific prophylactic or therapeutic drugs. Antimalarial drug chloroquine (CHL) and its safer derivative hydroxychloroquine (HCHL) have been proposed to be repurposed to treat SARS coronavirus-2 (SARS-CoV-2), the causative agent of COVID-19. CHL/HCHL have anti-inflammatory activity and are used to treat rheumatoid arthritis, osteoarthritis and lupus. Although, CHL/HCHL have an anti-viral activity against several viruses in cell-cultures, the anti-viral activity in-vivo is questionable. Repurposing of CHL/HCHL to treat SARS-CoV-2 infection is appealing. However, there is empirical evidence from animal studies with other viruses suggesting that CHL/HCHL may have an untoward paradoxical effect. One thus cannot exclude the possibility that CHL may increase the severity of the disease and prove deleterious both for the patients and public health efforts to contain the highly contagious and explosive spread of SARS-CoV-2.
86vzsrym
86vzsrym
2020
3
Chapter 36 SARS
Abstract Five years after the first severe acute respiratory syndrome (SARS) outbreak, several candidate SARS-coronavirus (CoV) vaccines are at various stages of preclinical and clinical development. Based on the observation that SARSCoV infection is efficiently controlled upon passive transfer of antibodies directed against the spike (S) protein of SARS-CoV, vaccines containing the S protein have been formulated. Animals immunized with inactivated whole virus vaccines or live-recombinant vaccines expressing the SARS-CoV S protein (e.g., using rabies virus, vesicular stomatitis virus, bovine parainfluenza virus type 3, adenovirus, or attenuated vaccinia virus MVA as a vector), as well as mice immunized with DNA vaccines expressing the S protein gene all developed neutralizing antibodies to SARS-CoV and were protected against SARS-CoV challenge. Although much effort has been focused on developing a SARS vaccine, the commercial viability of such a vaccine for SARS-CoV will ultimately depend on whether the virus re-emerges in the near future. This vaccine should induce highly cross-reactive neutralizing antibodies to protect against newly emerging viruses related to SARS-CoV and protect both the gastrointestinal and respiratory tract in the absence of significant side effects. Given the fact that in the previous outbreak mainly the elderly succumbed to the infection, special attention should be given to vaccines that are able to efficiently protect aged individuals.
87g7g5au
87g7g5au
2009-12-31
10.1016/b978-0-12-369408-9.00036-6
1
Prise en charge des cancers du sein pendant la pandémie de COVID 19: le CNGOF se mobilise
88yf7igp
88yf7igp
2020-04-19
10.1016/j.gofs.2020.04.008
3.5
A tug-of-war between severe acute respiratory syndrome coronavirus 2 and host antiviral defence: lessons from other pathogenic viruses
World Health Organization has declared the ongoing outbreak of coronavirus disease 2019 (COVID-19) a Public Health Emergency of International Concern. The virus was named severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) by the International Committee on Taxonomy of Viruses. Human infection with SARS-CoV-2 leads to a wide range of clinical manifestations ranging from asymptomatic, mild, moderate to severe. The severe cases present with pneumonia, which can progress to acute respiratory distress syndrome. The outbreak provides an opportunity for real-time tracking of an animal coronavirus that has just crossed species barrier to infect humans. The outcome of SARS-CoV-2 infection is largely determined by virus-host interaction. Here, we review the discovery, zoonotic origin, animal hosts, transmissibility and pathogenicity of SARS-CoV-2 in relation to its interplay with host antiviral defense. A comparison with SARS-CoV, Middle East respiratory syndrome coronavirus, community-acquired human coronaviruses and other pathogenic viruses including human immunodeficiency viruses is made. We summarize current understanding of the induction of a proinflammatory cytokine storm by other highly pathogenic human coronaviruses, their adaptation to humans and their usurpation of the cell death programmes. Important questions concerning the interaction between SARS-CoV-2 and host antiviral defence, including asymptomatic and presymptomatic virus shedding, are also discussed.
89fol3pq
89fol3pq
2020-03-14
10.1080/22221751.2020.1736644
1.5
Atlas of ACE2 gene expression in mammals reveals novel insights in transmisson of SARS-Cov-2
Background COVID-19 has become a worldwide pandemic. It is caused by a novel coronavirus named SARS-CoV-2 with elusive origin. SARS-CoV-2 infects mammalian cells by binding to ACE2, a transmembrane protein. Therefore, the conservation of ACE2 and its expression pattern across mammalian species, which are yet to be comprehensively investigated, may provide valuable insights into tracing potential hosts of SARS-CoV-2. Methods We analyzed gene conservation of ACE2 across mammals and collected more than 140 transcriptome datasets from human and common mammalian species, including presumed hosts of SARS-CoV-2 and other animals in close contact with humans. In order to enable comparisons across species and tissues, we used a unified pipeline to quantify and normalize ACE2 expression levels. Results We first found high conservation of ACE2 genes among common mammals at both DNA and peptide levels, suggesting that a broad range of mammalian species can potentially be the hosts of SARS-CoV-2. Next, we showed that high level of ACE2 expression in certain human tissues is consistent with clinical symptoms of COVID-19 patients. Furthermore, we observed that ACE2 expressed in a species-specific manner in the mammals examined. Notably, high expression in skin and eyes in cat and dog suggested that these animals may play roles in transmitting SARS-CoV-2 to humans. Conclusions Through building the first atlas of ACE2 expression in pets and livestock, we identified species and tissues susceptible to SARS-CoV-2 infection, yielding novel insights into the viral transmission.
89sg0cpk
89sg0cpk
2020-03-31
10.1101/2020.03.30.015644
1.5
COVID-19 and pets: When pandemic meets panic
Abstract As the novel coronavirus outbreak spreads globally with devastating effects on human health, pets are also becoming unnecessary victims amidst the pandemic panic. Many have been reluctantly left home alone by owners who have been forced to temporarily evacuate their homes. And, although no evidence exists to indicate that they can either transmit the virus or develop its associated coronavirus disease 2019 (COVID-19), fear among the public that pets might play a role in spreading COVID-19 has resulted in pets being abandoned or even killed. This article outlines some of the ways in which the current pandemic has negatively impacted the welfare of pets. It also highlights the relationships between animal, human, and environmental health, as well as the importance of taking a collaborative transdisciplinary One Health approach to help prevent future COVID-19 outbreaks.
8a1cia8s
8a1cia8s
2020-12-31
10.1016/j.fsir.2020.100090
2.5
Feline coronavirus drug inhibits the main protease of SARS-CoV-2 and blocks virus replication
The COVID-19 pandemic, attributed to the SARS-CoV-2 coronavirus infection, resulted in millions infected worldwide and an immediate need for antiviral treatments. The main protease (Mpro) in SARS-CoV-2 is a viable drug target because of its essential role in the cleavage of the virus polypeptide and subsequent viral replication. Feline infectious peritonitis, a fatal infection in cats caused by a coronavirus, was successfully treated previously with a dipeptide-based protease inhibitor. Here we show this drug, GC376, and its analog GC373, are effective inhibitors of the Mpro from both SARS-CoV and SARS-CoV-2 with IC50 values in the nanomolar range. Crystal structures of the SARS-CoV and SARS-CoV-2 Mpro with these inhibitors have a covalent modification of the nucleophilic Cys145. NMR analysis reveals that inhibition proceeds via reversible formation of a hemithioacetal. GC373 and GC376 are potent inhibitors of SARS-CoV-2 in cell culture, with EC50 values near one micromolar and little to no toxicity. These protease inhibitors are soluble, non-toxic, and bind reversibly. They are strong drug candidates for the treatment of human coronavirus infections because they have already been successful in animals (cats). The work here lays the framework for their use in human trials for the treatment of COVID-19.
8agznchi
8agznchi
2020-05-05
10.1101/2020.05.03.073080
3
The coming plague
A killer pandemic is now more likely than ever. Where will it come from and how can we beat it, asks Debora MacKenzie
8bgnppzf
8bgnppzf
2017-02-25
10.1016/s0262-4079(17)30371-8
2
Molecular Evolution of Human Coronavirus Genomes
Human coronaviruses (HCoVs), including SARS-CoV and MERS-CoV, are zoonotic pathogens that originated in wild animals. HCoVs have large genomes that encode a fixed array of structural and nonstructural components, as well as a variety of accessory proteins that differ in number and sequence even among closely related CoVs. Thus, in addition to recombination and mutation, HCoV genomes evolve through gene gains and losses. In this review we summarize recent findings on the molecular evolution of HCoV genomes, with special attention to recombination and adaptive events that generated new viral species and contributed to host shifts and to HCoV emergence. Video Abstract
8bw843ek
8bw843ek
2017-01-31
10.1016/j.tim.2016.09.001
1.5
Pharmacologic Treatments for Coronavirus Disease 2019 (COVID-19): A Review.
Importance The pandemic of coronavirus disease 2019 (COVID-19) caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) presents an unprecedented challenge to identify effective drugs for prevention and treatment. Given the rapid pace of scientific discovery and clinical data generated by the large number of people rapidly infected by SARS-CoV-2, clinicians need accurate evidence regarding effective medical treatments for this infection. Observations No proven effective therapies for this virus currently exist. The rapidly expanding knowledge regarding SARS-CoV-2 virology provides a significant number of potential drug targets. The most promising therapy is remdesivir. Remdesivir has potent in vitro activity against SARS-CoV-2, but it is not US Food and Drug Administration approved and currently is being tested in ongoing randomized trials. Oseltamivir has not been shown to have efficacy, and corticosteroids are currently not recommended. Current clinical evidence does not support stopping angiotensin-converting enzyme inhibitors or angiotensin receptor blockers in patients with COVID-19. Conclusions and Relevance The COVID-19 pandemic represents the greatest global public health crisis of this generation and, potentially, since the pandemic influenza outbreak of 1918. The speed and volume of clinical trials launched to investigate potential therapies for COVID-19 highlight both the need and capability to produce high-quality evidence even in the middle of a pandemic. No therapies have been shown effective to date.
8cvjsisw
8cvjsisw
2020-04-13
10.1001/jama.2020.6019
4
Repurposed Therapeutic Agents Targeting the Ebola Virus: A Systematic Review
BACKGROUND: The Ebola virus has been responsible for numerous outbreaks since the 1970s, with the most recent outbreak taking place between 2014 and 2016 and causing an international public health emergency. Ebola virus disease (EVD) has a high mortality rate and no approved targeted treatment exists to date. A number of established drugs are being considered as potential therapeutic agents for the treatment of EVD. OBJECTIVE: We aimed to identify potential drug repositioning candidates and to assess the scientific evidence available on their efficacy. METHODS: We conducted a systematic literature search in MEDLINE, Embase, and other relevant trial registry platforms for studies published between January 1976 and January 2017. We included drug screening, preclinical studies, and clinical studies on repurposed drugs for the treatment of EVD. The risk of bias for animal studies and nonrandomized clinical studies was assessed. The quality of reporting for case series and case reports was evaluated. Finally, we selected drugs approved by established regulatory authorities, which have positive in vitro study outcomes and at least one additional animal or clinical trial. RESULTS: We identified 3301 publications, of which 37 studies fulfilled our inclusion criteria. Studies were highly heterogeneous in terms of study type, methodology, and intervention. The risk of bias was high for 13 out of 14 animal studies. We selected 11 drugs with potential anti-EVD therapeutic effects and summarized their evidence. CONCLUSIONS: Several established drugs may have therapeutic effects on EVD, but the quality and quantity of current scientific evidence is lacking. This review highlights the need for well-designed and conducted preclinical and clinical research to establish the efficacy of potential repurposed drugs against EVD.
8dbenul1
8dbenul1
2017-02-02
10.1016/j.curtheres.2017.01.007
3.5
Molecules inhibit the enzyme activity of 3-chymotrypsin-like cysteine protease of SARS-CoV-2 virus: the experimental and theory studies
SARS-CoV-2 has emerged as a world public health threat. Herein, we report that the clinical approved auranofin could perfectly inhibit the activity of 3-chymotrypsin-like cysteine protease (Mpro or 3CLpro) of SARS-CoV-2. Gold cluster could significantly inhibit 3CLpro of SARS-COV-2. Phenyl isothiocyanate and Vitamin K3 could well suppress the activity of 3CLpro. For Mpro inhibition, IC50 of auranofin, Vitamin K3, phenyl isothiocyanate, gold cluster are about 0.51μM, 7.96μM, 10.13μM, 1.61μM, respectively. These compounds may be with potentials for treatment SARS-CoV-2 virus replication. Especially for FDA approved auranofin, it is an anti-inflammation drug in clinic, thus it may with strong potential to inhibit virus replication and suppress the inflammation damage in COVID-19 patients. Gold cluster is with better safety index and well anti-inflammation in vitro/vivo, therefore it is with potential to inhibit virus replication and suppress the inflammation damage caused by COVID-19 virus. As Au(I) ion is active metabolism specie derived from gold compounds or gold clusters in vivo, further computational studies revealed Au ion could tightly bind thiol group of Cys145 residue of 3CLpro thus inhibit enzyme activity. Also, phenyl isothiocyanate and Vitamin K3 may interact with thiol group of Cys145 via Michael addition reaction, molecular dynamic (MD) theory studied are applied to confirmed these small molecules are stable in the pocket and inhibit Mpro activity.
8dgngwmw
8dgngwmw
2020-05-31
10.1101/2020.05.28.120642
4
Prediction of potential inhibitors for RNA-dependent RNA polymerase of SARS-CoV-2 using comprehensive drug repurposing and molecular docking approach
The pandemic prevalence of COVID-19 has become a very serious global health issue. Scientists all over the world have been heavily invested in the discovery of a drug to combat SARS-CoV-2. It has been found that RNA-dependent RNA Polymerase (RdRp) plays a crucial role in SARS-CoV-2 replication, and thus could be a potential drug target. Here, comprehensive computational approaches including drug repurposing and molecular docking were employed to predict an effective drug candidate targeting RdRp of SARS-CoV-2. This study revealed that Rifabutin, Rifapentine, Fidaxomicin, 7-methyl-guanosine-5'-triphosphate-5'-guanosine and Ivermectin have a potential inhibitory interaction with RdRp of SARS-CoV-2, and could be effective drugs for COVID-19. In addition, virtual screening of the compounds from ZINC database also allowed the prediction of two compounds (ZINC09128258 and ZINC 09883305) with pharmacophore features that interact effectively with RdRp of SARS-CoV-2; indicating their potentiality as effective inhibitors of the enzyme. Furthermore, ADME analysis along with analysis of toxicity was also investigated to check the pharmacokinetics and drug-likeness properties of the two compounds. Comparative structural analysis of protein-inhibitor complexes revealed that positions of the amino acid Y32, K47, Y122, Y129, H133, N138, D140, T141, S709 and N781 are crucial for drug surface hotspot in the RdRp of SARS-CoV-2.
8e50vgyi
8e50vgyi
2020-04-15
2
Cleavage of spike protein of SARS coronavirus by protease factor Xa is associated with viral infectivity
The spike (S) protein of SARS coronavirus (SARS-CoV) has been known to recognize and bind to host receptors, whose conformational changes then facilitates fusion between the viral envelope and host cell membrane, leading to viral entry into target cells. However, other functions of SARS-CoV S protein such as proteolytic cleavage and its implications to viral infection are incompletely understood. In this study, we demonstrated that the infection of SARS-CoV and a pseudovirus bearing the S protein of SARS-CoV was inhibited by a protease inhibitor Ben-HCl. Also, the protease Factor Xa, a target of Ben-HCl abundantly expressed in infected cells, was able to cleave the recombinant and pseudoviral S protein into S1 and S2 subunits, and the cleavage was inhibited by Ben-HCl. Furthermore, this cleavage correlated with the infectivity of the pseudovirus. Taken together, our study suggests a plausible mechanism by which SARS-CoV cleaves its S protein to facilitate viral infection.
8ehpdwze
8ehpdwze
2007-07-01
10.1016/j.bbrc.2007.05.092
3
The Criteria to Confirm the Role of Epstein-Barr Virus in Nasopharyngeal Carcinoma Initiation
Epstein-Barr virus (EBV) is associated with nasopharyngeal carcinoma (NPC), but it remains obscure whether EBV is a viral cause of, or only an accompaniment of, NPC. We will discuss the accumulated evidence pointing to the relationship between EBV infection and NPC initiation from epidemiologic, pathogenic, molecular oncogenic, and experimental animal studies. We believe that convincing evidence from these perspectives must be provided before we can ascertain the causal role of EBV infection in NPC. Specifically, (1) epidemiological studies should reveal EBV infection as a risk factor; (2) the introduction of EBV into an animal model should produce NPC; (3) in the animal model NPC, the main molecular event(s) or the involved signaling pathway(s) should be identical to that in human NPC; and (4) finally and most importantly, prevention of EBV infection or clearance of EBV from infected individuals must be able to reduce the incidence rate of NPC.
8f1eqp2n
8f1eqp2n
2012-10-23
10.3390/ijms131013737
1
Authors' Response to Hogan
8futmq6e
8futmq6e
2006-09-26
10.1371/journal.pmed.0030415
0.5
The potential of drug repositioning as a short-term strategy for the control and treatment of COVID-19 (SARS-CoV-2): a systematic review
The novel human coronavirus (SARS-CoV-2), the causative agent of COVID-19, has quickly become a threat to the public health and economy worldwide. Despite the severity of some cases, there are no current pathogen-specific antivirals available to treat the disease. Therefore, many studies have focused on the evaluation of the anti-SARS-CoV-2 activity of clinically available drugs. Here, we conducted a systematic review to describe the drug repositioning strategy against SARS-CoV-2 and to discuss the clinical impact of this approach in the current pandemic context. The systematic review was performed on March 23, 2020, using PubMed/MEDLINE, Scopus, Cochrane Library, and Biblioteca Virtual de Saúde (BVS). The data were summarized in tables and critically analyzed. After the database search, 12 relevant studies were identified as eligible for the review. Among the drugs reported in these studies, 57 showed some evidence of antiviral activity. Antivirals, especially antiretrovirals, are the main class of therapeutic agents evaluated against COVID-19. Moreover, studies have reported the anti-SARS-CoV-2 activity of antitumor (16%; 9/57), antimalarial (7%, 4/57), and antibacterial (5%; 3/57) agents. Additionally, seven pharmacological agents (chloroquine, tetrandrine, umifenovir (arbidol), carrimycin, damageprevir, lopinavir/ritonavir) are in phase IV of clinical trials. Due to the evidence of the anti-SARS-CoV-2 activity of various clinically available agents, drug repositioning stands out as a promising strategy for a short-term response in the fight against the novel coronavirus.
8gmn0tae
8gmn0tae
2020
4.5
Potential Rapid Diagnostics, Vaccine and Therapeutics for 2019 Novel Coronavirus (2019-nCoV): A Systematic Review
Rapid diagnostics, vaccines and therapeutics are important interventions for the management of the 2019 novel coronavirus (2019-nCoV) outbreak. It is timely to systematically review the potential of these interventions, including those for Middle East respiratory syndrome-Coronavirus (MERS-CoV) and severe acute respiratory syndrome (SARS)-CoV, to guide policymakers globally on their prioritization of resources for research and development. A systematic search was carried out in three major electronic databases (PubMed, Embase and Cochrane Library) to identify published studies in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Supplementary strategies through Google Search and personal communications were used. A total of 27 studies fulfilled the criteria for review. Several laboratory protocols for confirmation of suspected 2019-nCoV cases using real-time reverse transcription polymerase chain reaction (RT-PCR) have been published. A commercial RT-PCR kit developed by the Beijing Genomic Institute is currently widely used in China and likely in Asia. However, serological assays as well as point-of-care testing kits have not been developed but are likely in the near future. Several vaccine candidates are in the pipeline. The likely earliest Phase 1 vaccine trial is a synthetic DNA-based candidate. A number of novel compounds as well as therapeutics licensed for other conditions appear to have in vitro efficacy against the 2019-nCoV. Some are being tested in clinical trials against MERS-CoV and SARS-CoV, while others have been listed for clinical trials against 2019-nCoV. However, there are currently no effective specific antivirals or drug combinations supported by high-level evidence.
8gncbgot
8gncbgot
2020-02-26
10.3390/jcm9030623
0.5
Antihypertensive drugs and risk of COVID-19?
8hpg90co
8hpg90co
2020-03-26
10.1016/s2213-2600(20)30153-3
4
The SARS-CoV-2 pandemic impact on rhinology research: A survey of the American Rhinologic Society
BACKGROUND: The COVID-19 pandemic has radically shifted healthcare operations within hospitals and universities across the globe. However, the effect of the COVID-19 pandemic on research endeavors and clinical trials is unclear. OBJECTIVE: This study investigates the impact of the COVID-19 pandemic on basic science and clinical research within the rhinology community. METHODS: A cross-sectional study was designed utilizing an 8-question survey to identify changes to rhinology research. Questions evaluated the impact of the COVID-19 pandemic on administrative research support and staffing, basic science research, clinical trials and resident research involvement. RESULTS: Seventy-one participants responded to the survey (8.5% response rate). Most respondents noted changes in IACUC/IRB approval (faster, 33%; slower, 31%). Of those who employed laboratory personnel, 64% were able to continue staff employment with full salary. The majority of animal research and in vitro studies were halted (64% and 56%, respectively), but animal care and cell line maintenance were allowed to continue. Clinical trial enrollment was most commonly limited to COVID derived studies (51%). Forty-seven percent of respondents noted increased resident research participation. CONCLUSION: The rapid spread of the SARS-CoV-2 virus has markedly impacted rhinology-related research. Maintaining safe workplace practices as restrictions are lifted will hopefully mitigate the spread of the virus and allow research productivity to resume.
8is889uq
8is889uq
2020-06-18
10.1016/j.amjoto.2020.102617
4
Deducing the N- and O- glycosylation profile of the spike protein of novel coronavirus SARS-CoV-2
The current emergence of the novel coronavirus pandemic caused by SARS-CoV-2 demands the development of new therapeutic strategies to prevent rapid progress of mortalities. The coronavirus spike (S) protein, which facilitates viral attachment, entry and membrane fusion is heavily glycosylated and plays a critical role in the elicitation of the host immune response. The spike protein is comprised of two protein subunits (S1 and S2), which together possess 22 potential N-glycosylation sites. Herein, we report the glycosylation mapping on spike protein subunits S1 and S2 expressed on human cells through high resolution mass spectrometry. We have characterized the quantitative N-glycosylation profile on spike protein and interestingly, observed unexpected O-glycosylation modifications on the receptor binding domain (RBD) of spike protein subunit S1. Even though O-glycosylation has been predicted on the spike protein of SARS-CoV-2, this is the first report of experimental data for both the site of O-glycosylation and identity of the O-glycans attached on the subunit S1. Our data on the N- and O- glycosylation is strengthened by extensive manual interpretation of each glycopeptide spectra in addition to using bioinformatics tools to confirm the complexity of glycosylation in the spike protein. The elucidation of the glycan repertoire on the spike protein provides insights into the viral binding studies and more importantly, propels research towards the development of a suitable vaccine candidate.
8j7c9grl
8j7c9grl
2020-05-04
10.1093/glycob/cwaa042
3
Calcium channel blocker amlodipine besylate is associated with reduced case fatality rate of COVID-19 patients with hypertension
The coronavirus disease (COVID-19) caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has now spread to more than 100 countries posing as a serious threat to the public health on a global scale. Patients with comorbidity such as hypertension suffer more severe infection with elevated case fatality rate. Development of effective anti-viral drug is in urgent need to treat COVID-19 patients. Here we report that calcium channel blockers (CCBs), a type of anti-hypertension drugs that are widely used in the clinics, can significantly inhibit the post-entry replication events of SARS-CoV-2 in vitro. Comparison with two other major types of anti-hypertension drugs, the angiotensin converting enzyme inhibitors (ACEI) and angiotensin II receptor blockers (ARB), showed that only CCBs display significant anti-SARS-CoV-2 efficacy. Combined treatment with chloroquine and CCBs significantly enhanced the anti-SARS-CoV-2 efficacy. Retrospective clinical investigation of COVID-19 patients revealed that the CCB amlodipine besylate administration distinctly reduced the case fatality rate of patients with hypertension. Results from this study suggest that CCB administration for COVID-19 patients with hypertension as the comorbidity might improve the disease outcome.
8jhwamfv
8jhwamfv
2020-04-14
10.1101/2020.04.08.20047134
4
Molecular targets for the rational design of drugs to inhibit SARS coronavirus
Despite years of research, the precise determinants of coronavirus replication and pathogenesis remain unidentified. What is known of the pathogenesis of the severe acute respiratory syndrome coronavirus (SARS-CoV) is limited, but clinical observations suggest that both viral-induced cytotoxicity and host immune-mediated destruction contribute to the severity of disease. This summary discusses recent advances in coronavirus research that will facilitate the identification of crucial molecular targets for the rational design of SARS therapeutics. Section Editor: Anne Moscona – Department of Pediatrics, Mount Sinai School of Medicine, One Gustave L. Levy Place, Box 1198, New York, NY 10029, USA When the SARS coronavirus came dramatically to attention as a fatal and potentially pandemic respiratory disease, the scientific response was swift and effective. The etiological agent was identified, the genome was cloned and sequenced, and large strides have been made in understanding key points in the viral life cycle, including recent identification of a functional host cell receptor and solution of the three-dimensional structure of the viral attachment protein. Much of this progress was possible only because a foundation of basic coronavirus biology existed. The Denison laboratory has been at the forefront of the small group of investigators who have dissected the basic features of coronaviruses. Denison has discovered critical mechanisms in the life cycle of the coronaviruses and is a key figure in the effective and urgent application of this knowledge to SARS.
8kg6wi88
8kg6wi88
2004-11-30
10.1016/j.ddmec.2004.08.016
0.5
Analysis of the Worldwide Corona Virus (COVID-19) Pandemic Trend;A Modelling Study to Predict Its Spread
Objective: The Coronavirus (COVID-19) has advanced into 197 countries and territories leaving behind a total of 372,757 confirmed cases and 16231 deaths. Methods: One the basis of WHO situation reports data of COVID-19 along with daily official reports from the Japan, China and the Korea we modeled the spread of COVID19 by using the Successive Approximation Method. We defined the two state of data to find the mean ratio (η) of the present cases count to the sum of previous and present cases. This ratio further predicts the future state of COVID-19 pandemic. Results: The mean ratio (η) of expected cases were found 0.485, while the mean ratio for deaths was found to be 0.49. We calculated worldwide expected lower bound value for confirmed cases 247007 cases with maximum limit of 1667719 cases and minimum deaths count 8660 with upper limit of 117397 deaths in next 30 days. While in the case of Iran, a large increase in the number of deaths are expected in the upcoming 30 days with lower bound value of 1140 deaths and maximum value of 598478 deaths. Interpretation: Iran whole population is on risk.
8lku99jc
8lku99jc
2020-04-01
10.1101/2020.03.30.20048215
1
Joint HFSA/ACC/AHA Statement Addresses Concerns Re: Using RAAS Antagonists in COVID-19
8osoi86y
8osoi86y
2020-05-18
10.1016/j.cardfail.2020.04.013
5
Amino acids 270 to 510 of the severe acute respiratory syndrome coronavirus spike protein are required for interaction with receptor.
A novel coronavirus, severe acute respiratory syndrome coronavirus (SARS-CoV), has recently been identified as the causative agent of severe acute respiratory syndrome (SARS). SARS-CoV appears similar to other coronaviruses in both virion structure and genome organization. It is known for other coronaviruses that the spike (S) glycoprotein is required for both viral attachment to permissive cells and for fusion of the viral envelope with the host cell membrane. Here we describe the construction and expression of a soluble codon-optimized SARS-CoV S glycoprotein comprising the first 1,190 amino acids of the native S glycoprotein (S(1190)). The codon-optimized and native S glycoproteins exhibit similar molecular weight as determined by Western blot analysis, indicating that synthetic S glycoprotein is modified correctly in a mammalian expression system. S(1190) binds to the surface of Vero E6 cells, a cell permissive to infection, as demonstrated by fluorescence-activated cell sorter analysis, suggesting that S(1190) maintains the biologic activity present in native S glycoprotein. This interaction is blocked with serum obtained from recovering SARS patients, indicating that the binding is specific. In an effort to map the ligand-binding domain of the SARS-CoV S glycoprotein, carboxy- and amino-terminal truncations of the S(1190) glycoprotein were constructed. Amino acids 270 to 510 were the minimal receptor-binding region of the SARS-CoV S glycoprotein as determined by flow cytometry. We speculate that amino acids 1 to 510 of the SARS-CoV S glycoprotein represent a unique domain containing the receptor-binding site (amino acids 270 to 510), analogous to the S1 subunit of other coronavirus S glycoproteins.
8pod36pz
8pod36pz
2004
2
Nucleotide Analogues as Inhibitors of SARS-CoV-2 Polymerase
SARS-CoV-2, a member of the coronavirus family, is responsible for the current COVID-19 pandemic. Based on our analysis of hepatitis C virus and coronavirus replication, and the molecular structures and activities of viral inhibitors, we previously demonstrated that three nucleotide analogues inhibit the SARS-CoV RNA-dependent RNA polymerase (RdRp). Here, using polymerase extension experiments, we have demonstrated that the active triphosphate form of Sofosbuvir (a key component of the FDA approved hepatitis C drug EPCLUSA), is incorporated by SARS-CoV-2 RdRp, and blocks further incorporation. Using the same molecular insight, we selected the active triphosphate forms of three other anti-viral agents, Alovudine, AZT (an FDA approved HIV/AIDS drug) and Tenofovir alafenamide (TAF, an FDA approved drug for HIV and hepatitis B) for evaluation as inhibitors of SARS-CoV-2 RdRp. We demonstrated the ability of these three viral polymerase inhibitors, 3’-fluoro-3’-deoxythymidine triphosphate, 3’-azido-3’-deoxythymidine triphosphate and Tenofovir diphosphate (the active triphosphate forms of Alovudine, AZT and TAF, respectively) to be incorporated by SARS-CoV-2 RdRp, where they also terminate further polymerase extension. These results offer a strong molecular basis for these nucleotide analogues to be evaluated as potential therapeutics for COVID-19.
8prn86g6
8prn86g6
2020-03-20
10.1101/2020.03.18.997585
0.5
Nano Research for COVID-19
8qzqjtw7
8qzqjtw7
2020-03-31
10.1021/acsnano.0c02540
3
Discovering drugs to treat coronavirus disease 2019 (COVID-19).
The SARS-CoV-2 virus emerged in December 2019 and then spread rapidly worldwide, particularly to China, Japan, and South Korea. Scientists are endeavoring to find antivirals specific to the virus. Several drugs such as chloroquine, arbidol, remdesivir, and favipiravir are currently undergoing clinical studies to test their efficacy and safety in the treatment of coronavirus disease 2019 (COVID-19) in China; some promising results have been achieved thus far. This article summarizes agents with potential efficacy against SARS-CoV-2.
8ruux4sw
8ruux4sw
2020
10.5582/ddt.2020.01012
1
Evaluation of metal-conjugated compounds as inhibitors of 3CL protease of SARS-CoV
3C-like (3CL) protease is essential for the life cycle of severe acute respiratory syndrome-coronavirus (SARS-CoV) and therefore represents a key anti-viral target. A compound library consisting of 960 commercially available drugs and biologically active substances was screened for inhibition of SARS-CoV 3CL protease. Potent inhibition was achieved using the mercury-containing compounds thimerosal and phenylmercuric acetate, as well as hexachlorophene. As well, 1–10 μM of each compound inhibited viral replication in Vero E6 cell culture. Detailed mechanism studies using a fluorescence-based protease assay demonstrated that the three compounds acted as competitive inhibitors (K(i)=0.7, 2.4, and 13.7 μM for phenylmercuric acetate, thimerosal, and hexachlorophene, respectively). A panel of metal ions including Zn(2+) and its conjugates were then evaluated for their anti-3CL protease activities. Inhibition was more pronounced using a zinc-conjugated compound (1-hydroxypyridine-2-thione zinc; Ki=0.17 μM) than using the ion alone (Ki=1.1 μM).
8sc6nbqp
8sc6nbqp
2004-09-10
10.1016/j.febslet.2004.08.015
2.5
Modeling the Effective Control Strategy for Transmission Dynamics of Global Pandemic COVID-19
The novel coronavirus disease (namely COVID-19) has taken attention because of its deadliness across the globe, causing a massive death as well as critical situation around the world. It is an infectious disease which is caused by newly discovered coronavirus. Our study demonstrates with a nonlinear model of this devastating COVID-19 which narrates transmission from human-to-human in the society. Pontryagin Maximum principle has also been applied in order to obtain optimal control strategies where the maintenance of social distancing is the major control. The target of this study is to find out the most fruitful control measures of averting coronavirus infection and eventually, curtailed of the COVID-19 transmission among people. The model is investigated analytically by using most familiar necessary conditions of Pontryagin maximum principle. Furthermore, numerical simulations have been performed to illustrate the analytical results. The analysis reveals that implementation of educational campaign, social distancing and developing human immune system are the major factors which can be able to plunge the scenario of becoming infected.
8tyrnajb
8tyrnajb
2020-04-23
10.1101/2020.04.22.20076158
2.5
Achievements and highlights for Infection, Disease and Health
8uctsgh1
8uctsgh1
2019-01-25
10.1016/j.idh.2018.12.004
3
Investigation of Some Antiviral N-Heterocycles as COVID 19 Drug: Molecular Docking and DFT Calculations
The novel coronavirus, COVID-19, caused by SARS-CoV-2, is a global health pandemic that started in December 2019. The effective drug target among coronaviruses is the main protease Mpro, because of its essential role in processing the polyproteins that are translated from the viral RNA. In this study, the bioactivity of some selected heterocyclic drugs named Favipiravir (1), Amodiaquine (2), 2'-Fluoro-2'-deoxycytidine (3), and Ribavirin (4) was evaluated as inhibitors and nucleotide analogues for COVID-19 using computational modeling strategies. The density functional theory (DFT) calculations were performed to estimate the thermal parameters, dipole moment, polarizability, and molecular electrostatic potential of the present drugs; additionally, Mulliken atomic charges of the drugs as well as the chemical reactivity descriptors were investigated. The nominated drugs were docked on SARS-CoV-2 main protease (PDB: 6LU7) to evaluate the binding affinity of these drugs. Besides, the computations data of DFT the docking simulation studies was predicted that the Amodiaquine (2) has the least binding energy (-7.77 Kcal/mol) and might serve as a good inhibitor to SARS-CoV-2 comparable with the approved medicines, hydroxychloroquine, and remdesivir which have binding affinity -6.06 and -4.96 Kcal/mol, respectively. The high binding affinity of 2 was attributed to the presence of three hydrogen bonds along with different hydrophobic interactions between the drug and the critical amino acids residues of the receptor. Finally, the estimated molecular electrostatic potential results by DFT were used to illustrate the molecular docking findings. The DFT calculations showed that drug 2 has the highest of lying HOMO, electrophilicity index, basicity, and dipole moment. All these parameters could share with different extent to significantly affect the binding affinity of these drugs with the active protein sites.
8uumu8mk
8uumu8mk
2020
4
Crystal structure of SARS-CoV-2 nucleocapsid protein RNA binding domain reveals potential unique drug targeting sites
Abstract The outbreak of coronavirus disease (COVID-19) caused by SARS-CoV-2 virus continually led to worldwide human infections and deaths. Currently, there is no specific viral protein-targeted therapeutics. Viral nucleocapsid protein is a potential antiviral drug target, serving multiple critical functions during the viral life cycle. However, the structural information of SARS-CoV-2 nucleocapsid protein remains unclear. Herein, we have determined the 2.7 Å crystal structure of the N-terminal RNA binding domain of SARS-CoV-2 nucleocapsid protein. Although the overall structure is similar as other reported coronavirus nucleocapsid protein N-terminal domain, the surface electrostatic potential characteristics between them are distinct. Further comparison with mild virus type HCoV-OC43 equivalent domain demonstrates a unique potential RNA binding pocket alongside the β-sheet core. Complemented by in vitro binding studies, our data provide several atomic resolution features of SARS-CoV-2 nucleocapsid protein N-terminal domain, guiding the design of novel antiviral agents specific targeting to SARS-CoV-2.
8vkrh70j
8vkrh70j
2020-04-20
10.1016/j.apsb.2020.04.009
3
Site-specific N-glycosylation Characterization of Recombinant SARS-CoV-2 Spike Proteins
The glycoprotein spike (S) on the surface of SARS-CoV-2 is a determinant for viral invasion and host immune response. Herein, we characterized the site-specific N-glycosylation of S protein at the level of intact glycopeptides. All 22 potential N-glycosites were identified in the S-protein protomer and were found to be preserved among the 753 SARS-CoV-2 genome sequences. The glycosites exhibited glycoform heterogeneity as expected for a human cell-expressed protein subunits. We identified masses that correspond to 157 N-glycans, primarily of the complex type. In contrast, the insect cell-expressed S protein contained 38 N-glycans, primarily of the high-mannose type. Our results revealed that the glycan types were highly determined by the differential processing of N-glycans among human and insect cells. This N-glycosylation landscape and the differential N-glycan patterns among distinct host cells are expected to shed light on the infection mechanism and present a positive view for the development of vaccines and targeted drugs.
8xck5832
8xck5832
2020-06-30
10.1101/2020.03.28.013276
4.5
Coronavirus 2019-nCoV: A brief perspective from the front line
Abstract A novel coronavirus, designated as 2019-nCoV, hit the central Chinese city of Wuhan in late December 2019, and subsequently spread rapidly to all provinces of China and multiple countries. As of 0:00 am February 9, 2020, a total of 37,287 cases have been confirmed infection of 2019-nCoV in China mainland, and 302 cases have also been cumulatively reported from 24 countries. According to the latest data, a total of 813 deaths occurred in China mainland, with the mortality reaching approximately 2.2%. At present, there is no vaccine or specific drugs for the human coronavirus. Therefore, it is critical to understand the nature of the virus and its clinical characteristics, in order to respond to the 2019-nCoV outbreak. Thus, the present study briefly but comprehensively summarizes the not much but timely reports on the 2019-nCoV.
8xz0ddci
8xz0ddci
2020-04-30
10.1016/j.jinf.2020.02.010
1.5
COVID-19 Coronavirus spike protein analysis for synthetic vaccines, a peptidomimetic antagonist, and therapeutic drugs, and analysis of a proposed achilles' heel conserved region to minimize probability of escape mutations and drug resistance
This paper continues a recent study of the spike protein sequence of the COVID-19 virus (SARS-CoV-2). It is also in part an introductory review to relevant computational techniques for tackling viral threats, using COVID-19 as an example. Q-UEL tools for facilitating access to knowledge and bioinformatics tools were again used for efficiency, but the focus in this paper is even more on the virus. Subsequence KRSFIEDLLFNKV of the S2' spike glycoprotein proteolytic cleavage site continues to appear important. Here it is shown to be recognizable in the common cold coronaviruses, avian coronaviruses and possibly as traces in the nidoviruses of reptiles and fish. Its function or functions thus seem important to the coronaviruses. It might represent SARS-CoV-2 Achilles' heel, less likely to acquire resistance by mutation, as has happened in some early SARS vaccine studies discussed in the previous paper. Preliminary conformational analysis of the receptor (ACE2) binding site of the spike protein is carried out suggesting that while it is somewhat conserved, it appears to be more variable than KRSFIEDLLFNKV. However compounds like emodin that inhibit SARS entry, apparently by binding ACE2, might also have functions at several different human protein binding sites. The enzyme 11ß-hydroxysteroid dehydrogenase type 1 is again argued to be a convenient model pharmacophore perhaps representing an ensemble of targets, and it is noted that it occurs both in lung and alimentary tract. Perhaps it benefits the virus to block an inflammatory response by inhibiting the dehydrogenase, but a fairly complex web involves several possible targets.
8y4j510s
8y4j510s
2020
5
Novel human coronavirus (SARS-CoV-2): A lesson from animal coronaviruses
Abstract The recent pandemic caused by the novel human coronavirus, referrred to as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), not only is having a great impact on the health care systems and economies in all continents but it is also causing radical changes of common habits and life styles. The novel coronavirus (CoV) recognises, with high probability, a zoonotic origin but the role of animals in the SARS-CoV-2 epidemiology is still largely unknown. However, CoVs have been known in animals since several decades, so that veterinary coronavirologists have a great expertise on how to face CoV infections in animals, which could represent a model for SARS-CoV-2 infection in humans. In the present paper, we provide an up-to-date review of the literature currently available on animal CoVs, focusing on the molecular mechanisms that are responsible for the emergence of novel CoV strains with different antigenic, biologic and/or pathogenetic features. A full comprehension of the mechanisms driving the evolution of animal CoVs will help better understand the emergence, spreading, and evolution of SARS-CoV-2.
8ybfiz8f
8ybfiz8f
2020-05-31
10.1016/j.vetmic.2020.108693
3
The replication of a mouse adapted SARS-CoV in a mouse cell line stably expressing the murine SARS-CoV receptor mACE2 efficiently induces the expression of proinflammatory cytokines
Infection of conventional mice with a mouse adapted (MA15) severe acute respiratory syndrome (SARS) coronavirus (CoV) reproduces many aspects of human SARS such as pathological changes in lung, viremia, neutrophilia, and lethality. However, established mouse cell lines highly susceptible to mouse-adapted SARS-CoV infection are not available. In this work, efficiently transfectable mouse cell lines stably expressing the murine SARS-CoV receptor angiotensin converting enzyme 2 (ACE2) have been generated. These cells yielded high SARS-CoV-MA15 titers and also served as excellent tools for plaque assays. In addition, in these cell lines, SARS-CoV-MA15 induced the expression of proinflammatory cytokines and IFN-β, mimicking what has been observed in experimental animal models infected with SARS-CoV and SARS patients. These cell lines are valuable tools to perform in vitro studies in a mouse cell system that reflects the species used for in vivo studies of SARS-CoV-MA15 pathogenesis.
8zwfkken
8zwfkken
2013-11-01
10.1016/j.jviromet.2013.07.039
0.5
Saracatinib Inhibits Middle East Respiratory Syndrome-Coronavirus Replication In Vitro
The Middle East respiratory syndrome-coronavirus (MERS-CoV), first identified in Saudi Arabia, is an emerging zoonotic pathogen that causes severe acute respiratory illness in humans with a high fatality rate. Since its emergence, MERS-CoV continues to spread to countries outside of the Arabian Peninsula and gives rise to sporadic human infections following the entry of infected individuals to other countries, which can precipitate outbreaks similar to the one that occurred in South Korea in 2015. Current therapeutics against MERS-CoV infection have primarily been adapted from previous drugs used for the treatment of severe acute respiratory syndrome. In search of new potential drug candidates, we screened a library composed of 2334 clinically approved drugs and pharmacologically active compounds. The drug saracatinib, a potent inhibitor of Src-family of tyrosine kinases (SFK), was identified as an inhibitor of MERS-CoV replication in vitro. Our results suggest that saracatinib potently inhibits MERS-CoV at the early stages of the viral life cycle in Huh-7 cells, possibly through the suppression of SFK signaling pathways. Furthermore, saracatinib exhibited a synergistic effect with gemcitabine, an anticancer drug with antiviral activity against several RNA viruses. These data indicate that saracatinib alone or in combination with gemcitabine can provide a new therapeutic option for the treatment of MERS-CoV infection.
90j0a49r
90j0a49r
2018-05-24
10.3390/v10060283
3.5
Recent developments in the use of transgenic plants for the production of human therapeutics and biopharmaceuticals
In recent years there has been a dramatic increase in the application of plant biotechnology for the production of a variety of commercially valuable simple and complex biological molecules (biologics) for use in human and animal healthcare. Transgenic whole plants and plant cell culture systems have been developed that have the capacity to economically produce large-scale quantities of antibodies and antibody fragments, antigens and/or vaccine epitopes, metabolic enzymes, hormones, (neuro)peptides and a variety of biologically active complexes and secondary metabolites for direct use as therapeutic agents or diagnostic tools in the medical healthcare industry. As the products of genetically modified plants make their way from concept to commercialization the associated risks and acceptance by the public has been become a focal point. In this paper, we summarize the recent advances made in the use of transgenic plants and plant cell cultures as biological factories for the production of human therapeutics and biopharmaceuticals and discuss the long-term potential of `molecular farming' as a low-cost, efficient method for the production of biological materials with demonstrated utility to the pharmaceutical industry or medical community.
91xe475p
91xe475p
2004
10.1007/s11240-004-0653-0
3.5
The Role of Animal Models In Influenza Vaccine Research
A major challenge for research on influenza vaccines is the selection of an appropriate animal model that accurately reflects the disease and the protective immune response to influenza infection in humans. Vaccines for seasonal influenza have been available for decades and there is a wealth of data available on the immune response to these vaccines in humans, with well-established correlates of protection for inactivated influenza virus vaccines. Many of the seminal studies on vaccines for epidemic influenza have been conducted in human subjects. Studies in humans are performed less frequently now than they were in the past. Therefore, as the quest for improved influenza vaccines continues, it is important to consider the use of animal models for the evaluation of influenza vaccines, and a major challenge is the selection of an appropriate animal model that accurately reflects the disease and the protective immune response to influenza infection in humans. The emergence of highly pathogenic H5N1 avian influenza (AI) viruses and the threat of a pandemic caused by AI viruses of this or another subtype has resulted in a resurgence of interest in influenza vaccine research. The development of vaccines for pandemic influenza presents a unique set of obstacles, not the least of which is that the demonstration of efficacy in humans is not possible. As the correlates of protection from pandemic influenza are not known, we rely on extrapolation of the lessons from seasonal influenza vaccines and on data from the evaluation of pandemic influenza vaccines in animal models to guide our decisions on vaccines for use in humans. The features and contributions of commonly used animal models for influenza vaccine research are discussed. The recent emergence of the pandemic 2009 H1N1 influenza virus underscores the unpredictable nature of influenza viruses and the importance of pandemic preparedness.
92t646ti
92t646ti
2010-06-18
10.1007/978-3-0346-0279-2_10
4
Any possible role of phosphodiesterase type 5 inhibitors in the treatment of severe COVID19 infections? A lesson from urology
94u821us
94u821us
2020-05-31
10.1016/j.clim.2020.108414
1.5
Novel coronavirus disease (COVID-19): a pandemic (epidemiology, pathogenesis and potential therapeutics)
The coronavirus disease (COVID-19) is highly pathogenic viral infection caused by SARS-CoV-2. Currently, COVID-19 has caused global health concern. It is assumed that COVID-19 has zoonotic origin based on the large number of infected people who were exposed to the wet market in Wuhan City, China. The phylogenetic analysis has revealed that SARS-CoV-2 has significant sequence similarity with severe acute respiratory syndrome-like (SARS-like) bat viruses, thus bats could be primary possible reservoir. The intermediate host and there subsequent transfer is not known yet, although human to human transfer is widely confirmed. The transmission of COVID-19 infection from one person to another resulted in the isolation of patients who were subsequently given a variety of treatments. To monitor the current outbreak, robust steps have been taken around the globe to reduce the transmission of COVID-19 infection particularly banning international and domestic flights, inducting lockdowns in vulnerable areas, social distancing etc. No clinically approved antiviral drug or vaccine against COVID-19 is reported yet. However, in clinical trials, few broad-spectrum antiviral drugs were evaluated against COVID-19 infection which resulted in clinical recovery. In this article emergence and pathogenicity of COVID-19 infection along with potential therapeutic strategies are analyzed to combat the COVID-19 pandemic.
958u08vb
958u08vb
2020-04-14
10.1016/j.nmni.2020.100679
2
SARS-CoV-2 specific antibody responses in COVID-19 patients
A new coronavirus, SARS-CoV-2, has recently emerged to cause a human pandemic. Whereas molecular diagnostic tests were rapidly developed, serologic assays are still lacking, yet urgently needed. Validated serologic assays are important for contact tracing, identifying the viral reservoir and epidemiological studies. Here, we developed serological assays for the detection of SARS-CoV-2 neutralizing, spike- and nucleocapsid-specific antibodies. Using serum samples from patients with PCR-confirmed infections of SARS-CoV-2, other coronaviruses, or other respiratory pathogenic infections, we validated and tested various antigens in different in-house and commercial ELISAs. We demonstrate that most PCR-confirmed SARS-CoV-2 infected individuals seroconverted, as revealed by sensitive and specific in-house ELISAs. We found that commercial S1 IgG or IgA ELISAs were of lower specificity while sensitivity varied between the two, with IgA showing higher sensitivity. Overall, the validated assays described here can be instrumental for the detection of SARS-CoV-2-specific antibodies for diagnostic, seroepidemiological and vaccine evaluation studies.
9595vm0k
9595vm0k
2020-03-20
10.1101/2020.03.18.20038059
2.5
Current knowledge about the antivirals remdesivir (GS-5734) and GS-441524 as therapeutic options for coronaviruses
Abstract Recent international epidemics of coronavirus-associated illnesses underscore the urgent medical and public health need for vaccine development and regulatory body approved therapies. In particular, the current coronavirus disease 2019 (COVID-19) pandemic has quickly intensified interest in developing treatment options to mitigate impact on human life. Remdesivir (GS-5734™) is a broad-spectrum antiviral drug that is now being tested as a potential treatment for COVID-19 in international, multi-site clinical trials. Currently available evidence about the antiviral effects of remdesivir against coronaviruses is primarily based on in vitro and in vivo studies (including some on a chemically related compound, GS-441524™), which have demonstrated largely favorable findings. As the pandemic progresses, information from human compassionate use cases will continue to accumulate before the clinical trials are concluded. It is imperative for public health practitioners and the One Health community to stay up to date on the most promising potential therapeutic options that are under investigation. Thus, the purpose of this review is to synthesize the knowledge to date about remdesivir as a therapeutic option for coronaviruses, with a special focus on information relevant to the One Health community.
95fc828i
95fc828i
2020-06-30
10.1016/j.onehlt.2020.100128
1.5
Spike protein recognition of mammalian ACE2 predicts the host range and an optimized ACE2 for SARS-CoV-2 infection
Abstract SARS-CoV-2 causes the recent global COVID-19 public health emergency. ACE2 is the receptor for both SARS-CoV-2 and SARS-CoV. To predict the potential host range of SARS-CoV-2, we analyzed the key residues of ACE2 for recognizing S protein. We found that most of the selected mammals including pets (dog and cat), pangolin and Circetidae mammals remained the most of key residues for association with S protein from SARS-CoV and SARS-CoV-2. The interaction interface between cat/dog/pangolin/Chinese hamster ACE2 and SARS-CoV/SARS-CoV-2 S protein was simulated through homology modeling. We identified that N82 in ACE2 showed a closer contact with SARS-CoV-2 S protein than M82 in human ACE2. Our finding will provide important insights into the host range of SARS-CoV-2 and a new strategy to design an optimized ACE2 for SARS-CoV-2 infection.
96v185b2
96v185b2
2020-03-19
10.1016/j.bbrc.2020.03.047
1
The SARS-CoV-2 outbreak from a one health perspective
Abstract The SARS-CoV-2 is a new human coronavirus candidate recently detected in China that is now reported in people on inhabited continents. The virus shares a high level of identity with some bat coronaviruses and is recognised as a potentially zoonotic virus. We are utilizing the One Health concept to understand the emergence of the virus, as well as to point to some possible control strategies that might reduce the spread of the virus across the globe; thus, containment of such virus would be possible.
971d0sir
971d0sir
2020-03-16
10.1016/j.onehlt.2020.100127
2
Homology Modeling of TMPRSS2 Yields Candidate Drugs That May Inhibit Entry of SARS-CoV-2 into Human Cells.
The most rapid path to discovering treatment options for the novel coronavirus SARS-CoV-2 is to find existing medications that are active against the virus. We have focused on identifying repurposing candidates for the transmembrane serine protease family member II (TMPRSS2), which is critical for entry of coronaviruses into cells. Using known 3D structures of close homologs, we created seven homology models. We also identified a set of serine protease inhibitor drugs, generated several conformations of each, and docked them into our models. We used three known chemical (non-drug) inhibitors and one validated inhibitor of TMPRSS2 in MERS as benchmark compounds and found six compounds with predicted high binding affinity in the range of the known inhibitors. We also showed that a previously published weak inhibitor, Camostat, had a significantly lower binding score than our six compounds. All six compounds are anticoagulants with significant and potentially dangerous clinical effects and side effects. Nonetheless, if these compounds significantly inhibit SARS-CoV-2 infection, they could represent a potentially useful clinical tool.
97l3r5tv
97l3r5tv
2020-03-20
10.26434/chemrxiv.12009582.v1
5
Identification of Drugs Blocking SARS-CoV-2 Infection using Human Pluripotent Stem Cell-derived Colonic Organoids
The current COVID-19 pandemic is caused by SARS-coronavirus 2 (SARS-CoV-2). There are currently no therapeutic options for mitigating this disease due to lack of a vaccine and limited knowledge of SARS-CoV-2 biology. As a result, there is an urgent need to create new disease models to study SARS-CoV-2 biology and to screen for therapeutics using human disease-relevant tissues. COVID-19 patients typically present with respiratory symptoms including cough, dyspnea, and respiratory distress, but nearly 25% of patients have gastrointestinal indications including anorexia, diarrhea, vomiting, and abdominal pain. Moreover, these symptoms are associated with worse COVID-19 outcomes1. Here, we report using human pluripotent stem cell-derived colonic organoids (hPSC-COs) to explore the permissiveness of colonic cell types to SARS-CoV-2 infection. Single cell RNA-seq and immunostaining showed that the putative viral entry receptor ACE2 is expressed in multiple hESC-derived colonic cell types, but highly enriched in enterocytes. Multiple cell types in the COs can be infected by a SARS-CoV-2 pseudo-entry virus, which was further validated in vivo using a humanized mouse model. We used hPSC-derived COs in a high throughput platform to screen 1280 FDA-approved drugs against viral infection. Mycophenolic acid and quinacrine dihydrochloride were found to block the infection of SARS-CoV-2 pseudo-entry virus in COs both in vitro and in vivo, and confirmed to block infection of SARS-CoV-2 virus. This study established both in vitro and in vivo organoid models to investigate infection of SARS-CoV-2 disease-relevant human colonic cell types and identified drugs that blocks SARS-CoV-2 infection, suitable for rapid clinical testing.
97n1j0jj
97n1j0jj
2020-05-02
10.1101/2020.05.02.073320
3
Advanced bioinformatics rapidly identifies existing therapeutics for patients with coronavirus disease-2019 (COVID-19)
BACKGROUND: The recent global pandemic has placed a high priority on identifying drugs to prevent or lessen clinical infection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), caused by Coronavirus disease-2019 (COVID-19). METHODS: We applied two computational approaches to identify potential therapeutics. First, we sought to identify existing FDA approved drugs that could block coronaviruses from entering cells by binding to ACE2 or TMPRSS2 using a high-throughput AI-based binding affinity prediction platform. Second, we sought to identify FDA approved drugs that could attenuate the gene expression patterns induced by coronaviruses, using our Disease Cancelling Technology (DCT) platform. RESULTS: Top results for ACE2 binding iincluded several ACE inhibitors, a beta-lactam antibiotic, two antiviral agents (Fosamprenavir and Emricasan) and glutathione. The platform also assessed specificity for ACE2 over ACE1, important for avoiding counterregulatory effects. Further studies are needed to weigh the benefit of blocking virus entry against potential counterregulatory effects and possible protective effects of ACE2. However, the data herein suggest readily available drugs that warrant experimental evaluation to assess potential benefit. DCT was run on an animal model of SARS-CoV, and ranked compounds by their ability to induce gene expression signals that counteract disease-associated signals. Top hits included Vitamin E, ruxolitinib, and glutamine. Glutathione and its precursor glutamine were highly ranked by two independent methods, suggesting both warrant further investigation for potential benefit against SARS-CoV-2. CONCLUSIONS: While these findings are not yet ready for clinical translation, this report highlights the potential use of two bioinformatics technologies to rapidly discover existing therapeutic agents that warrant further investigation for established and emerging disease processes.
99v6mi9t
99v6mi9t
2020
5
Induction of interferon-gamma-inducible protein 10 by SARS-CoV infection, interferon alfacon 1 and interferon inducer in human bronchial epithelial Calu-3 cells and BALB/c mice.
BACKGROUND The pathogenesis of severe acute respiratory syndrome coronavirus (SARS-CoV) is poorly understood. Several mechanisms involving both direct effects on target cells and indirect effects via the immune system might exist. SARS-CoV has been shown in vitro to induce changes of cytokines and chemokines in various human and animal cells. We previously reported that interferon (IFN) alfacon-1 was more active against SARS-CoV infection in human bronchial epithelial Calu-3 cells than in African green monkey kidney epithelial cells on day 3 post-infection. METHODS In the current study, we first evaluated the efficacy of IFN-alfacon 1 in Calu-3 cells during the first 7 days of virus infection. We then used the two-antibody sandwich ELISA method to detect IFN-gamma-inducible protein 10 (IP-10). We further evaluated the efficacy of antivirals directed against SARS-CoV infection in BALB/c mice. RESULTS A potent, prolonged inhibition of SARS-CoV replication in Calu-3 cells with IFN-alfacon 1 was observed. Furthermore, IP-10, an IFN-inducible leukocyte chemoattractant, was detected in Calu-3 cells after SARS-CoV infection. Interestingly, IP-10 expression was shown to be significantly increased when SARS-CoV-infected Calu-3 cells were treated with IFN alfacon-1. IP-10 expression was detected in the lungs of SARS-CoV-infected BALB/c mice. Significantly high levels of mouse IP-10 in BALB/c mice was also detected when SARS-CoV-infected mice were treated with the interferon inducer, polyriboinosinic-polyribocytidylic acid stabilized with poly-L-lysine and carboxymethyl cellulose (poly IC:LC). Treatment with poly IC:LC by intranasal route were effective in protecting mice against a lethal infection with mouse-adapted SARS-CoV and reduced the viral lung titres. CONCLUSIONS Our data might provide an important insight into the mechanism of pathogenesis of SARS-CoV and these properties might be therapeutically advantageous.
9aohx31y
9aohx31y
2010
10.3851/imp1477
5
Pathogenic Priming Likely Contributes to Serious and Critical Illness and Mortality in COVID-19 via Autoimmunity
Homology between human and viral proteins is an established factor in viral- or vaccine-induced autoimmunity. Failure of SARS and MERS vaccines in animal trials involved pathogenesis consistent with an immunological priming that could involve autoimmunity in lung tissues due to previous exposure to the SARS and MERS spike protein. Exposure pathogenesis to SARS-CoV-2 in COVID-19 likely will lead to similar outcomes. Immunogenic peptides in viruses or bacteria that match human proteins are good candidates for pathogenic priming peptides (similar to the more diffuse idea of "immune enhancement"). Here I provide an assessment of potential for human pathogenesis via autoimmunity via exposure, via infection or injection. SAR-CoV-2 spike proteins, and all other SARS-CoV-2 proteins, immunogenic epitopes in each SARS-CoV-2 protein were compared to human proteins in search of high local homologous matching. Only one immunogenic epitope in a SARS-CoV-2 had no homology to human proteins. If all of the parts of the epitopes that are homologous to human proteins are excluded from consideration due to risk of pathogenic priming, the remaining immunogenic parts of the epitopes may be still immunogenic and remain as potentially viable candidates for vaccine development. Mapping of the genes encoding human protein matches to pathways point to targets that could explain the observed presentation of symptoms in COVID-19 disease. It also strongly points to a large number of opportunities for expected disturbances in the immune system itself, targeting elements of MCH Class I and Class II antigen presentation, PD-1 signaling, cross-presentation of soluble exogenous antigens and the ER-Phagosome pathway. Translational consequences of these findings are explored.
9aw41qhp
9aw41qhp
2020
3
Potential anti-viral activity of approved repurposed drug against main protease of SARS-CoV-2: an in silico based approach.
The Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) which was first reported in Wuhan province of China, has become a deadly pandemic causing alarmingly high morbidity and mortality. In the absence of new targeted drugs and vaccines against SARS-CoV-2 at present, the choices for effective treatments are limited. Therefore, considering the exigency of the situation, we focused on identifying the available approved drugs as potential inhibitor against the promising Coronavirus drug target, the Main Protease, using computer-aided methods. We created a library of U. S. Food and Drug Administration approved anti-microbial drugs and virtually screened it against the available crystal structures of Main Protease of the virus. The study revealed that Viomycin showed the highest -CDocker energy after docking at the active site of SARS-CoV-2 Main Protease. It is noteworthy that Viomycin showed higher -CDocker energy as compared to the drugs currently under clinical trial for SARS-CoV-2 treatment viz. Ritonavir and Lopinavir. Additionally, Viomycin formed higher number of H-bonds with SARS-CoV-2 Main Protease than its co-crystallised inhibitor compound N3. Molecular dynamics simulation further showed that Viomycin embedded deeply inside the binding pocket and formed robust binding with SARS-CoV-2 Main Protease. Therefore, we propose that Viomycin may act as a potential inhibitor of the Main Protease of SARS-CoV-2. Further optimisations with the drug may support the much-needed rapid response to mitigate the pandemic.
9bhp3lph
9bhp3lph
2020-05-14
10.1080/07391102.2020.1768902
3
Safety Guidelines for Sterility of Face Shields During COVID 19 Pandemic
Face shields are personal protective equipment devices that are to be used by many health care workers during COVID 19 pandemic for protection of the facial area and associated mucous membranes (eyes, nose, mouth) from droplet spread of infection. Face shields are generally not used alone, but in conjunction with other protective equipment like cap, mask, goggle, and are therefore classified as adjunctive personal protective equipment. In the wake of scarcity of face shields during the COVID 19 Pandemic, consideration of innovating newer methods of manufacturing must be considered to overcome the present day scarcity without jeopardising the safety of front line Heath care workers. All initial fast innovations comes with advantages and disadvantages, hence we thought of putting down simple guidelines for new emerged face shield use.
9ec6hygx
9ec6hygx
2020-04-30
10.1007/s12070-020-01865-2
3.5
ACVIM consensus statement on the diagnosis of immune‐mediated hemolytic anemia in dogs and cats
Immune‐mediated hemolytic anemia (IMHA) is an important cause of morbidity and mortality in dogs. IMHA also occurs in cats, although less commonly. IMHA is considered secondary when it can be attributed to an underlying disease, and as primary (idiopathic) if no cause is found. Eliminating diseases that cause IMHA may attenuate or stop immune‐mediated erythrocyte destruction, and adverse consequences of long‐term immunosuppressive treatment can be avoided. Infections, cancer, drugs, vaccines, and inflammatory processes may be underlying causes of IMHA. Evidence for these comorbidities has not been systematically evaluated, rendering evidence‐based decisions difficult. We identified and extracted data from studies published in the veterinary literature and developed a novel tool for evaluation of evidence quality, using it to assess study design, diagnostic criteria for IMHA, comorbidities, and causality. Succinct evidence summary statements were written, along with screening recommendations. Statements were refined by conducting 3 iterations of Delphi review with panel and task force members. Commentary was solicited from several professional bodies to maximize clinical applicability before the recommendations were submitted. The resulting document is intended to provide clinical guidelines for diagnosis of, and underlying disease screening for, IMHA in dogs and cats. These should be implemented with consideration of animal, owner, and geographical factors.
9gy3lnk0
9gy3lnk0
2019-02-26
10.1111/jvim.15441
1.5
Synthesis and evaluation of isatin derivatives as effective SARS coronavirus 3CL protease inhibitors
Abstract N-Substituted isatin derivatives were prepared from the reaction of isatin and various bromides via two steps. Bioactivity assay results (in vitro tests) demonstrated that some of these compounds are potent and selective inhibitors against SARS coronavirus 3CL protease with IC50 values ranging from 0.95 to 17.50μM. Additionally, isatin 4o exhibited more potent inhibition for SARS coronavirus protease than for other proteases including papain, chymotrypsin, and trypsin.
9he52hq5
9he52hq5
2005-06-15
10.1016/j.bmcl.2005.04.027
3
SARS-CoV-2 RNA dependent RNA polymerase (RdRp) targeting: an in silico perspective
New treatment against SARS-CoV-2 now is a must. Nowadays, the world encounters a huge health crisis by the COVID-19 viral infection. Nucleotide inhibitors gave a lot of promising results in terms of its efficacy against different viral infections. In this work, molecular modeling, docking, and dynamics simulations are used to build a model for the viral protein RNA-dependent RNA polymerase (RdRp) and test its binding affinity to some clinically approved drugs and drug candidates. Molecular dynamics is used to equilibrate the system upon binding calculations to ensure the successful reproduction of previous results, to include the dynamics of the RdRp, and to understand how it affects the binding. The results show the effectiveness of Sofosbuvir, Ribavirin, Galidesivir, Remdesivir, Favipiravir, Cefuroxime, Tenofovir, and Hydroxychloroquine, in binding to SARS-CoV-2 RdRp. Additionally, Setrobuvir, YAK, and IDX-184, show better results, while four novel IDX-184 derivatives show promising results in attaching to the SARS-CoV-2 RdRp. There is an urgent need to specify drugs that can selectively bind and subsequently inhibit SARS-CoV-2 proteins. The availability of a punch of FDA-approved anti-viral drugs can help us in this mission, aiming to reduce the danger of COVID-19. The compounds 2 and 3 may tightly bind to the SARS-CoV-2 RdRp and so may be successful in the treatment of COVID-19.
9hkh806d
9hkh806d
2020
3
Arguments in favour of remdesivir for treating SARS-CoV-2 infections
9hxihlw9
9hxihlw9
2020-03-06
10.1016/j.ijantimicag.2020.105933
1
Inhibition of severe acute respiratory syndrome-associated coronavirus infection by equine neutralizing antibody in golden Syrian hamsters.
Equine anti-severe acute respiratory syndrome-associated coronavirus F(ab')(2) has been verified to protect mice from infection with severe acute respiratory syndrome-associated coronavirus (SARS-CoV). However, before potential clinical application, the antibody needs to be tested in as many animal models as possible to ensure its safety and efficiency. In this study, after verification by various methods that the golden Syrian hamster constitutes a model susceptible to SARS-CoV infection, we confirmed that the antibody could protect animals completely from SARS-CoV infection in the preventive setting. More importantly, the antibody could reduce viral titers or copies by approximately 10(3)- to 10(4)-fold in animal lung after virus exposure, compared with negative control. These data provide further evidence to warrant clinical studies of this antibody in the treatment and prevention of SARS.
9i47w641
9i47w641
2007
4
COVID-19: Epidemiology, Evolution, and Cross-Disciplinary Perspectives
The recent outbreak of COVID-19 in Wuhan turned into a public health emergency of international concern. With no antiviral drugs nor vaccines, and the presence of carriers without obvious symptoms, traditional public health intervention measures are significantly less effective. Here, we report the epidemiological and virological characteristics of the COVID-19 outbreak. Originated in bats, 2019-nCoV/ severe acute respiratory syndrome coronavirus (SARS-CoV)-2 likely experienced adaptive evolution in intermediate hosts before transfer to humans at a concentrated source of transmission. Similarities of receptor sequence binding to 2019-nCoV between humans and animals suggest a low species barrier for transmission of the virus to farm animals. We propose, based on the One Health model, that veterinarians and animal specialists should be involved in a cross-disciplinary collaboration in the fight against this epidemic.
9il7coyk
9il7coyk
2020-03-21
10.1016/j.molmed.2020.02.008
0.5
Nonhuman Primate Models of Respiratory Disease: Past, Present, and Future
The respiratory system consists of an integrated network of organs and structures that primarily function for gas exchange. In mammals, oxygen and carbon dioxide are transmitted through a complex respiratory tract, consisting of the nasal passages, pharynx, larynx, and lung. Exposure to ambient air throughout the lifespan imposes vulnerability of the respiratory system to environmental challenges that can contribute toward development of disease. The importance of the respiratory system to human health is supported by statistics from the Centers for Disease Control and Prevention; in 2015, chronic lower respiratory diseases were the third leading cause of death in the United States. In light of the significant mortality associated with respiratory conditions that afflict all ages of the human population, this review will focus on basic and preclinical research conducted in nonhuman primate models of respiratory disease. In comparison with other laboratory animals, the nonhuman primate lung most closely resembles the human lung in structure, physiology, and mucosal immune mechanisms. Studies defining the influence of inhaled microbes, pollutants, or allergens on the nonhuman primate lung have provided insight on disease pathogenesis, with the potential for elucidation of molecular targets leading to new treatment modalities. Vaccine trials in nonhuman primates have been crucial for confirmation of safety and protective efficacy against infectious diseases of the lung in a laboratory animal model that recapitulates pathology observed in humans. In looking to the future, nonhuman primate models of respiratory diseases will continue to be instrumental for translating biomedical research for improvement of human health.
9j34u77w
9j34u77w
2017-01-01
10.1093/ilar/ilx030
1.5
Insights from molecular structure predictions of the infectious bronchitis virus S1 spike glycoprotein
Abstract Infectious bronchitis virus is an important respiratory pathogen in chickens. The IBV S1 spike is a viral structural protein that is responsible for attachment to host receptors and is a major target for neutralizing antibodies. To date, there is no experimentally determined structure for the IBV S1 spike. In this study, we sought to find a predicted tertiary structure for IBV S1 using I-TASSER, which is an automated homology modeling platform. We found that the predicted structures obtained were robust and consistent with experimental data. For instance, we observed that all four residues (38, 43, 63, and 68) that have been shown to be critical for binding to host tissues, were found at the surface of the predicted structure of Massachusetts (Mass) S1 spike. Together with antigenicity index analysis, we were also able to show that Ma5 vaccine has higher antigenicity indices at residues close to the receptor-binding region than M41 vaccine, thereby providing a possible mechanism on how Ma5 achieves better protection against challenge. Examination of the predicted structure of the Arkansas IBV S1 spike also gave insights on the effect of polymorphisms at position 43 on the surface availability of receptor binding residues. This study showcases advancements in protein structure prediction and contributes useful, inexpensive tools to provide insights into the biology of IBV.
9jhn0b7q
9jhn0b7q
2016-12-31
10.1016/j.meegid.2016.11.006
1
Inhibitors of SARS-CoV-2 Entry: Current and Future Opportunities
[Image: see text] Recently, a novel coronavirus initially designated 2019-nCoV but now termed SARS-CoV-2 has emerged and raised global concerns due to its virulence. SARS-CoV-2 is the etiological agent of “coronavirus disease 2019”, abbreviated to COVID-19, which despite only being identified at the very end of 2019, has now been classified as a pandemic by the World Health Organization (WHO). At this time, no specific prophylactic or postexposure therapy for COVID-19 are currently available. Viral entry is the first step in the SARS-CoV-2 lifecycle and is mediated by the trimeric spike protein. Being the first stage in infection, entry of SARS-CoV-2 into host cells is an extremely attractive therapeutic intervention point. Within this review, we highlight therapeutic intervention strategies for anti-SARS-CoV, MERS-CoV, and other coronaviruses and speculate upon future directions for SARS-CoV-2 entry inhibitor designs.
9jwma2y6
9jwma2y6
2020-06-15
10.1021/acs.jmedchem.0c00502
5
The genetic sequence, origin, and diagnosis of SARS-CoV-2
Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is a new infectious disease that first emerged in Hubei province, China, in December 2019, which was found to be associated with a large seafood and animal market in Wuhan. Airway epithelial cells from infected patients were used to isolate a novel coronavirus, named the SARS-CoV-2, on January 12, 2020, which is the seventh member of the coronavirus family to infect humans. Phylogenetic analysis of full-length genome sequences obtained from infected patients showed that SARS-CoV-2 is similar to severe acute respiratory syndrome coronavirus (SARS-CoV) and uses the same cell entry receptor, angiotensin-converting enzyme 2 (ACE2), as SARS-CoV. The possible person-to-person disease rapidly spread to many provinces in China as well as other countries. Without a therapeutic vaccine or specific antiviral drugs, early detection and isolation become essential against novel Coronavirus. In this review, we introduced current diagnostic methods and criteria for the SARS-CoV-2 in China and discuss the advantages and limitations of the current diagnostic methods, including chest imaging and laboratory detection.
9mxvbf17
9mxvbf17
2020-04-24
10.1007/s10096-020-03899-4
3
A human monoclonal antibody blocking SARS-CoV-2 infection
The emergence of the novel human coronavirus SARS-CoV-2 in Wuhan, China has caused a worldwide epidemic of respiratory disease (COVID-19). Vaccines and targeted therapeutics for treatment of this disease are currently lacking. Here we report a human monoclonal antibody that neutralizes SARS-CoV-2 (and SARS-CoV) in cell culture. This cross-neutralizing antibody targets a communal epitope on these viruses and may offer potential for prevention and treatment of COVID-19.
9n7bkayx
9n7bkayx
2020-05-04
10.1038/s41467-020-16256-y
3
Design, synthesis and evaluation of a series of acyclic fleximer nucleoside analogues with anti-coronavirus activity
A series of doubly flexible nucleoside analogues were designed based on the acyclic sugar scaffold of acyclovir and the flex-base moiety found in the fleximers. The target compounds were evaluated for their antiviral potential and found to inhibit several coronaviruses. Significantly, compound 2 displayed selective antiviral activity (CC(50) > 3x EC(50)) towards human coronavirus (HCoV)-NL63 and Middle East respiratory syndrome-coronavirus, but not severe acute respiratory syndrome-coronavirus. In the case of HCoV-NL63 the activity was highly promising with an EC(50) < 10 μM and a CC(50) > 100 μM. As such, these doubly flexible nucleoside analogues are viewed as a novel new class of drug candidates with potential for potent inhibition of coronaviruses.
9o0mc3rd
9o0mc3rd
2015-08-01
10.1016/j.bmcl.2015.05.039
2
Legal and Ethical Aspects of ‘Best Interests’ Decision-Making for Medical Treatment of Companion Animals in the UK
SIMPLE SUMMARY: Making decisions about medical treatment for animal patients involves two key decision-makers, the animal owner and the veterinary surgeon. We aim to show that these decisions should and can be based on the ‘best interests’ of the animal, with both human decision-makers acting as advocates for the animal requiring treatment. We suggest that the role of the animal owner is similar to that of a parent in making decisions for a child, drawing on legal cases to demonstrate the limits of parental (and owner) decision-making. To provide a firmer basis for ‘best interests’ decision-making, we adapt the factors included in the United Nations Convention on the Rights of the Child and demonstrate how these could be used with a typical clinical situation. Finally, we analyse the decisions from an ethical point of view. ABSTRACT: Medical decisions for young children are made by those with parental responsibility, with legal involvement only if the decision is potentially detrimental to the child’s welfare. While legally classified as property, some argue that animals are in a similar position to children; treatment decisions are made by their owners, posing a legal challenge only if the proposed treatment has the potential to cause harm or unnecessary suffering, as defined by animal protection legislation. This paper formulates the approach to a ‘best interests’ calculation, utilising the factors included in the United Nations Convention on the Rights of the Child and relying on exchange of information between the human parties involved. Although this form of decision-making must primarily protect the animal from unnecessary suffering, it recognises that the information provided by the owner is critical in articulating the animal’s non-medical interests, and hence in formulating what is in the animal’s best overall welfare interests. While statute law does not mandate consideration of ‘best interests’ for animals, this approach might reasonably be expected as a professional imperative for veterinary surgeons. Importantly, this version of a ‘best interests’ calculation can be incorporated into existing ethical frameworks for medical decision-making and the humane treatment of animals.
9o3utlfx
9o3utlfx
2020-06-09
10.3390/ani10061009
5
Oral drug repositioning candidates and synergistic remdesivir combinations for the prophylaxis and treatment of COVID-19
The ongoing pandemic caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), necessitates strategies to identify prophylactic and therapeutic drug candidates for rapid clinical deployment. A high-throughput, high-content imaging assay of human HeLa cells expressing the SARS-CoV-2 receptor ACE2 was used to screen ReFRAME, a best-in-class drug repurposing library. From nearly 12,000 compounds, we identified 66 compounds capable of selectively inhibiting SARS-CoV-2 replication in human cells. Twenty-four of these drugs show additive activity in combination with the RNA-dependent RNA polymerase inhibitor remdesivir and may afford increased in vivo efficacy. We also identified synergistic interaction of the nucleoside analog riboprine and a folate antagonist 10-deazaaminopterin with remdesivir. Overall, seven clinically approved drugs (halofantrine, amiodarone, nelfinavir, simeprevir, manidipine, ozanimod, osimertinib) and 19 compounds in other stages of development may have the potential to be repurposed as SARS-CoV-2 oral therapeutics based on their potency, pharmacokinetic and human safety profiles.
9od553a6
9od553a6
2020-06-16
10.1101/2020.06.16.153403
5
Chloroquine and hydroxychloroquine as available weapons to fight COVID-19
9q3lmsd3
9q3lmsd3
2020-04-30
10.1016/j.ijantimicag.2020.105932
1
Therapeutic Development and Drugs for the Treatment of COVID-19
SARS-CoV-2/novel coronavirus (2019-nCoV) is a new strain that has recently been confirmed in Wuhan City, Hubei Province of China, and spreads to more than 165 countries of the world including India. The virus infection leads to 245,922 confirmed cases and 10,048 deaths worldwide as of March 20, 2020. Coronaviruses (CoVs) are lethal zoonotic viruses, highly pathogenic in nature, and responsible for diseases ranging from common cold to severe illness such as Middle East respiratory syndrome (MERS) and severe acute respiratory syndrome (SARS) in humans for the past 15 years. Considering the severity of the current and previous outbreaks, no approved antiviral agent or effective vaccines are present for the prevention and treatment of infection during the epidemics. Although, various molecules have been shown to be effective against coronaviruses both in vitro and in vivo, but the antiviral activities of these molecules are not well established in humans. Therefore, this chapter is planned to provide information about available treatment and preventive measures for the coronavirus infections during outbreaks. This chapter also discusses the possible role of supportive therapy, repurposing drugs, and complementary and alternative medicines for the management of coronaviruses including COVID-19.
9q7zbmwp
9q7zbmwp
2020-04-30
10.1007/978-981-15-4814-7_10
3
Epidemiological Identification of A Novel Pathogen in Real Time: Analysis of the Atypical Pneumonia Outbreak in Wuhan, China, 2019–2020
Virological tests have now shown conclusively that a novel coronavirus is causing the 2019–2020 atypical pneumonia outbreak in Wuhan, China. We demonstrate that non-virological descriptive characteristics could have determined that the outbreak is caused by a novel pathogen in advance of virological testing. Characteristics of the ongoing outbreak were collected in real time from two medical social media sites. These were compared against characteristics of eleven pathogens that have previously caused cases of atypical pneumonia. The probability that the current outbreak is due to “Disease X” (i.e., previously unknown etiology) as opposed to one of the known pathogens was inferred, and this estimate was updated as the outbreak continued. The probability (expressed as a percentage) that Disease X is driving the outbreak was assessed as over 29% on 31 December 2019, one week before virus identification. After some specific pathogens were ruled out by laboratory tests on 5 January 2020, the inferred probability of Disease X was over 49%. We showed quantitatively that the emerging outbreak of atypical pneumonia cases is consistent with causation by a novel pathogen. The proposed approach, which uses only routinely observed non-virological data, can aid ongoing risk assessments in advance of virological test results becoming available.
9quf59td
9quf59td
2020-02-27
10.3390/jcm9030637
2.5
Is SARS-CoV-2 Also an Enteric Pathogen with Potential Fecal-Oral Transmission: A COVID-19 Virological and Clinical Review
Abstract In as short as 3 months, COVID-19 has spread and ravaged the world in an unprecedented speed in modern history rivaling the 1918 flu pandemic. SARS-CoV-2, the culprit virus, is highly contagious and stable in the environment and predominantly transmits among humans via the respiratory route. Accumulating evidence suggest that this virus, like many of its related viruses, may also be an enteric virus that can spread via the fecal-oral route. Such a hypothesis would also contribute to the rapidity and proliferation of this pandemic. Here we briefly summarize what is known about this family of viruses and literature basis of the hypothesis that SARS-CoV-2 is capable of infecting the gastrointestinal tract and shedding in the environment for potential human-to-human transmission.
9rg9xe57
9rg9xe57
2020-04-27
10.1053/j.gastro.2020.04.052
2
Absence of SARS-CoV-2 infection in cats and dogs in close contact with a cluster of COVID-19 patients in a veterinary campus
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which originated in Wuhan, China, in 2019, is responsible for the COVID-19 pandemic. It is now accepted that the wild fauna, probably bats, constitute the initial reservoir of the virus, but little is known about the role pets can play in the spread of the disease in human communities, knowing the ability of SARS-CoV-2 to infect some domestic animals. We tested 21 domestic pets (9 cats and 12 dogs) living in close contact with their owners (belonging to a veterinary community of 20 students) in which two students tested positive for COVID-19 and several others (n = 11/18) consecutively showed clinical signs (fever, cough, anosmia, etc.) compatible with COVID-19 infection. Although a few pets presented many clinical signs indicative for a coronavirus infection, no animal tested positive for SARS-CoV-2 by RT-PCR and no antibodies against SARS-CoV-2 were detectable in their blood using an immunoprecipitation assay. These original data can serve a better evaluation of the host range of SARS-CoV-2 in natural environment exposure conditions.
9rhydy8u
9rhydy8u
2020-04-09
10.1101/2020.04.07.029090
2
Pharmacotherapy in COVID-19; A narrative review for emergency providers
INTRODUCTION: The COVID-19 pandemic has been particularly challenging due to a lack of established therapies and treatment guidelines. With the rapid transmission of disease, even the off-label use of available therapies has been impeded by limited availability. Several antivirals, antimalarials, and biologics are being considered for treatment at this time. The purpose of this literature review is to synthesize the available information regarding treatment options for COVID-19 and serve as a resource for health care professionals. OBJECTIVES: This narrative review was conducted to summarize the effectiveness of current therapy options for COVID-19 and address the controversial use of non-steroidal anti-inflammatory drugs (NSAIDs), angiotensin converting enzyme (ACE) inhibitors, and angiotensin receptor blockers (ARBs). PubMed and SCOPUS were queried using a combination of the keywords “COVID 19,” “SARS-CoV-2,” and “treatment.” All types of studies were evaluated including systematic reviews, case-studies, and clinical guidelines. DISCUSSION: There are currently no therapeutic drugs available that are directly active against SARS-CoV-2; however, several antivirals (remdesivir, favipiravir) and antimalarials (chloroquine, hydroxychloroquine) have emerged as potential therapies. Current guidelines recommend combination treatment with hydroxychloroquine/azithromycin or chloroquine, if hydroxychloroquine is unavailable, in patients with moderate disease, although these recommendations are based on limited evidence. Remdesivir and convalescent plasma may be considered in critical patients with respiratory failure; however, access to these therapies may be limited. Interleukin-6 (IL-6) antagonists may be used in patients who develop evidence of cytokine release syndrome (CRS). Glucocorticoids should be avoided unless there is evidence of refractory septic shock, acute respiratory distress syndrome (ARDS), or another compelling indication for their use. ACE inhibitors and ARBs should not be discontinued at this time and ibuprofen may be used for fever. CONCLUSION: There are several ongoing clinical trials that are testing the efficacy of single and combination treatments with the drugs mentioned in this review and new agents are under development. Until the results of these trials become available, we must use the best available evidence for the prevention and treatment of COVID-19. Additionally, we can learn from the experiences of healthcare providers around the world to combat this pandemic.
9ryu9ady
9ryu9ady
2020-04-15
10.1016/j.ajem.2020.04.035
2
Remdesivir inhibits SARS-CoV-2 in human lung cells and chimeric SARS-CoV expressing the SARS-CoV-2 RNA polymerase in mice.
Summary Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of the novel viral disease COVID-19. With no approved therapies, this pandemic illustrates the urgent need for broad-spectrum antiviral countermeasures against SARS-CoV-2 and future emerging CoVs. We report that remdesivir (RDV) potently inhibits SARS-CoV-2 replication in human lung cells and primary human airway epithelial cultures (EC50 = 0.01 μM). Weaker activity is observed in Vero E6 cells (EC50 = 1.65 μM) due to their low capacity to metabolize RDV. To rapidly evaluate in vivo efficacy, we engineered a chimeric SARS-CoV encoding the viral target of RDV, the RNA-dependent RNA polymerase, of SARS-CoV-2. In mice infected with chimeric virus, therapeutic RDV administration diminishes lung viral load and improves pulmonary function compared to vehicle treated animals. These data demonstrate that RDV is potently active against SARS-CoV-2 in vitro and in vivo, supporting its further clinical testing for treatment of COVID-19.
9sjdb7f3
9sjdb7f3
2020-07-07
10.1016/j.celrep.2020.107940
5
The Role of Host Genetic Factors in Coronavirus Susceptibility: Review of Animal and Systematic Review of Human Literature
Background: The recent SARS-CoV-2 pandemic raises many scientific and clinical questions. One set of questions involves host genetic factors that may affect disease susceptibility and pathogenesis. New work is emerging related to SARS-CoV-2; previous work has been conducted on other coronaviruses that affect different species. Objectives: We aimed to review the literature on host genetic factors related to coronaviruses, with a systematic focus on human studies. Methods: We conducted a PubMed-based search and analysis for articles relevant to host genetic factors in coronavirus. We categorized articles, summarized themes related to animal studies, and extracted data from human studies for analyses. Results: We identified 1,187 articles of potential relevance. Forty-five studies were related to human host genetic factors related to coronavirus, of which 35 involved analysis of specific genes or loci; aside from one meta-analysis on respiratory infections, all were candidate-driven studies, typically investigating small number of research subjects and loci. Multiple significant loci were identified, including 16 related to susceptibility to coronavirus (of which 7 identified protective alleles), and 16 related to outcomes or clinical variables (of which 3 identified protective alleles). The types of cases and controls used varied considerably; four studies used traditional replication/validation cohorts. Of the other studies, 28 involved both human and non-human host genetic factors related to coronavirus, 174 involved study of non-human (animal) host genetic factors related to coronavirus, 584 involved study of non-genetic host factors related to coronavirus, including involving immunopathogenesis, 16 involved study of other pathogens (not coronavirus), 321 involved other studies of coronavirus, and 18 studies were assigned to the other categories and removed. Key findings: We have outlined key genes and loci from animal and human host genetic studies that may bear investigation in the nascent host genetic factor studies of COVID-19. Previous human studies to date have been limited by issues that may be less impactful on current endeavors, including relatively low numbers of eligible participants and limited availability of advanced genomic methods.
9sx2jrit
9sx2jrit
2020-06-03
10.1101/2020.05.30.20117788
4.5
The antiviral and the coronavirus-host protein pathways inhibiting properties of herbs and natural compounds - Additional weapons in the fight against the COVID-19 pandemic?
INTRODUCTION: As of March 11th, 2020, the World Health Organization declared the COVID-19 outbreak a pandemic. Articles published after the SARS-CoV-1 (2002) epidemic suggest that the use of an herbal-drug integrative medical approach could have contributed to a lower fatality rate and a more rapid response in controlling the outbreak. METHODS: Pubmed was searched for articles that investigated the antiviral properties and mechanisms of action of herbs or natural compounds against the SARS-coronavirus (CoV). RESULTS: Forty-three (43) relevant papers were located. A general count rendered 450+ herbs and natural compounds with antiviral properties against the SARS-CoV and related viruses. From the 43 articles, thirty-one (31) uncovered the mechanisms of action of the natural substances able to oppose the coronavirus. DISCUSSION: A series of herbs and natural compounds demonstrated moderate to strong antiviral activity. Research on many herbs-natural compounds also showed potent and significant inhibition of CoV-host protein pathways responsible for different phases of viral replication specifically targeting 3CL(PRO), PL(PRO), RdRp, helicase protein, S protein, N protein, 3a protein, Cathepsin L, Nsp1, Nsp3c, and ORF7a, and the S protein-ACE-2 interaction. CONCLUSION: The herbs-natural compounds with antiviral activity and that caused inhibition/blockade of the CoV-host protein pathways are potential therapeutic candidates. The homology between the SARS-CoV-1 and SARS-CoV-2 is around 80%. Thus, effective herbs-compounds for the former would likely be beneficial for the latter also depending on target protein similarities between the viruses. Here we provide the mechanistic bases supporting an integrative approach that includes natural compounds to fight coronavirus infections.
9tdqbwtg
9tdqbwtg
2020-05-30
10.1016/j.jtcme.2020.05.003
4
Development of antiviral therapy for severe acute respiratory syndrome
Abstract A new disease, the severe acute respiratory distress syndrome (SARS), caused by the SARS coronavirus (SARS-CoV), emerged at the beginning of 2003 and rapidly spread throughout the world. Although the disease had disappeared in June 2003 its re-emergence cannot be excluded. The development of vaccines against SARS-CoV may take years. Therefore, the availability of effective antiviral drugs against SARS-CoV may be crucial for the control of future SARS outbreaks. In this review, experimental and clinical data about potential anti-SARS drugs is summarised and discussed. Animal model studies will be needed to help to determine which interventions warrant controlled clinical testing.
9ujofcsm
9ujofcsm
2005-06-30
10.1016/j.antiviral.2005.03.002
0.5
COVID-19: combining antiviral and anti-inflammatory treatments
9ukf9vpg
9ukf9vpg
2020-04-30
10.1016/s1473-3099(20)30132-8
2.5
Construction of a non-infectious SARS coronavirus replicon for application in drug screening and analysis of viral protein function
Abstract Severe acute respiratory syndrome virus (SARS-CoV) was the causative agent of the SARS outbreaks in 2002–2003. A safer in vitro system is desirable for conducting research on SARS-CoV and to screen for antiviral drugs against the virus. Based on the infectious cDNA clone of rSARS-CoV-ΔE, in which the E gene has been deleted, a safe non-infectious replicon was constructed by replacing the S gene with the enhanced green fluorescent protein (eGFP) gene. Successful replication was achieved as evident from continuous expression of eGFP detected by both fluorescence and Western blot. Treatment with antiviral drugs demonstrated that the replication could be significantly inhibited by 0.4mg/ml of cysteine proteinase inhibitor E-64D, but not by ribavirin. The same replicons containing further deletion of the coding regions for non-structural proteins (nsp) 1, 2 or 16 confirmed previous observation that nsp16, but not nsp1 or nsp2, was essential for efficient viral replication or transcription.
9vi8xwu7
9vi8xwu7
2008-09-12
10.1016/j.bbrc.2008.06.129
1
COVID-19 infection and rheumatoid arthritis: Faraway, so close!
Abstract The outbreak of the new coronavirus infections COVID-19 in December 2019 in China has quickly become a global health emergency. Given the lack of specific anti-viral therapies, the current management of severe acute respiratory syndrome coronaviruses (SARS-CoV-2) is mainly supportive, even though several compounds are now under investigation for the treatment of this life-threatening disease. COVID-19 pandemic is certainly conditioning the treatment strategy of a complex disorder as rheumatoid arthritis (RA), whose infectious risk is increased compared to the general population because of an overall impairment of immune system typical of autoimmune diseases combined with the iatrogenic effect generated by corticosteroids and immunosuppressive drugs. However, the increasing knowledge about the pathophysiology of SARS-CoV-2 infection is leading to consider some anti-rheumatic drugs as potential treatment options for the management of COVID-19. In this review we will critically analyse the evidences on either positive or negative effect of drugs commonly used to treat RA in this particular scenario, in order to optimize the current approach to RA patients.
9vrny92m
9vrny92m
2020-03-20
10.1016/j.autrev.2020.102523
1
Diacerein: a potential multi-target therapeutic drug for COVID-19
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which causes coronavirus disease 19 (COVID-19), was declared pandemic by the World Health Organization in March 2020. SARS-CoV-2 binds its host cell receptor, angiotensin-converting enzyme 2 (ACE2), through the viral spike (S) protein. The mortality related to severe acute respiratory distress syndrome (ARDS) and multi-organ failure in COVID-19 patients has been suggested to be connected with cytokine storm syndrome (CSS), an excessive immune response that severely damages healthy lung tissue. In addition, cardiac symptoms, including fulminant myocarditis, are frequent in patients in a severe state of illness. Diacerein (DAR) is an anthraquinone derivative drug whose active metabolite is rhein. Different studies have shown that this compound inhibits the IL-1, IL-2, IL-6, IL-8, IL-12, IL-18, TNF-α, NF-κB and NALP3 inflammasome pathways. The antiviral activity of rhein has also been documented. This metabolite prevents hepatitis B virus (HBV) replication and influenza A virus (IAV) adsorption and replication through mechanisms involving regulation of oxidative stress and alterations of the TLR4, Akt, MAPK, and NF-κB signalling pathways. Importantly, rhein inhibits the interaction between the SARS-CoV S protein and ACE2 in a dose-dependent manner, suggesting rhein as a potential therapeutic agent for the treatment of SARS-CoV infection. Based on these findings, we hypothesize that DAR is a multi-target drug useful for COVID-19 treatment. This anthraquinone may control hyperinflammatory conditions by multi-faceted cytokine inhibition and by reducing viral infection.
9wbq9qo2
9wbq9qo2
2020-06-01
10.1016/j.mehy.2020.109920
4.5
P1460 – P1884
9wnmdvg5
9wnmdvg5
2015-12-28
10.1111/j.1470-9465.2006.12_4_1431.x
2.5
Occupational Health of Animal Workers
9ydjwa2g
9ydjwa2g
2010-12-27
10.1016/b978-1-4160-6837-2.00012-9
5
COVID-19 Blockchain Framework: Innovative Approach
The world is currently witnessing dangerous shifts in the epidemic of emerging SARS-CoV-2, the causative agent of (COVID-19) coronavirus. The infection, and death numbers reported by World Health Organization (WHO) about this epidemic forecasts an increasing threats to the lives of people and the economics of countries. The greatest challenge that most governments are currently suffering from is the lack of a precise mechanism to detect unknown infected cases and predict the infection risk of COVID-19 virus. In response to mitigate this challenge, this study proposes a novel innovative approach for mitigating big challenges of (COVID-19) coronavirus propagation and contagion. This study propose a blockchain-based framework which investigate the possibility of utilizing peer-to peer, time stamping, and decentralized storage advantages of blockchain to build a new system for verifying and detecting the unknown infected cases of COVID-19 virus. Moreover, the proposed framework will enable the citizens to predict the infection risk of COVID-19 virus within conglomerates of people or within public places through a novel design of P2P-Mobile Application. The proposed approach is forecasted to produce an effective system able to support governments, health authorities, and citizens to take critical decision regarding the infection detection, infection prediction, and infection avoidance. The framework is currently being developed and implemented as a new system consists of four components, Infection Verifier Subsystem, Blockchain platform, P2P-Mobile Application, and Mass-Surveillance System. This four components work together for detecting the unknown infected cases and predicting and estimating the infection Risk of Corona Virus (COVID-19).
9zdqyeaa
9zdqyeaa
2020-04-05
2
Forecasting of COVID-19 Confirmed Cases in Different Countries with ARIMA Models
The epidemic of a novel coronavirus illness (COVID-19) becomes as a global threat. The aim of this study is first to find the best prediction models for daily confirmed cases in countries with high number of confirmed cases in the world and second to predict confirmed cases with these models in order to have more readiness in healthcare systems. This study was conducted based on daily confirmed cases of COVID-19 that were collected from the official website of Johns Hopkins University from January 22th, 2020 to March 1th, 2020. Auto Regressive Integrated Moving Average (ARIMA) model was used to predict the trend of confirmed cases. Stata version 12 was used. Mainland China and Thailand had almost a stable trend. The trend of South Korea was decreasing and will become stable in near future. Iran and Italy had unstable trends. Mainland China and Thailand were successful in haltering COVID-19 epidemic. Investigating their protocol in this control like quarantine should be in the first line of other countries program
a0pf12jo
a0pf12jo
2020-03-18
10.1101/2020.03.13.20035345
1
Type 1 interferons as a potential treatment against COVID-19
Abstract Type 1 interferons have a broad antiviral activity in vitro and are currently evaluated in a clinical trial to treat MERS-CoV. In this review, we discuss preliminary data concerning the potential activity of type 1 interferons on SARS-CoV-2, and the relevance of evaluating these molecules in clinical trials for the treatment of COVID-19.
a0ribcmv
a0ribcmv
2020-06-30
10.1016/j.antiviral.2020.104791
1
CovidAID: COVID-19 Detection Using Chest X-Ray
The exponential increase in COVID-19 patients is overwhelming healthcare systems across the world. With limited testing kits, it is impossible for every patient with respiratory illness to be tested using conventional techniques (RT-PCR). The tests also have long turn-around time, and limited sensitivity. Detecting possible COVID-19 infections on Chest X-Ray may help quarantine high risk patients while test results are awaited. X-Ray machines are already available in most healthcare systems, and with most modern X-Ray systems already digitized, there is no transportation time involved for the samples either. In this work we propose the use of chest X-Ray to prioritize the selection of patients for further RT-PCR testing. This may be useful in an inpatient setting where the present systems are struggling to decide whether to keep the patient in the ward along with other patients or isolate them in COVID-19 areas. It would also help in identifying patients with high likelihood of COVID with a false negative RT-PCR who would need repeat testing. Further, we propose the use of modern AI techniques to detect the COVID-19 patients using X-Ray images in an automated manner, particularly in settings where radiologists are not available, and help make the proposed testing technology scalable. We present CovidAID: COVID-19 AI Detector, a novel deep neural network based model to triage patients for appropriate testing. On the publicly available covid-chestxray-dataset [2], our model gives 90.5% accuracy with 100% sensitivity (recall) for the COVID-19 infection. We significantly improve upon the results of Covid-Net [10] on the same dataset.
a2mqvbj2
a2mqvbj2
2020-04-21
3.5
Diagnosing COVID-19 Pneumonia from X-Ray and CT Images using Deep Learning and Transfer Learning Algorithms
COVID-19 (also known as 2019 Novel Coronavirus) first emerged in Wuhan, China and spread across the globe with unprecedented effect and has now become the greatest crisis of the modern era. The COVID-19 has proved much more pervasive demands for diagnosis that has driven researchers to develop more intelligent, highly responsive and efficient detection methods. In this work, we focus on proposing AI tools that can be used by radiologists or healthcare professionals to diagnose COVID-19 cases in a quick and accurate manner. However, the lack of a publicly available dataset of X-ray and CT images makes the design of such AI tools a challenging task. To this end, this study aims to build a comprehensive dataset of X-rays and CT scan images from multiple sources as well as provides a simple but an effective COVID-19 detection technique using deep learning and transfer learning algorithms. In this vein, a simple convolution neural network (CNN) and modified pre-trained AlexNet model are applied on the prepared X-rays and CT scan images dataset. The result of the experiments shows that the utilized models can provide accuracy up to 98 % via pre-trained network and 94.1 % accuracy by using the modified CNN.
a2ms5ci4
a2ms5ci4
2020-03-31
2
Inhibition of SARS-CoV-2 (previously 2019-nCoV) infection by a highly potent pan-coronavirus fusion inhibitor targeting its spike protein that harbors a high capacity to mediate membrane fusion
The recent outbreak of coronavirus disease (COVID-19) caused by SARS-CoV-2 infection in Wuhan, China has posed a serious threat to global public health. To develop specific anti-coronavirus therapeutics and prophylactics, the molecular mechanism that underlies viral infection must first be defined. Therefore, we herein established a SARS-CoV-2 spike (S) protein-mediated cell-cell fusion assay and found that SARS-CoV-2 showed a superior plasma membrane fusion capacity compared to that of SARS-CoV. We solved the X-ray crystal structure of six-helical bundle (6-HB) core of the HR1 and HR2 domains in the SARS-CoV-2 S protein S2 subunit, revealing that several mutated amino acid residues in the HR1 domain may be associated with enhanced interactions with the HR2 domain. We previously developed a pan-coronavirus fusion inhibitor, EK1, which targeted the HR1 domain and could inhibit infection by divergent human coronaviruses tested, including SARS-CoV and MERS-CoV. Here we generated a series of lipopeptides derived from EK1 and found that EK1C4 was the most potent fusion inhibitor against SARS-CoV-2 S protein-mediated membrane fusion and pseudovirus infection with IC50s of 1.3 and 15.8 nM, about 241- and 149-fold more potent than the original EK1 peptide, respectively. EK1C4 was also highly effective against membrane fusion and infection of other human coronavirus pseudoviruses tested, including SARS-CoV and MERS-CoV, as well as SARSr-CoVs, and potently inhibited the replication of 5 live human coronaviruses examined, including SARS-CoV-2. Intranasal application of EK1C4 before or after challenge with HCoV-OC43 protected mice from infection, suggesting that EK1C4 could be used for prevention and treatment of infection by the currently circulating SARS-CoV-2 and other emerging SARSr-CoVs.
a4d0h6iz
a4d0h6iz
2020
5
Perspectives on therapeutic neutralizing antibodies against the Novel Coronavirus SARS-CoV-2
A newly identified novel coronavirus (SARS-CoV-2) is causing pneumonia-associated respiratory syndrome across the world. Epidemiology, genomics, and pathogenesis of the SARS-CoV-2 show high homology with that of SARS-CoV. Current efforts are focusing on development of specific antiviral drugs. Therapeutic neutralizing antibodies (NAbs) against SARS-CoV-2 will be greatly important therapeutic agents for the treatment of coronavirus disease 2019 (COVID-19). Herein, the host immune responses against SARS-CoV discussed in this review provide implications for developing NAbs and understanding clinical interventions against SARS-CoV-2. Further, we describe the benefits, challenges and considerations of NAbs against SARS-CoV-2. Although many challenges exist, NAbs still offer a therapeutic option to control the current pandemic and the possible re-emergence of the virus in the future, and their development therefore remains a high priority.
a5udnv5f
a5udnv5f
2020-03-15
10.7150/ijbs.45123
1
Generation of human bronchial organoids for SARS-CoV-2 research
Coronavirus disease 2019 (COVID-19) is a disease that causes fatal disorders including severe pneumonia. To develop a therapeutic drug for COVID-19, a model that can reproduce the viral life cycle and evaluate the drug efficacy of anti-viral drugs is essential. In this study, we established a method to generate human bronchial organoids (hBO) from commercially available cryopreserved human bronchial epithelial cells and examined whether they could be used as a model for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) research. Our hBO contain basal, club, ciliated, and goblet cells. Angiotensin-converting enzyme 2 (ACE2), which is a receptor for SARS-CoV-2, and transmembrane serine proteinase 2 (TMPRSS2), which is an essential serine protease for priming spike (S) protein of SARS-CoV-2, were highly expressed. After SARS-CoV-2 infection, not only the intracellular viral genome, but also progeny virus, cytotoxicity, pyknotic cells, and moderate increases of the type I interferon signal could be observed. Treatment with camostat, an inhibitor of TMPRSS2, reduced the viral copy number to 2% of the control group. Furthermore, the gene expression profile in SARS-CoV-2-infected hBO was obtained by performing RNA-seq analysis. In conclusion, we succeeded in generating hBO that can be used for SARS-CoV-2 research and COVID-19 drug discovery. Graphical abstract
a6296nkd
a6296nkd
2020-06-01
10.1101/2020.05.25.115600
4
Hydroxychloroquine as an aerosol might markedly reduce and even prevent severe clinical symptoms after SARS-CoV-2 infection
Abstract Covid-19 is a new coronavirus disease first described in December 2019. This respiratory illness is severe and potentially fatal. Severe cases make up to 15%, lethality ranges between 1.5 and more than 10 %. What is urgently needed is an efficient pharmacological treatment for the treatment of severe cases. During the infection of alveolar epithelial cells of the lung, the ACE2 receptor has a central function. The antimalarial drugs chloroquine phosphate (CQ) and hydroxychloroquine (HCQ) impair in vitro the terminal glycosylation of ACE2 without significant change of cell-surface ACE2 and, therefore, might be potent inhibitors of SARS-CoV-2 infections. Starting inhibition at 0.1 µM, CQ completely prevented in vitro infections at 10 µM, suggesting a prophylactic effect and preventing the virus spread 5 hours after infection. In a first clinical trial, CQ was effective in inhibiting exacerbation of pneumonia, improving lung imaging findings, promotion of virus-negative conversion, and shortening the disease. In addition, HCQ, which is three times more potent than CQ in SARS-CoV-2 infected cells (EC50 0.72 µM), was significantly associated with viral load reduction/disappearance in COVID-19 patients compared to controls. Theoretically, CQ and HCQ could thus be effectively used in the treatment of SARS-CoV pneumonia. From a pharmacological standpoint, however, the major problems of oral treatment with these drugs are possible severe side effects and toxicity. Concretely, this relates to (a) the inconsistent individual bioavailability of these drugs at the alveolar target cells, depending on intestinal resorption, hepatic first-pass metabolism and accumulation in liver, spleen and lung, and (b) the need for a relatively high concentration of 1-5 µM at the alveolar surface. Therefore, we propose in a first dose estimation the use of HCQ as an aerosol in a dosage of 2-4 mg per inhalation in order to reach sufficient therapeutic levels at the alveolar epithelial cells. By using a low-dose non-systemic aerosol, adverse drug reactions will markedly be reduced compared with oral application. This increase in tolerability enables a broader use for prevention and after contact with an infected person, which would be an advantage especially for the high-risk, often multi-morbid and elderly patients. Empirical data on self-medication with a one-week aerosol application by two of the authors is presented. Inhalation was well tolerated without relevant side effects.
a62k3lma
a62k3lma
2020-04-27
10.1016/j.mehy.2020.109783
3
Abstract book of the 7th ISNI Congress
a714injz
a714injz
2004-08-30
10.1016/j.jneuroim.2004.06.010
1
Pharmacoinformatics and molecular dynamics simulation studies reveal potential covalent and FDA-approved inhibitors of SARS-CoV-2 main protease 3CLpro
The SARS-CoV-2 was confirmed to cause the global pandemic of coronavirus disease 2019 (COVID-19). The 3-chymotrypsin-like protease (3CLpro), an essential enzyme for viral replication, is a valid target to combat SARS-CoV and MERS-CoV. In this work, we present a structure-based study to identify potential covalent inhibitors containing a variety of chemical warheads. The targeted Asinex Focused Covalent (AFCL) library was screened based on different reaction types and potential covalent inhibitors were identified. In addition, we screened FDA-approved protease inhibitors to find candidates to be repurposed against SARS-CoV-2 3CLpro. A number of compounds with significant covalent docking scores were identified. These compounds were able to establish a covalent bond (C-S) with the reactive thiol group of Cys145 and to form favorable interactions with residues lining the substrate-binding site. Moreover, paritaprevir and simeprevir from FDA-approved protease inhibitors were identified as potential inhibitors of SARS-CoV-2 3CLpro. The mechanism and dynamic stability of binding between the identified compounds and SARS-CoV-2 3CLpro were characterized by molecular dynamics (MD) simulations. The identified compounds are potential inhibitors worthy of further development as COVID-19 drugs. Importantly, the identified FDA-approved anti-hepatitis-C virus (HCV) drugs paritaprevir and simeprevir could be ready for clinical trials to treat infected patients and help curb COVID-19. Communicated by Ramaswamy H. Sarma.
a73plf6x
a73plf6x
2020
5
Pathogenesis of SARS-CoV-2 in transgenic mice expressing human angiotensin-converting enzyme 2
Summary COVID-19 has spread worldwide since 2019 and is now a severe threat to public health. We previously identified the causative agent as a novel SARS-related coronavirus (SARS-CoV-2) that uses human angiotensin-converting enzyme 2 (hACE2) as the entry receptor. Here, we successfully developed a SARS-CoV-2 hACE2 transgenic mouse (HFH4-hACE2 in C3B6 mice) infection model. The infected mice generated typical interstitial pneumonia and pathology that were similar to those of COVID-19 patients. Viral quantification revealed the lungs as the major site of infection, although viral RNA could also be found in the eye, heart, and brain in some mice. Virus identical to SARS-CoV-2 in full-genome sequences was isolated from the infected lung and brain tissues. Lastly, we showed that pre-exposure to SARS-CoV-2 could protect mice from severe pneumonia. Our results show that the hACE2 mouse would be a valuable tool for testing potential vaccines and therapeutics.
a793bgc1
a793bgc1
2020-05-21
10.1016/j.cell.2020.05.027
4.5
Gain-of-Function Research and the Relevance to Clinical Practice
The ongoing moratorium on gain-of-function (GOF) research with highly pathogenic avian influenza virus, severe acute respiratory syndrome coronavirus, and Middle East respiratory syndrome coronavirus has drawn attention to the current debate on these research practices and the potential benefits and risks they present. While much of the discussion has been steered by members of the microbiology and policy communities, additional input from medical practitioners will be highly valuable toward developing a broadly inclusive policy that considers the relative value and harm of GOF research. This review attempts to serve as a primer on the topic for the clinical community by providing a historical context for GOF research, summarizing concerns about its risks, and surveying the medical products that it has yielded.
a7kwf2yo
a7kwf2yo
2016-05-01
10.1093/infdis/jiv473
1.5
CogMol: Target-Specific and Selective Drug Design for COVID-19 Using Deep Generative Models
The novel nature of SARS-CoV-2 calls for the development of efficient de novo drug design approaches. In this study, we propose an end-to-end framework, named CogMol (Controlled Generation of Molecules), for designing new drug-like small molecules targeting novel viral proteins with high affinity and off-target selectivity. CogMol combines adaptive pre-training of a molecular SMILES Variational Autoencoder (VAE) and an efficient multi-attribute controlled sampling scheme that uses guidance from attribute predictors trained on latent features. To generate novel and optimal drug-like molecules for unseen viral targets, CogMol leverages a protein-molecule binding affinity predictor that is trained using SMILES VAE embeddings and protein sequence embeddings learned unsupervised from a large corpus. CogMol framework is applied to three SARS-CoV-2 target proteins: main protease, receptor-binding domain of the spike protein, and non-structural protein 9 replicase. The generated candidates are novel at both molecular and chemical scaffold levels when compared to the training data. CogMol also includes insilico screening for assessing toxicity of parent molecules and their metabolites with a multi-task toxicity classifier, synthetic feasibility with a chemical retrosynthesis predictor, and target structure binding with docking simulations. Docking reveals favorable binding of generated molecules to the target protein structure, where 87-95 % of high affinity molecules showed docking free energy<-6 kcal/mol. When compared to approved drugs, the majority of designed compounds show low parent molecule and metabolite toxicity and high synthetic feasibility. In summary, CogMol handles multi-constraint design of synthesizable, low-toxic, drug-like molecules with high target specificity and selectivity, and does not need target-dependent fine-tuning of the framework or target structure information.
a82mf4gl
a82mf4gl
2020-04-02
2.5
Gastrointestinal and hepatic manifestations of COVID-19: A comprehensive review
The severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) that causes coronavirus disease-2019 (COVID-19) is a global pandemic, manifested by an infectious pneumonia. Although patients primarily present with fever, cough and dyspnea, some patients also develop gastrointestinal (GI) and hepatic manifestations. The most common GI symptoms reported are diarrhea, nausea, vomiting, and abdominal discomfort. Liver chemistry abnormalities are common and include elevation of aspartate transferase, alanine transferase, and total bilirubin. Studies have shown that SARS-CoV-2 infects the GI tract via its viral receptor angiotensin converting enzyme II, which is expressed on enterocytes of the ileum and colon. Viral RNA has also been isolated from stool specimens of COVID-19 patients, which raised the concern for fecal-oral transmission in addition to droplet transmission. Although indirect evidence has suggested possible fecal-oral transmission of SARS-CoV-2, more effort is needed to establish the role of the fecal-oral transmission route. Further research will help elucidate the association between patients with underlying GI diseases, such as chronic liver disease and inflammatory bowel disease, and severity of COVID-19. In this review, we summarize the data on GI involvement to date, as well as the impact of COVID-19 on underlying GI diseases.
a8pgh56q
a8pgh56q
2020-05-21
10.3748/wjg.v26.i19.2323
4.5
Animal models of human viral diseases: Relevance to developmental therapeutics
a9lfuas1
a9lfuas1
2004-02-19
10.1002/jcb.240440704
5
The Pathology and Pathogenesis of Experimental Severe Acute Respiratory Syndrome and Influenza in Animal Models
Summary Respiratory viruses that emerge in the human population may cause high morbidity and mortality, as well as concern about pandemic spread. Examples are severe acute respiratory syndrome coronavirus (SARS-CoV) and novel variants of influenza A virus, such as H5N1 and pandemic H1N1. Different animal models are used to develop therapeutic and preventive measures against such viruses, but it is not clear which are most suitable. Therefore, this review compares animal models of SARS and influenza, with an emphasis on non-human primates, ferrets and cats. Firstly, the pathology and pathogenesis of SARS and influenza are compared. Both diseases are similar in that they affect mainly the respiratory tract and cause inflammation and necrosis centred on the pulmonary alveoli and bronchioles. Important differences are the presence of multinucleated giant cells and intra-alveolar fibrosis in SARS and more fulminant necrotizing and haemorrhagic pneumonia in H5N1 influenza. Secondly, the pathology and pathogenesis of SARS and influenza in man and experimental animals are compared. Host species, host age, route of inoculation, location of sampling and timing of sampling are important to design an animal model that most closely mimics human disease. The design of appropriate animal models requires an accurate pathological description of human cases, as well as a good understanding of the effect of experimental variables on disease outcome.
aa08u19x
aa08u19x
2014-07-31
10.1016/j.jcpa.2014.01.004
1.5
Individualized System for Augmenting Ventilator Efficacy (iSAVE): A Rapidly deployable system to expand ventilator capacity
The COVID-19 pandemic is overwhelming healthcare systems worldwide. A significant portion of COVID-19 patients develop pneumonia and acute respiratory distress syndrome (ARDS), necessitating ventilator support. Some health systems do not have the capacity to accommodate this surge in ventilator demand, leading to shortages and inevitable mortality. Some clinicians have, of necessity, jerry-rigged ventilators to support multiple patients, but these devices lack protected air streams or individualized controls for each patient. Moreover, some have not been tested under conditions of ARDS. We have developed the Individualized System for Augmenting Ventilator Efficacy (iSAVE), a rapidly deployable platform to more safely use a single ventilator to simultaneously support multiple critically-ill patients. The iSAVE enables patient-specific volume and pressure control and incorporates safety features to mitigate cross-contamination between patients and flow changes due to patient interdependencies within the respiratory circuit. Here we demonstrate through simulated and in vivo pig evaluation the capacity of the iSAVE to support a range of respiratory clinical states. By leveraging off-the-shelf components that are readily available to intensive care unit (ICU) caregivers, the iSAVE could potentially be translated for human application to expand the ventilation capacity of hospitals using existing ventilators, minimizing the need to procure additional ventilators.
aarthz9w
aarthz9w
2020-03-29
10.1101/2020.03.28.012617
1.5
Interpretable detection of novel human viruses from genome sequencing data
Viruses evolve extremely quickly, so reliable methods for viral host prediction are necessary to safeguard biosecurity and biosafety alike. Novel human-infecting viruses are difficult to detect with standard bioinformatics workflows. Here, we predict whether a virus can infect humans directly from next-generation sequencing reads. We show that deep neural architectures significantly outperform both shallow machine learning and standard, homology-based algorithms, cutting the error rates in half and generalizing to taxonomic units distant from those presented during training. We propose a new approach for convolutional filter visualization to disentangle the information content of each nucleotide from its contribution to the final classification decision. Nucleotide-resolution maps of the learned associations between pathogen genomes and the infectious phenotype can be used to detect virulence-related genes in novel agents, as we show here for the SARS-CoV-2 coronavirus, unknown before it caused a COVID-19 pandemic in 2020.
ac00tai9
ac00tai9
2020-01-30
10.1101/2020.01.29.925354
1.5
Potential antivirals and antiviral strategies against SARS coronavirus infections
There are a number of antivirals as well as antiviral strategies that could be envisaged to prevent or treat severe acute respiratory syndrome (SARS) (or similar) coronavirus (CoV) infections. Targets for the prophylactic or therapeutic interventions include interaction of the spike (S) glycoprotein (S1 domain) with the host cell receptor, fusion of the S2 domain with the host cell membrane, processing of the replicase polyproteins by the virus-encoded proteases (3C-like cysteine protease [3CLpro] and papain-like cysteine protease) and other virus-encoded enzymes such as the NTPase/helicase and RNA-dependent RNA polymerase. Human monoclonal antibody blocking S1 may play an important role in the immunoprophylaxis of SARS. Fusion inhibitors reminiscent of enfuvirtide in the case of HIV may also be developed for SARS-CoV. Various peptidomimetic and nonpeptidic inhibitors of 3CLpro have been described, the best ones inhibiting SARS-CoV replication with a selectivity index greater than 1000. Human interferons, in particular α- and β-interferon, as well as short interfering RNAs could further be pursued for the control of SARS. Various other compounds, often with an ill-defined mode of action but selectivity indexes up to 100, have been reported to exhibit in vitro activity against SARS-CoV: valinomycin, glycopeptide antibiotics, plant lectins, hesperetin, glycyrrhizin, aurintricarboxylic acid, chloroquine, niclosamide, nelfinavir and calpain inhibitors.
ae8y9exx
ae8y9exx
2014-01-10
10.1586/14787210.4.2.291
1.5
Genetic evolution analysis of 2019 novel coronavirus and coronavirus from other species
The Corona Virus Disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a Public Health Emergency of International Concern. However, so far, there are still controversies about the source of the virus and its intermediate host. Here, we found the novel coronavirus was closely related to coronaviruses derived from five wild animals, including Paguma larvata, Paradoxurus hermaphroditus, Civet, Aselliscus stoliczkanus and Rhinolophus sinicus, and was in the same branch of the phylogenetic tree. However, genome and ORF1a homology show that the virus is not the same coronavirus as the coronavirus derived from these five animals, whereas the virus has the highest homology with Bat coronavirus isolate RaTG13.
aeogp8c7
aeogp8c7
2020-03-10
10.1016/j.meegid.2020.104285
1
Antiviral treatment of SARS-CoV-2-infected hamsters reveals a weak effect of favipiravir and a complete lack of effect for hydroxychloroquine
SARS-CoV-2 rapidly spread around the globe after its emergence in Wuhan in December 2019. With no specific therapeutic and prophylactic options available, the virus was able to infect millions of people. To date, close to half a million patients succumbed to the viral disease, COVID-19. The high need for treatment options, together with the lack of small animal models of infection has led to clinical trials with repurposed drugs before any preclinical in vivo evidence attesting their efficacy was available. We used Syrian hamsters to establish a model to evaluate antiviral activity of small molecules in both an infection and a transmission setting. Upon intranasal infection, the animals developed high titers of SARS-CoV-2 in the lungs and pathology similar to that observed in mild COVID-19 patients. Treatment of SARS-CoV-2-infected hamsters with favipiravir or hydroxychloroquine (with and without azithromycin) resulted in respectively a mild or no reduction in viral RNA and infectious virus. Micro-CT scan analysis of the lungs showed no improvement compared to non-treated animals, which was confirmed by histopathology. In addition, both compounds did not prevent virus transmission through direct contact and thus failed as prophylactic treatments. By modelling the PK profile of hydroxychloroquine based on the trough plasma concentrations, we show that the total lung exposure to the drug was not the limiting factor. In conclusion, we here characterized a hamster infection and transmission model to be a robust model for studying in vivo efficacy of antiviral compounds. The information acquired using hydroxychloroquine and favipiravir in this model is of critical value to those designing (current and) future clinical trials. At this point, the data here presented on hydroxychloroquine either alone or combined with azithromycin (together with previously reported in vivo data in macaques and ferrets) provide no scientific basis for further use of the drug in humans.
aexlwq79
aexlwq79
2020-06-19
10.1101/2020.06.19.159053
5
Drug repositioning is an alternative for the treatment of coronavirus COVID-19
Abstract Given the extreme importance of the current pandemic caused by COVID-19, and as scientists agree there is no identified pharmacological treatment, where possible, therapeutic alternatives are raised through drug repositioning. This paper presents a selection of studies involving drugs from different pharmaceutical classes with activity against SARS-CoV-2 and SARS-CoV, with the potential for use in the treatment of COVID-19 disease.
agc89fqv
agc89fqv
2020-04-09
10.1016/j.ijantimicag.2020.105969
3
Perspectives for repurposing drugs for the coronavirus disease 2019
The newly emerged 2019 novel coronavirus (CoV), named as severe acute respiratory syndrome CoV-2 (SARS-CoV-2), like SARS-CoV (now, SARS-CoV-1) and Middle East respiratory syndrome CoV (MERS-CoV), has been associated with high infection rates with over 36,405 deaths. In the absence of approved marketed drugs against coronaviruses, the treatment and management of this novel CoV disease (COVID-19) worldwide is a challenge. Drug repurposing that has emerged as an effective drug discovery approach from earlier approved drugs could reduce the time and cost compared to de novo drug discovery. Direct virus-targeted antiviral agents target specific nucleic acid or proteins of the virus while host-based antivirals target either the host innate immune responses or the cellular machineries that are crucial for viral infection. Both the approaches necessarily interfere with viral pathogenesis. Here we summarize the present status of both virus-based and host-based drug repurposing perspectives for coronaviruses in general and the SARS-CoV-2 in particular.
agio2sqv
agio2sqv
2020-04-28
10.4103/ijmr.ijmr_585_20
5
SARS‐CoV‐2 spike protein favors ACE2 from Bovidae and Cricetidae
Severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) causes the recent COVID‐19 public health crisis. Bat is the widely believed original host of SARS‐CoV‐2. However, its intermediate host before transmitting to humans is not clear. Some studies proposed pangolin, snake, or turtle as the intermediate hosts. Angiotensin‐converting enzyme 2 (ACE2) is the receptor for SARS‐CoV‐2, which determines the potential host range for SARS‐CoV‐2. On the basis of structural information of the complex of human ACE2 and SARS‐CoV‐2 receptor‐binding domain (RBD), we analyzed the affinity to S protein of the 20 key residues in ACE2 from mammal, bird, turtle, and snake. Several ACE2 proteins from Primates, Bovidae, Cricetidae, and Cetacea maintained the majority of key residues in ACE2 for associating with SARS‐CoV‐2 RBD. The simulated structures indicated that ACE2 proteins from Bovidae and Cricetidae were able to associate with SARS‐CoV‐2 RBD. We found that nearly half of the key residues in turtle, snake, and bird were changed. The simulated structures showed several key contacts with SARS‐CoV‐2 RBD in turtle and snake ACE2 were abolished. This study demonstrated that neither snake nor turtle was the intermediate hosts for SARS‐CoV‐2, which further reinforced the concept that the reptiles are resistant against infection of coronavirus. This study suggested that Bovidae and Cricetidae should be included in the screening of intermediate hosts for SARS‐CoV‐2.
ah8uyfe7
ah8uyfe7
2020-04-10
10.1002/jmv.25817
3.5
Evaluation of 19 antiviral drugs against SARS-CoV-2 Infection
The global pandemic of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2 or 2019-nCoV) has prompted multiple clinical trials to jumpstart search for anti-SARS-CoV-2 therapies from existing drugs, including those with reported in vitro efficacies as well as those ones that are not known to inhibit SARS-CoV-2, such as ritonavir/lopinavir and favilavir. Here we report that after screening 19 antiviral drugs that are either in clinical trials or with proposed activity against SARS-CoV-2, remdesivir was the most effective. Chloroquine only effectively protected virus-induced cytopathic effect at around 30 µM with a therapeutic index of 1.5. Our findings also suggest that velpatasvir, ledipasvir, ritonavir, litonavir, lopinavir, favilavir, sofosbuvir, danoprevir, and pocapavir do not have direct antiviral effect.
ai2zcke5
ai2zcke5
2020-05-07
10.1101/2020.04.29.067983
2
A Fluorogenic Peptide Containing the Processing Site of Human SARS Corona Virus S‐Protein: Kinetic Evaluation and NMR Structure Elucidation
Human severe acute respiratory syndrome coronavirus (hSARS‐CoV) is the causative agent for SARS infection. Its surface glycoprotein (spike protein) is considered to be one of the prime targets for SARS therapeutics and intervention because its proteolytic maturation by a host protease is crucial for host–virus fusion. Using intramolecularly quenched fluorogenic (IQF) peptides based on hSARS‐CoV spike protein (Abz‐(755)Glu‐Gln‐Asp‐Arg‐Asn‐Thr‐Arg‐Glu‐Val‐Phe‐Ala‐Gln(766)‐Tyx‐NH(2)) and in vitro studies, we show that besides furin, other PCs, like PC5 and PC7, might also be involved in this cleavage event. Through kinetic measurements with recombinant PCs, we observed that the peptide was cleaved efficiently by both furin and PC5, but very poorly by PC7. The cleavage could be blocked by a PC‐inhibitor, α1‐PDX, in a dose‐dependent manner. Circular dichroism spectra indicated that this peptide possesses a high degree of sheet structure. Following cleavage by furin, the sheet content increased, possibly at the expense of turn and random structures. (1)H NMR spectra from 2D COSY and ROESY experiments under physiological buffer and pH conditions indicated that this peptide possesses a structure with a turn at its C‐terminal segment, close to the cleavage site. The data suggest that the cleavable peptide bond is located within the most exposed domain; this is supported by the nearby turn structure. Several strong to weak NMR ROESY correlations were detected, and a 3D structure of the spike IQF peptide that contains the crucial cleavage site R(761)↓E has been proposed.
aijn1g38
aijn1g38
2007-04-30
10.1002/cbic.200700007
2.5
The journey of remdesivir: from Ebola to COVID-19
Countries around the world are currently fighting the coronavirus disease 2019 (COVID-19) pandemic, which is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). SARS-CoV-2 is a betacoronavirus, belonging to the same genus as severe acute respiratory syndrome (SARS)-CoV and Middle East respiratory syndrome (MERS)-CoV. Currently, there are no proven antiviral therapies for COVID-19. Numerous clinical trials have been initiated to identify an effective treatment. One leading candidate is remdesivir (GS-5734), a broad-spectrum antiviral that was initially developed for the treatment of Ebola virus (EBOV). Although remdesivir performed well in preclinical studies, it did not meet efficacy endpoints in a randomized trial conducted during an Ebola outbreak. Remdesivir holds promise for treating COVID-19 based on in vitro activity against SARS-CoV-2, uncontrolled clinical reports, and limited data from randomized trials. Overall, current data are insufficient to judge the efficacy of remdesivir for COVID-19, and the results of additional randomized studies are eagerly anticipated. In this narrative review, we provide an overview of Ebola and coronavirus outbreaks. We then summarize preclinical and clinical studies of remdesivir for Ebola and COVID-19.
aivub6mi
aivub6mi
2020-05-22
10.7573/dic.2020-4-14
4.5
More than efficacy revealed by single-cell analysis of antiviral therapeutics
Development of antiviral therapeutics emphasizes minimization of the effective dose and maximization of the toxic dose, first in cell culture and later in animal models. Long-term success of an antiviral therapeutic is determined not only by its efficacy but also by the duration of time required for drug-resistance to evolve. We have developed a microfluidic device comprised of ~6000 wells, with each well containing a microstructure to capture single cells. We have used this device to characterize enterovirus inhibitors with distinct mechanisms of action. In contrast to population methods, single-cell analysis reveals that each class of inhibitor interferes with the viral infection cycle in a manner that can be distinguished by principal component analysis. Single-cell analysis of antiviral candidates reveals not only efficacy but also properties of the members of the viral population most sensitive to the drug, the stage of the lifecycle most affected by the drug, and perhaps even if the drug targets an interaction of the virus with its host.
aiyg061l
aiyg061l
2019-04-12
10.1101/606715
3.5
Deep learning-based multi-view fusion model for screening 2019 novel coronavirus pneumonia: a multicentre study
Abstract Purpose To develop a deep learning-based method to assist radiologists to fast and accurately identify patients with COVID-19 by CT images. Methods We retrospectively collected chest CT images of 495 patients from three hospitals in China. 495 datasets were randomly divided into 395 cases (80%, 294 of COVID-19, 101 of other pneumonia) of the training set, 50 cases (10%, 37 of COVID-19, 13 of other pneumonia) of the validation set and 50 cases (10%, 37 of COVID-19, 13 of other pneumonia) of the testing set. We trained a multi-view fusion model using deep learning network to screen patients with COVID-19 using CT images with the maximum lung regions in axial, coronal and sagittal views. The performance of the proposed model was evaluated by both the validation and testing sets. Results The multi-view deep learning fusion model achieved the area under the receiver-operating characteristics curve (AUC) of 0.732, accuracy of 0.700, sensitivity of 0.730 and specificity of 0.615 in validation set. In the testing set, we can achieve AUC, accuracy, sensitivity and specificity of 0.819, 0.760, 0.811 and 0.615 respectively. Conclusions Based on deep learning method, the proposed diagnosis model trained on multi-view images of chest CT images showed great potential to improve the efficacy of diagnosis and mitigate the heavy workload of radiologists for the initial screening of COVID-19 pneumonia.
akdjoeqk
akdjoeqk
2020-05-05
10.1016/j.ejrad.2020.109041
3.5
Potenciales efectos pro-arrítmicos de la farmacoterapia contra SARS-CoV-2./ Potential pro-arrhythmic effects of pharmacotherapy against SARS-CoV-2
The pandemic caused by the SARS-COV-2 or COVID-19 virus has been a global challenge given its high rate of transmission and lack of effective therapy or vaccine. This scenario has led to the use of various drugs that have demonstrated a potential effect against the virus in vitro. However, time has not been enough to properly evaluate their clinical effectiveness. The use of chloroquine/hydroxychloroquine, azithromycin and antiviral treatment and has been proposed by various groups, supported by in-vitro studies and limited patient series, without the adequate scientific rigor that precedes drug prescription. Although it may represent the only hope for many patients, it is important to know the main adverse effects associated with the use of these drugs and to better select patients who may benefit from them.
akicyht4
akicyht4
2020
4.5
In vitro testing of combined hydroxychloroquine and azithromycin on SARS-CoV-2 shows synergistic effect
Abstract Human coronaviruses SARS-CoV-2 appeared at the end of 2019 and led to a pandemic with high morbidity and mortality. As there are currently no effective drugs targeting this virus, drug repurposing represents a short-term strategy to treat millions of infected patients at low costs. Hydroxychloroquine showed an antiviral effect in vitro. In vivo it showed efficacy, especially when combined with azithromycin in a preliminary clinical trial. Here we demonstrate that the combination of hydroxychloroquine and azithromycin has a synergistic effect in vitro on SARS-CoV-2 at concentrations compatible with that obtained in human lung.
aku5atqh
aku5atqh
2020-04-25
10.1016/j.micpath.2020.104228
2
Expression and functional characterization of the putative protein 8b of the severe acute respiratory syndrome-associated coronavirus
SARS 8b is one of the putative accessory proteins of the severe acute respiratory syndrome-associated coronavirus (SARS-CoV) with unknown functions. In this study, the cellular localization and activity of this estimated 9.6 kDa protein were examined. Confocal microscopy results indicated that SARS 8b is localized in both nucleus and cytoplasm of mammalian cells. Functional study revealed that overexpression of SARS 8b induced DNA synthesis. Coexpression of SARS 8b and SARS 6, a previously characterized SARS-CoV accessory protein, did not elicit synergistic effects on DNA synthesis.
anbetkt3
anbetkt3
2006-06-26
10.1016/j.febslet.2006.05.051
1
TMPRSS2 and furin are both essential for proteolytic activation and spread of SARS-CoV-2 in human airway epithelial cells and provide promising drug targets
In December 2019, a novel coronavirus named SARS-CoV-2 first reported in Wuhan, China, emerged and rapidly spread to numerous other countries globally, causing the current pandemic. SARS-CoV-2 causes acute infection of the respiratory tract (COVID-19) that can result in severe disease and lethality. Currently, there is no approved antiviral drug for treating COVID-19 patients and there is an urgent need for specific antiviral therapies and vaccines. In order for SARS-CoV-2 to enter cells, its surface glycoprotein spike (S) must be cleaved at two different sites by host cell proteases, which therefore represent potential drug targets. In the present study we investigated which host cell proteases activate the SARS-CoV-2 S protein in Calu-3 human airway epithelial cells. We show that S can be cleaved by both the proprotein convertase furin at the S1/S2 site and the transmembrane serine protease 2 (TMPRSS2) at the S2’ site. We demonstrate that TMPRSS2 is essential for activation of SARS-CoV-2 S in Calu-3 cells through antisense-mediated knockdown of TMPRSS2 expression. Further, we show that SARS-CoV-2 replication can be efficiently inhibited by two synthetic inhibitors of TMPRSS2 and also by the broad range serine protease inhibitor aprotinin. Additionally, SARS-CoV-2 replication was also strongly inhibited by the synthetic furin inhibitor MI-1851. Combining various TMPRSS2 inhibitors with MI-1851 produced more potent antiviral activity against SARS-CoV-2 than an equimolar amount of any single serine protease inhibitor. In contrast, inhibition of endosomal cathepsins by E64d did not affect virus replication. Our data demonstrate that both TMPRSS2 and furin are essential for SARS-CoV-2 activation in human airway cells and are promising drug targets for the treatment of COVID-19 either by targeting one of these proteases alone or by a combination of furin and TMPRSS2 inhibitors. Therefore, this approach has a high therapeutic potential for treatment of COVID-19.
anedg12x
anedg12x
2020-04-15
10.1101/2020.04.15.042085
2
Compounds with Therapeutic Potential against Novel Respiratory 2019 Coronavirus
Currently, the expansion of the novel human respiratory coronavirus (known as SARS-CoV-2 [severe acute respiratory syndrome coronavirus 2], COVID-2019 [coronavirus disease 2019], or 2019-nCoV [2019 novel coronavirus]) has stressed the need for therapeutic alternatives to alleviate and stop this new epidemic. The previous epidemics of infections by high-morbidity human coronaviruses, such as SARS-CoV in 2003 and the Middle East respiratory syndrome coronavirus (MERS-CoV) in 2012, prompted the characterization of compounds that could be potentially active against the currently emerging novel coronavirus, SARS-CoV-2. The most promising compound is remdesivir (GS-5734), a nucleotide analog prodrug currently in clinical trials for treating Ebola virus infections. Remdesivir inhibited the replication of SARS-CoV and MERS-CoV in tissue cultures, and it displayed efficacy in nonhuman animal models. In addition, a combination of the human immunodeficiency virus type 1 (HIV-1) protease inhibitors lopinavir/ritonavir and interferon beta (LPV/RTV-IFN-ß) was shown to be effective in patients infected with SARS-CoV. LPV/RTV-IFN-ß also improved clinical parameters in marmosets and mice infected with MERS-CoV. Remarkably, the therapeutic efficacy of remdesivir appeared to be superior to that of LPV/RTV-IFN-ß against MERS-CoV in a transgenic humanized mouse model. The relatively high mortality rates associated with these three novel human coronavirus infections, SARS-CoV, MERS-CoV, and SARS-CoV-2, have suggested that proinflammatory responses might play a role in the pathogenesis. It remains unknown whether the generated inflammatory state should be targeted. Therapeutics that target the coronavirus alone might not be able to reverse highly pathogenic infections. This minireview aims to provide a summary of therapeutic compounds that have shown potential in fighting SARS-CoV-2 infections.
anen3dor
anen3dor
2020
4
Computational analysis on the ACE2-derived peptides for neutralizing the ACE2 binding to the spike protein of SARS-CoV-2
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of the COVID-19, is spreading globally and has infected more than 3 million people. It has been discovered that SARS-CoV-2 initiates the entry into cells by binding to human angiotensin-converting enzyme 2 (hACE2) through the receptor binding domain (RBD) of its spike glycoprotein. Hence, drugs that can interfere the SARS-CoV-2-RBD binding to hACE2 potentially can inhibit SARS-CoV-2 from entering human cells. Here, based on the N-terminal helix α1 of human ACE2, we designed nine short peptides that have potential to inhibit SARS-CoV-2 binding. Molecular dynamics simulations of peptides in the their free and SARS-CoV-2 RBD-bound forms allow us to identify fragments that are stable in water and have strong binding affinity to the SARS-CoV-2 spike proteins. The important interactions between peptides and RBD are highlighted to provide guidance for the design of peptidomimetics against the SARS-CoV-2.
aoti88v7
aoti88v7
2020-05-04
10.1101/2020.05.03.075473
3
Public Exposure to Live Animals, Behavioural Change, and Support in Containment Measures in response to COVID-19 Outbreak: a population-based cross sectional survey in China
Background In response to the COVID-19 outbreak, we aimed to investigate behavioural change on exposure to live animals before and during the outbreak, and public support and confidence for governmental containment measures. Methods A population-based cross-sectional telephone survey via random dialing was conducted in Wuhan (the epicentre) and Shanghai (an affected city with imported cases) between 1 and 10 February, 2020. 510 residents in Wuhan and 501 residents in Shanghai were randomly sampled. Differences of outcome measures were compared before and during the outbreak, and between two cities. Findings Proportion of respondents visiting wet markets at usual was 23.3% (119/510) in Wuhan and 20.4% (102/501) in Shanghai. During the outbreak, it decreased to 3.1% (16) in Wuhan (p<0.001), and 4.4% (22) in Shanghai (p<0.001). Proportion of those consuming wild animal products declined from 10.2% (52) to 0.6% (3) in Wuhan (p<0.001), and from 5.2% (26) to 0.8% (4) in Shanghai (p<0.001). 79.0% (403) of respondents in Wuhan and 66.9% (335) of respondents in Shanghai supported permanent closure of wet markets (P<0.001). 95% and 92% of respondents supported banning wild animal trade and quarantining Wuhan, and 75% were confident towards containment measures. Females and the more educated were more supportive for the above containment measures. Interpretation The public responded quickly to the outbreak, and reduced exposure to live animals, especially in Wuhan. With high public support in containment measures, better regulation of wet markets and healthy diets should be promoted.
aoyyk5fl
aoyyk5fl
2020-02-23
10.1101/2020.02.21.20026146
1
Display technologies: application for the discovery of drug and gene delivery agents
Recognition of molecular diversity of cell surface proteomes in disease is essential for the development of targeted therapies. Progress in targeted therapeutics requires establishing effective approaches for high-throughput identification of agents specific for clinically relevant cell surface markers. Over the past decade, a number of platform strategies have been developed to screen polypeptide libraries for ligands targeting receptors selectively expressed in the context of various cell surface proteomes. Streamlined procedures for identification of ligand-receptor pairs that could serve as targets in disease diagnosis, profiling, imaging and therapy have relied on the display technologies, in which polypeptides with desired binding profiles can be serially selected, in a process called biopanning, based on their physical linkage with the encoding nucleic acid. These technologies include virus/phage display, cell display, ribosomal display, mRNA display and covalent DNA display (CDT), with phage display being by far the most utilized. The scope of this review is the recent advancements in the display technologies with a particular emphasis on molecular mapping of cell surface proteomes with peptide phage display. Prospective applications of targeted compounds derived from display libraries in the discovery of targeted drugs and gene therapy vectors are discussed.
ap6yzgbi
ap6yzgbi
2006-12-30
10.1016/j.addr.2006.09.018
1.5
Discovery and development of safe-in-man broad-spectrum antiviral agents
Abstract Viral diseases are one of the leading causes of morbidity and mortality in the world. Virus-specific vaccines and antiviral drugs are the most powerful tools to combat viral diseases. However, broad-spectrum antiviral agents (BSAAs, i.e. compounds targeting viruses belonging to two or more viral families) could provide additional protection of the general population from emerging and re-emerging viral diseases, reinforcing the arsenal of available antiviral options. Here, we review discovery and development of BSAAs and summarize the information on 120 safe-in-man agents in a freely accessible database (https://drugvirus.info/). Future and ongoing pre-clinical and clinical studies will increase the number of BSAAs, expand the spectrum of their indications, and identify drug combinations for treatment of emerging and re-emerging viral infections as well as co-infections.
aq76s37x
aq76s37x
2020-04-30
10.1016/j.ijid.2020.02.018
1.5
Emerging threats from zoonotic coronaviruses-from SARS and MERS to 2019-nCoV
aqdlfl37
aqdlfl37
2020-02-04
10.1016/j.jmii.2020.02.001
2.5
Repurposing cefuroxime for treatment of COVID-19: a scoping review of in silico studies
Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), the causative agent of Coronavirus disease 19 (COVID-19), is a novel human Coronavirus that is responsible for about 300,000 deaths worldwide. To date, there is no confirmed treatment or vaccine prevention strategy against COVID-19. Due to the urgent need for effective treatment, drug repurposing is regarded as the immediate option. Potential drugs can often be identified via in silico drug screening experiments. Consequently, there has been an explosion of in silico experiments to find drug candidates or investigate anecdotal claims. One drug with several anecdotal accounts of benefit is Cefuroxime. The aim of this study was to identify and summarize in silico evidence for possible activity of Cefuroxime against SARS-CoV-2.To this end, we performed a scoping review of literature of in silico drug repurposing experiments for SARS-CoV-2 using PRISMA-ScR. We searched Medline, Embase, Scopus, Web of Knowledge, and Google Scholar for original studies published between 1st Feb, 2020 and 15th May, 2020 that screened drug libraries, and identified Cefuroxime as a top-ranked potential inhibitor drug against SARS-CoV-2 proteins. Six studies were identified. These studies reported Cefuroxime as a potential inhibitor of 3 key SARS-CoV-2 proteins; main protease, RNA dependent RNA polymerase, and ACE2-Spike complex. We provided a summary of the methodology and findings of the identified studies. Our scoping review identified significant in silico evidence that Cefuroxime may be a potential multi-target inhibitor of SARS-CoV-2. Further in vitro and in vivo studies are required to evaluate the potential of Cefuroxime for COVID-19. Communicated by Ramaswamy H. Sarma
aqge7xuu
aqge7xuu
2020-06-13
10.1080/07391102.2020.1777904
4.5
EMERGING RESPIRATORY DISEASE - CORONAVIRUSES
auqh3vtr
auqh3vtr
2017-09-30
10.1016/j.disamonth.2017.03.019
1
COVID-19 R0: Magic number or conundrum?
auu02ibd
auu02ibd
2020-02-24
10.4081/idr.2020.8516
2
Keeping the Country Positive during the COVID 19 Pandemic: Evidence from India
aw15xmia
aw15xmia
2020-04-21
10.1016/j.ajp.2020.102118
3.5
Triphosphates of the Two Components in DESCOVY and TRUVADA are Inhibitors of the SARS-CoV-2 Polymerase
SARS-CoV-2, a member of the coronavirus family, is responsible for the current COVID-19 pandemic. We previously demonstrated that four nucleotide analogues (specifically, the active triphosphate forms of Sofosbuvir, Alovudine, AZT and Tenofovir alafenamide) inhibit the SARS-CoV-2 RNA-dependent RNA polymerase (RdRp). Tenofovir and emtricitabine are the two components in DESCOVY and TRUVADA, the two FDA-approved medications for use as pre-exposure prophylaxis (PrEP) to prevent HIV infection. This is a preventative method in which individuals who are HIV negative (but at high-risk of contracting the virus) take the combination drug daily to reduce the chance of becoming infected with HIV. PrEP can stop HIV from replicating and spreading throughout the body. We report here that the triphosphates of tenofovir and emtricitabine, the two components in DESCOVY and TRUVADA, act as terminators for the SARS-CoV-2 RdRp catalyzed reaction. These results provide a molecular basis to evaluate the potential of DESCOVY and TRUVADA as PrEP for COVID-19.
awbcw3gq
awbcw3gq
2020-04-05
10.1101/2020.04.03.022939
1
COVID-19 (Novel Coronavirus 2019) - recent trends.
The World Health Organization (WHO) has issued a warning that, although the 2019 novel coronavirus (COVID-19) from Wuhan City (China), is not pandemic, it should be contained to prevent the global spread. The COVID-19 virus was known earlier as 2019-nCoV. As of 12 February 2020, WHO reported 45,171 cases and 1115 deaths related to COVID-19. COVID-19 is similar to Severe Acute Respiratory Syndrome coronavirus (SARS-CoV) virus in its pathogenicity, clinical spectrum, and epidemiology. Comparison of the genome sequences of COVID-19, SARS-CoV, and Middle East Respiratory Syndrome coronavirus (MERS-CoV) showed that COVID-19 has a better sequence identity with SARS-CoV compared to MERS CoV. However, the amino acid sequence of COVID-19 differs from other coronaviruses specifically in the regions of 1ab polyprotein and surface glycoprotein or S-protein. Although several animals have been speculated to be a reservoir for COVID-19, no animal reservoir has been already confirmed. COVID-19 causes COVID-19 disease that has similar symptoms as SARS-CoV. Studies suggest that the human receptor for COVID-19 may be angiotensin-converting enzyme 2 (ACE2) receptor similar to that of SARS-CoV. The nucleocapsid (N) protein of COVID-19 has nearly 90% amino acid sequence identity with SARS-CoV. The N protein antibodies of SARS-CoV may cross react with COVID-19 but may not provide cross-immunity. In a similar fashion to SARS-CoV, the N protein of COVID-19 may play an important role in suppressing the RNA interference (RNAi) to overcome the host defense. This mini-review aims at investigating the most recent trend of COVID-19.
awitk3se
awitk3se
2020-02-01
10.26355/eurrev_202002_20378
1
The 3D structure analysis of SARS-CoV S1 protein reveals a link to influenza virus neuraminidase and implications for drug and antibody discovery
Abstract The spike protein of SARS-associated coronavirus (SARS-CoV) is an important target for anti-SARS drug discovery. Its S1 domain is responsible for receptor binding and SARS-CoV entry into cells. In this study, we constructed a rational 3D model for S1 domain of SARS-CoV spike protein by fold recognition and molecular modeling techniques. We found that there is a structure similarity between S1 protein and influenza virus neuraminidase. Our analyses suggest that the existing anti-influenza virus inhibitors and anti-neuraminidase antibody could be used as a starting point for designing anti-SARS drugs, vaccines and antibodies. Interestingly, our prediction for antibody is consistent with a recently experimental discovery of anti-SARS antibody.
awyln0kk
awyln0kk
2004-07-26
10.1016/j.theochem.2004.04.065
1
Unintended Consequences of COVID-19: Remember General Pediatrics
ax0p751o
ax0p751o
2020-05-08
10.1016/j.jpeds.2020.05.004
3.5
Why are HIV-1 fusion inhibitors not effective against SARS-CoV? Biophysical evaluation of molecular interactions
Abstract The envelope spike (S) glycoprotein of the severe acute respiratory syndrome associated coronavirus (SARS-CoV) mediates the entry of the virus into target cells. Recent studies point out to a cell entry mechanism of this virus similar to other enveloped viruses, such as HIV-1. As it happens with other viruses peptidic fusion inhibitors, SARS-CoV S protein HR2-derived peptides are potential therapeutic drugs against the virus. It is believed that HR2 peptides block the six-helix bundle formation, a key structure in the viral fusion, by interacting with the HR1 region. It is a matter of discussion if the HIV-1 gp41 HR2-derived peptide T20 (enfuvirtide) could be a possible SARS-CoV inhibitor given the similarities between the two viruses. We tested the possibility of interaction between both T20 (HIV-1 gp41 HR2-derived peptide) and T-1249 with S protein HR1- and HR2-derived peptides. Our biophysical data show a significant interaction between a SARS-CoV HR1-derived peptide and T20. However, the interaction is only moderate (K B =(1.1±0.3)×105 M−1). This finding shows that the reasoning behind the hypothesis that T20, already approved for clinical application in AIDS treatment, could inhibit the fusion of SARS-CoV with target cells is correct but the effect may not be strong enough for application.
axbibuo5
axbibuo5
2006-01-31
10.1016/j.bbagen.2005.10.001
1
Broad-spectrum antivirals for the emerging Middle East respiratory syndrome coronavirus
Summary Objectives Middle East respiratory syndrome coronavirus (MERS-CoV) has emerged to cause fatal infections in patients in the Middle East and traveler-associated secondary cases in Europe and Africa. Person-to-person transmission is evident in outbreaks involving household and hospital contacts. Effective antivirals are urgently needed. Methods We used small compound-based forward chemical genetics to screen a chemical library of 1280 known drugs against influenza A virus in Biosafety Level-2 laboratory. We then assessed the anti-MERS-CoV activities of the identified compounds and of interferons, nelfinavir, and lopinavir because of their reported anti-coronavirus activities in terms of cytopathic effect inhibition, viral yield reduction, and plaque reduction assays in Biosafety Level-3 laboratory. Results Ten compounds were identified as primary hits in high-throughput screening. Only mycophenolic acid exhibited low EC50 and high selectivity index. Additionally, ribavirin and interferons also exhibited in-vitro anti-MERS-CoV activity. The serum concentrations achievable at therapeutic doses of mycophenolic acid and interferon-β1b were 60–300 and 3–4 times higher than the concentrations at which in-vitro anti-MERS-CoV activities were demonstrated, whereas that of ribavirin was ∼2 times lower. Combination of mycophenolic acid and interferon-β1b lowered the EC50 of each drug by 1–3 times. Conclusions Interferon-β1b with mycophenolic acid should be considered in treatment trials of MERS.
ay4cnzn5
ay4cnzn5
2013-12-31
10.1016/j.jinf.2013.09.029
0.5
SARS‐CoV‐2: Structural diversity, phylogeny, and potential animal host identification of spike glycoprotein
To investigate the evolutionary history of the current pandemic outbreak of severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2), a total of 137 genomes of coronavirus strains with release dates between January 2019 and 25 March 2020, were analyzed. To investigate the potential intermediate host of the SARS‐CoV‐2, we analyzed spike glycoprotein sequences from different animals, with particular emphasis on bats. We performed phylogenetic analysis and structural reconstruction of the spike glycoproteins with subsequent alignment and comparison. Our phylogenetic results revealed that SARS‐CoV‐2 was more similar to the bats' betacoronavirus isolates: HKU5‐related from Pipistrellus abramus and HKU4‐related from Tylonycteris pachypus. We also identified a yak betacoronavirus strain, YAK/HY24/CH/2017, as the closest match in the comparison of the structural models of spike glycoproteins. Interestingly, a set of unique features has been described for this particular strain of the yak betacoronavirus. Therefore, our results suggest that the human SARS‐CoV‐2, responsible for the current outbreak of COVID‐19, could also come from yak as an intermediate host.
ayhsbfd1
ayhsbfd1
2020-05-17
10.1002/jmv.25976
3
Inhibition of SARS-CoV-2 (previously 2019-nCoV) infection by a highly potent pan-coronavirus fusion inhibitor targeting its spike protein that harbors a high capacity to mediate membrane fusion
The recent outbreak of coronavirus disease (COVID-19) caused by SARS-CoV-2 infection in Wuhan, China has posed a serious threat to global public health. To develop specific anti-coronavirus therapeutics and prophylactics, the molecular mechanism that underlies viral infection must first be defined. Therefore, we herein established a SARS-CoV-2 spike (S) protein-mediated cell–cell fusion assay and found that SARS-CoV-2 showed a superior plasma membrane fusion capacity compared to that of SARS-CoV. We solved the X-ray crystal structure of six-helical bundle (6-HB) core of the HR1 and HR2 domains in the SARS-CoV-2 S protein S2 subunit, revealing that several mutated amino acid residues in the HR1 domain may be associated with enhanced interactions with the HR2 domain. We previously developed a pan-coronavirus fusion inhibitor, EK1, which targeted the HR1 domain and could inhibit infection by divergent human coronaviruses tested, including SARS-CoV and MERS-CoV. Here we generated a series of lipopeptides derived from EK1 and found that EK1C4 was the most potent fusion inhibitor against SARS-CoV-2 S protein-mediated membrane fusion and pseudovirus infection with IC50s of 1.3 and 15.8 nM, about 241- and 149-fold more potent than the original EK1 peptide, respectively. EK1C4 was also highly effective against membrane fusion and infection of other human coronavirus pseudoviruses tested, including SARS-CoV and MERS-CoV, as well as SARSr-CoVs, and potently inhibited the replication of 5 live human coronaviruses examined, including SARS-CoV-2. Intranasal application of EK1C4 before or after challenge with HCoV-OC43 protected mice from infection, suggesting that EK1C4 could be used for prevention and treatment of infection by the currently circulating SARS-CoV-2 and other emerging SARSr-CoVs.
ayi928ct
ayi928ct
2020-03-30
10.1038/s41422-020-0305-x
1
Feasibility of Known RNA Polymerase Inhibitors as Anti-SARS-CoV-2 Drugs
Coronaviruses (CoVs) are positive-stranded RNA viruses that infect humans and animals. Infection by CoVs such as HCoV-229E, -NL63, -OC43 and -HKU1 leads to the common cold, short lasting rhinitis, cough, sore throat and fever. However, CoVs such as Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV), Middle East Respiratory Syndrome Coronavirus (MERS-CoV), and the newest SARS-CoV-2 (the causative agent of COVID-19) lead to severe and deadly diseases with mortality rates ranging between ~1 to 35% depending on factors such as age and pre-existing conditions. Despite continuous global health threats to humans, there are no approved vaccines or drugs targeting human CoVs, and the recent outbreak of COVID-19 emphasizes an urgent need for therapeutic interventions. Using computational and bioinformatics tools, here we present the feasibility of reported broad-spectrum RNA polymerase inhibitors as anti- SARS-CoV-2 drugs targeting its main RNA polymerase, suggesting that investigational and approved nucleoside RNA polymerase inhibitors have potential as anti-SARS-CoV-2 drugs. However, we note that it is also possible for SARS-CoV-2 to evolve and acquire drug resistance mutations against these nucleoside inhibitors.
b0a0s2fs
b0a0s2fs
2020
4
COVID-19 pandemic: an overview of epidemiology, parthenogenesis, diagnostics and potential vaccines and therapeutics
At the time of writing this review, severe acute respiratory coronavirus syndrome-2 (SARS-CoV-2) has infected more than 2,355,853 patients and resulted in more than 164,656 deaths worldwide (as of 20 April 2020). This review highlights the preventive measures, available clinical therapies and the potential of vaccine development against SARS-CoV-2 by taking into consideration the strong genetic similarities of the 2003 epidemic SARS-CoV. Recent studies are investigating the repurposing of US FDA-approved drugs as there is no available vaccine yet with many attempts under clinical evaluation. Several antivirals, antimalarials and immunomodulators that have shown activity against SARS-CoV and Middle East coronavirus respiratory syndromes are being evaluated. In particular, hydroxychloroquine, remdesivir, favipiravir, arbidol, tocilizumab and bevacizumab have shown promising results. The main aim of this review is to provide an overview of this pandemic and where we currently stand.
b0aaozmn
b0aaozmn
2020-05-13
10.4155/tde-2020-0035
3
Computational screening of antagonists against the SARS-CoV-2 (COVID-19) coronavirus by molecular docking
In the current spread of novel coronavirus (SARS-CoV-2), antiviral drug discovery is of great importance. AutoDock Vina was used to screen potential drugs by molecular docking with the structural protein and non-structural protein sites of new coronavirus. Ribavirin, a common antiviral drug, remdesivir, chloroquine and luteolin were studied. Honeysuckle is generally believed to have antiviral effects in traditional Chinese medicine. In this study, luteolin (the main flavonoid in honeysuckle) was found to bind with a high affinity to the same sites of the main protease of SARS-CoV-2 as the control molecule. Chloroquine has been proved clinically effective and can bind to the main protease; this may be the antiviral mechanism of this drug. The study was restricted to molecular docking without validation by molecular dynamics simulations. Interactions with the main protease may play a key role in fighting against viruses. Luteolin is a potential antiviral molecule worthy of attention.
b19pjjib
b19pjjib
2020
4.5
An investigation into the identification of potential inhibitors of SARS-CoV-2 main protease using molecular docking study
A new strain of a novel infectious disease affecting millions of people, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has recently been declared as a pandemic by the World Health Organization (WHO). Currently, several clinical trials are underway to identify specific drugs for the treatment of this novel virus. The inhibition of the SARS-CoV-2 main protease is necessary for the blockage of the viral replication. Here, in this study, we have utilized a blind molecular docking approach to identify the possible inhibitors of the SARS-CoV-2 main protease, by screening a total of 33 molecules which includes natural products, anti-virals, anti-fungals, anti-nematodes and anti-protozoals. All the studied molecules could bind to the active site of the SARS-CoV-2 protease (PDB: 6Y84), out of which rutin (a natural compound) has the highest inhibitor efficiency among the 33 molecules studied, followed by ritonavir (control drug), emetine (anti-protozoal), hesperidin (a natural compound), lopinavir (control drug) and indinavir (anti-viral drug). All the molecules, studied out here could bind near the crucial catalytic residues, HIS41 and CYS145 of the main protease, and the molecules were surrounded by other active site residues like MET49, GLY143, HIS163, HIS164, GLU166, PRO168, and GLN189. As this study is based on molecular docking, hence being particular about the results obtained, requires extensive wet-lab experimentation and clinical trials under in vitro as well as in vivo conditions.Communicated by Ramaswamy H. Sarma.
b1a1pkae
b1a1pkae
2020
5
Structural basis of SARS-CoV-2 3CLpro and anti-COVID-19 drug discovery from medicinal plants
The recent outbreak of coronavirus disease 2019 (COVID-19) caused by SARS-CoV-2 in December 2019 raised global health concerns. The viral 3-chymotrypsin-like cysteine protease (3CLpro) enzyme controls coronavirus replication and is essential for its life cycle. 3CLpro is a proven drug discovery target in the case of severe acute respiratory syndrome coronavirus (SARS-CoV) and middle east respiratory syndrome coronavirus (MERS-CoV). Recent studies revealed that the genome sequence of SARS-CoV-2 is very similar to that of SARS-CoV. Therefore, herein, we analysed the 3CLpro sequence, constructed its 3D homology model, and screened it against a medicinal plant library containing 32,297 potential anti-viral phytochemicals/traditional Chinese medicinal compounds. Our analyses revealed that the top nine hits might serve as potential anti- SARS-CoV-2 lead molecules for further optimisation and drug development process to combat COVID-19.
b1xq1v05
b1xq1v05
2020
4.5
Current status and progress of 2019 novel coronavirus pneumonia/ 中华危重病急救医学
Recently, the 2019 novel coronavirus (2019-nCoV) pneumonia outbroke in Wuhan and rapidly spread to all over China and even the world. Because of the strong infectivity and various clinical symptoms, it has brought certain difficulties to the epidemic prevention and control. Currently there is no specific drug for 2019-nCoV. Previous drugs used to treat other coronaviruses may be effective, but further clinical trials remain needed. We reviewed literature on the epidemiology, etiology, clinical manifestations, imaging manifestations, laboratory examination, diagnosis, complications, treatment and outcome of 2019-nCoV pneumonia.
b21szgvy
b21szgvy
2020
1.5
Clinical features and dynamics of viral load in imported and non-imported patients with COVID-19
OBJECTIVES: To compare the clinical characteristics and the dynamics of viral load between imported and non-imported patients with COVID-19. DESIGN AND METHODS: Data from 51 laboratory-confirmed patients were retrospectively analyzed. RESULTS: The incubation period in the tertiary group was longer than that in the imported and secondary groups (both p < 0.05). Fever was the most common symptom at the onset of illness (73.33%, 58.82%, and 68.42%, respectively), and half of the patients had a low-grade temperature (<38.0 °C) with a short duration of fever (<7 days). CT scans showed that most patients in the three groups had bilateral pneumonia (80.00%, 76.47%, and 73.68%, respectively). Ct values detected in the tertiary patients were similar to those for the imported and secondary groups at the time of admission (both p > 0.05). For the tertiary group, the viral load was undetectable in half of the patients (52.63%) on day 7, and in all patients on day 14. For one third of the patients in the imported and secondary groups, the viral load remained positive on day 14 after the admission. CONCLUSIONS: COVID-19 can present as pneumonia with a low onset of symptoms, and the infectivity of SARS-CoV2 may gradually decrease in tertiary patients.
b23xm6ox
b23xm6ox
2020-03-14
10.1016/j.ijid.2020.03.022
1.5
Rapid Detection of COVID-19 Causative Virus (SARS-CoV-2) in Human Nasopharyngeal Swab Specimens Using Field-Effect Transistor-Based Biosensor
[Image: see text] Coronavirus disease 2019 (COVID-19) is a newly emerging human infectious disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2, previously called 2019-nCoV). Based on the rapid increase in the rate of human infection, the World Health Organization (WHO) has classified the COVID-19 outbreak as a pandemic. Because no specific drugs or vaccines for COVID-19 are yet available, early diagnosis and management are crucial for containing the outbreak. Here, we report a field-effect transistor (FET)-based biosensing device for detecting SARS-CoV-2 in clinical samples. The sensor was produced by coating graphene sheets of the FET with a specific antibody against SARS-CoV-2 spike protein. The performance of the sensor was determined using antigen protein, cultured virus, and nasopharyngeal swab specimens from COVID-19 patients. Our FET device could detect the SARS-CoV-2 spike protein at concentrations of 1 fg/mL in phosphate-buffered saline and 100 fg/mL clinical transport medium. In addition, the FET sensor successfully detected SARS-CoV-2 in culture medium (limit of detection [LOD]: 1.6 × 10(1) pfu/mL) and clinical samples (LOD: 2.42 × 10(2) copies/mL). Thus, we have successfully fabricated a promising FET biosensor for SARS-CoV-2; our device is a highly sensitive immunological diagnostic method for COVID-19 that requires no sample pretreatment or labeling.
b2ju3poi
b2ju3poi
2020-04-15
10.1021/acsnano.0c02823
2
2019 novel coronavirus disease in hemodialysis (HD) patients: Report from one HD center in Wuhan, China
The outbreak of COVID-19 originated in Wuhan has become a global epidemic of contagious diseases, which poses a serious threat to human life and health, especially for those with underlined diseases. However, Impacts of COVID-19 epidemic on HD center and HD patients are still unknown. In this report, we reviewed the whole course of the epidemic emerged in the HD center of Renmin Hospital, Wuhan University from January 14, 2020, the day the first case was confirmed, to February 17, 2020, the day the epidemic extinction. There are totally 37 cases among 230 HD patients and 4 cases among 33 staff being diagnosed with COVID-19. The epidemiology, clinical presentation and immune profile of dialysis patients contracted COVID-19 were further studied. We found that the two key measures we took in response to the epidemic, one was upgrading level of prevention and protection on January 21 and the other one starting universal screening, isolating, and distributing the infected cases on February 4, were effective in the epidemic control. No new COVID-19 case had been diagnosed since February 13. During the epidemic, 7 HD patients died, including 6 with COVID-19 and 1 without COVID-19. The presumed causes of death were not directly related to pneumonia, but due to cardiovascular and cerebrovascular diseases, hyperkalemia, etc. Most of the leukocytes in the peripheral blood of the HD patients infected with COVID-19 decreased, and the CT images of the chest mostly showed the ground glass like changes on the right side. The symptoms of most of the patients were mild, and there were no cases admitted to ICU. The frequency of lymphocytes in PBMCs and the serum level of inflammatory cytokines were assessed in HD patients contracted COVID-19 or not, non-HD COVID-19 patients, as well as healthy volunteers. The results showed that lymphocytes of T cell, Th cells, killer T cells, as well as NK cells in PBMCs of HD patients decreased significantly than other groups. HD patients with COVID-19 also displayed remarkable lower serum level of inflammatory cytokines than other COVID-19 patients. Our study indicates that HD patients are the highly susceptible population and HD centers are high risk area in the outbreak of COVID-19 epidemic. Measures of prevention, protection, screening, isolation, and distribution are essential in the epidemic management and should be taken in the early stage. HD Patients with COVID-19 are mostly clinical mild and unlikely progress to severe pneumonia due to the impaired cellular immune function and incapability of mounting cytokines storm. More attention should be paid to prevent cardiovascular events, which may be the collateral impacts of COVID-19 epidemic on HD patients.
b2znv6pa
b2znv6pa
2020-02-25
10.1101/2020.02.24.20027201
1.5
Analysis of therapeutic targets for SARS-CoV-2 and discovery of potential drugs by computational methods
SARS-CoV-2 has caused tens of thousands of infections and more than one thousand deaths. There are currently no registered therapies for treating coronavirus infections. Because of time consuming process of new drug development, drug repositioning may be the only solution to the epidemic of sudden infectious diseases. We systematically analyzed all the proteins encoded by SARS-CoV-2 genes, compared them with proteins from other coronaviruses, predicted their structures, and built 19 structures that could be done by homology modeling. By performing target-based virtual ligand screening, a total of 21 targets (including two human targets) were screened against compound libraries including ZINC drug database and our own database of natural products. Structure and screening results of important targets such as 3-chymotrypsin-like protease (3CLpro), Spike, RNA-dependent RNA polymerase (RdRp), and papain like protease (PLpro) were discussed in detail. In addition, a database of 78 commonly used anti-viral drugs including those currently on the market and undergoing clinical trials for SARS-CoV-2 was constructed. Possible targets of these compounds and potential drugs acting on a certain target were predicted. This study will provide new lead compounds and targets for further in vitro and in vivo studies of SARS-CoV-2, new insights for those drugs currently ongoing clinical studies, and also possible new strategies for drug repositioning to treat SARS-CoV-2 infections.
b31ctbat
b31ctbat
2020-02-27
10.1016/j.apsb.2020.02.008
0.5
An Evolutionary Point of View of Animal Ethics
b3sahy31
b3sahy31
2020-04-02
10.3389/fpsyg.2020.00403
3
COVID-19: Melatonin as a potential adjuvant treatment
Abstract This article summarizes the likely benefits of melatonin in the attenuation of COVID-19 based on its putative pathogenesis. The recent outbreak of COVID-19 has become a pandemic with tens of thousands of infected patients. Based on clinical features, pathology, the pathogenesis of acute respiratory disorder induced by either highly homogenous coronaviruses or other pathogens, the evidence suggests that excessive inflammation, oxidation, and an exaggerated immune response very likely contribute to COVID-19 pathology. This leads to a cytokine storm and subsequent progression to acute lung injury (ALI)/acute respiratory distress syndrome (ARDS) and often death. Melatonin, a well-known anti-inflammatory and anti-oxidative molecule, is protective against ALI/ARDS caused by viral and other pathogens. Melatonin is effective in critical care patients by reducing vessel permeability, anxiety, sedation use, and improving sleeping quality, which might also be beneficial for better clinical outcomes for COVID-19 patients. Notably, melatonin has a high safety profile. There is significant data showing that melatonin limits virus-related diseases and would also likely be beneficial in COVID-19 patients. Additional experiments and clinical studies are required to confirm this speculation.
b3ui95vx
b3ui95vx
2020-06-01
10.1016/j.lfs.2020.117583
1
Synthesis of β-amino-α-trifluoromethyl alcohols and their applications in organic synthesis
Abstract A comprehensive overview on methods applied for syntheses of β-amino-α-trifluoromethyl alcohols, including stereocontrolled variants, is presented. In addition, reported cases of the exploration of β-amino-α-trifluoromethyl alcohols for the preparation of trifluoromethylated peptidomimetics and other biologically active, fluorinated compounds are discussed. Attractive opportunities for their applications as organocatalysts are also presented.
b3ukefxq
b3ukefxq
2010-08-31
10.1016/j.jfluchem.2010.05.014
2
Trials of anti-tumour necrosis factor therapy for COVID-19 are urgently needed
b48oun11
b48oun11
2020-04-09
10.1016/s0140-6736(20)30858-8
2.5
Structure-Based Design, Synthesis and Biological Evaluation of Peptidomimetic Aldehydes as a Novel Series of Antiviral Drug Candidates Targeting the SARS-CoV-2 Main Protease
SARS-CoV-2 is the etiological agent responsible for the COVID-19 outbreak in Wuhan. Specific antiviral drug are urgently needed to treat COVID-19 infections. The main protease (Mpro) of SARS-CoV-2 is a key CoV enzyme that plays a pivotal role in mediating viral replication and transcription, which makes it an attractive drug target. In an effort to rapidly discover lead compounds targeting Mpro, two compounds (11a and 11b) were designed and synthesized, both of which exhibited excellent inhibitory activity with an IC50 value of 0.05 μM and 0.04 μM respectively. Significantly, both compounds exhibited potent anti-SARS-CoV-2 infection activity in a cell-based assay with an EC50 value of 0.42 μM and 0.33 μM, respectively. The X-ray crystal structures of SARS-CoV-2 Mpro in complex with 11a and 11b were determined at 1.5 Å resolution, respectively. The crystal structures showed that 11a and 11b are covalent inhibitors, the aldehyde groups of which are bound covalently to Cys145 of Mpro. Both compounds showed good PK properties in vivo, and 11a also exhibited low toxicity which is promising drug leads with clinical potential that merits further studies.
b4joa5tx
b4joa5tx
2020-03-28
10.1101/2020.03.25.996348
2.5
Remdesivir for severe acute respiratory syndrome coronavirus 2 causing COVID-19: An evaluation of the evidence
Abstract The novel coronavirus infection that initially found at the end of 2019 has attracted great attention. So far, the number of infectious cases has increased globally to more than 100 thousand and the outbreak has been defined as a pandemic situation, but there are still no “specific drug” available. Relevant reports have pointed out the novel coronavirus has 80% homology with SARS. In the difficulty where new synthesized drug cannot be applied immediately to patients, “conventional drug in new use” becomes a feasible solution. The first medication experience of the recovered patients in the US has led remdesivir to be the “specific drug”. China has also taken immediate action to put remdesivir into clinical trials with the purpose of applying it into clinical therapeutics for Corona Virus Disease 2019 (COVID-19). We started from the structure, immunogenicity, and pathogenesis of coronavirus infections of the novel coronavirus. Further, we analyzed the pharmacological actions and previous trials of remdesivir to identify the feasibility of conducting experiments on COVID-19.
b518n9dx
b518n9dx
2020-04-02
10.1016/j.tmaid.2020.101647
1
Perspectives on monoclonal antibody therapy as potential therapeutic intervention for Coronavirus disease-19 (COVID-19).
Last decade witnessed the outbreak of many life-threatening human pathogens including Nipah, Ebola, Chikungunya, Zika, Middle East respiratory syndrome coronavirus (MERS-CoV), Severe Acute respiratory syndrome coronavirus (SARS-CoV) and more recently novel coronavirus (2019-nCoV or SARS-CoV-2). The disease condition associated with novel coronavirus, referred to as Coronavirus disease (COVID-19). The emergence of novel coronavirus in 2019 in Wuhan, China marked the third highly pathogenic coronavirus infecting humans in the 21st century. The continuing emergence of coronaviruses at regular intervals poses a significant threat to human health and economy. Ironically, even after a decade of research on coronavirus, still there are no licensed vaccines or therapeutic agents to treat coronavirus infection which highlights an urgent need to develop effective vaccines or post-exposure prophylaxis to prevent future epidemics. Several clinical, genetic and epidemiological features of COVID-19 resemble SARS-CoV infection. Hence, the research advancements on SARS-CoV treatment might help scientific community in quick understanding of this virus pathogenesis and develop effective therapeutic/prophylactic agents to treat and prevent this infection. Monoclonal antibodies represent the major class of biotherapeutics for passive immunotherapy to fight against viral infection. The therapeutic potential of monoclonal antibodies has been well recognized in the treatment of many diseases. Here, we summarize the potential monoclonal antibody based therapeutic intervention for COVID-19 by considering the existing knowledge on the neutralizing monoclonal antibodies against similar coronaviruses SARS-CoV and MERS-CoV. Further research on COVID-19 pathogenesis could identify appropriate therapeutic targets to develop specific anti-virals against this newly emerging pathogen.
b5329o75
b5329o75
2020-03-04
10.12932/ap-200220-0773
1.5
Influenza A Virus Encoding Secreted Gaussia Luciferase as Useful Tool to Analyze Viral Replication and Its Inhibition by Antiviral Compounds and Cellular Proteins
Reporter genes inserted into viral genomes enable the easy and rapid quantification of virus replication, which is instrumental to efficient in vitro screening of antiviral compounds or in vivo analysis of viral spread and pathogenesis. Based on a published design, we have generated several replication competent influenza A viruses carrying either fluorescent proteins or Gaussia luciferase. Reporter activity could be readily quantified in infected cultures, but the virus encoding Gaussia luciferase was more stable than viruses bearing fluorescent proteins and was therefore analyzed in detail. Quantification of Gaussia luciferase activity in the supernatants of infected culture allowed the convenient and highly sensitive detection of viral spread, and enzymatic activity correlated with the number of infectious particles released from infected cells. Furthermore, the Gaussia luciferase encoding virus allowed the sensitive quantification of the antiviral activity of the neuraminidase inhibitor (NAI) zanamivir and the host cell interferon-inducible transmembrane (IFITM) proteins 1–3, which are known to inhibit influenza virus entry. Finally, the virus was used to demonstrate that influenza A virus infection is sensitive to a modulator of endosomal cholesterol, in keeping with the concept that IFITMs inhibit viral entry by altering cholesterol levels in the endosomal membrane. In sum, we report the characterization of a novel influenza A reporter virus, which allows fast and sensitive detection of viral spread and its inhibition, and we show that influenza A virus entry is sensitive to alterations of endosomal cholesterol levels.
b5lldhi5
b5lldhi5
2014-05-19
10.1371/journal.pone.0097695
1.5
Characterization of the receptor-binding domain (RBD) of 2019 novel coronavirus: implication for development of RBD protein as a viral attachment inhibitor and vaccine
The outbreak of Coronavirus Disease 2019 (COVID-19) has posed a serious threat to global public health, calling for the development of safe and effective prophylactics and therapeutics against infection of its causative agent, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), also known as 2019 novel coronavirus (2019-nCoV). The CoV spike (S) protein plays the most important roles in viral attachment, fusion and entry, and serves as a target for development of antibodies, entry inhibitors and vaccines. Here, we identified the receptor-binding domain (RBD) in SARS-CoV-2 S protein and found that the RBD protein bound strongly to human and bat angiotensin-converting enzyme 2 (ACE2) receptors. SARS-CoV-2 RBD exhibited significantly higher binding affinity to ACE2 receptor than SARS-CoV RBD and could block the binding and, hence, attachment of SARS-CoV-2 RBD and SARS-CoV RBD to ACE2-expressing cells, thus inhibiting their infection to host cells. SARS-CoV RBD-specific antibodies could cross-react with SARS-CoV-2 RBD protein, and SARS-CoV RBD-induced antisera could cross-neutralize SARS-CoV-2, suggesting the potential to develop SARS-CoV RBD-based vaccines for prevention of SARS-CoV-2 and SARS-CoV infection.
b6dsdiux
b6dsdiux
2020-03-19
10.1038/s41423-020-0400-4
3.5
A mouse model of SARS-CoV-2 infection and pathogenesis
Summary Since December 2019, a novel coronavirus SARS-CoV-2 has emerged and rapidly spread throughout the world, resulting in a global public health emergency. The lack of vaccine and antivirals has brought an urgent need for animal model. Human Angiotensin converting enzyme II (ACE2) has been identified as a functional receptor for SARS-CoV-2. In this study, we generated a mouse model expressing human ACE2 (hACE2) using CRISPR/Cas9 knock-in technology. Compared with wild-type C57BL/6 mice, both young and aged hACE2 mice sustained high viral loads in lung, trachea and brain upon intranasal infection. Although fatalities were not observed, interstitial pneumonia and elevated cytokines were seen in SARS-CoV-2 infected- aged hACE2 mice. Interestingly, intragastric inoculation of SARS-CoV-2 was evidenced to cause productive infection and lead to pulmonary pathological changes in hACE2 mice. Overall, this animal model described here provides a useful tool for studying SARS-CoV-2 transmission and pathogenesis, and evaluating COVID-19 vaccines and therapeutics.
b6j89491
b6j89491
2020-05-27
10.1016/j.chom.2020.05.020
4
Dynamic change process of target genes by RT-PCR testing of SARS-Cov-2 during the course of a Coronavirus Disease 2019 patient
Abstract We report the dynamic change process of target genes by RT-PCR testing of SARS-Cov-2 during the course of a COVID-19 patient: from successive negative results to successive single positive nucleocapsid gene, to two positive target genes (orf1ab and nucleocapsid) by RT-PCR testing of SARS-Cov-2, and describe the diagnosis, clinical course, and management of the case. In this case, negative results of RT-PCR testing was not excluded to diagnose a suspected COVID-19 patient, clinical signs and symptoms, other laboratory findings, and chest CT images should be taken into account for the absence of enough positive evidence. This case highlights the importance of successive sampling and testing SARS-Cov-2 by RT-PCR as well as the increased value of single positive target gene from pending to positive in two specimens to diagnose laboratory-confirmed COVID-19.
b8j2hn9w
b8j2hn9w
2020-07-31
10.1016/j.cca.2020.03.032
1.5
Forecasting COVID-19 impact in India using pandemic waves Nonlinear Growth Models
The ongoing pandemic of the coronavirus disease 2019 (COVID-19) started in China and devastated a vast majority of countries. In India, COVID-19 cases are steadily increasing since January 30, 2020, and the government-imposed lockdown across the country to curtail community transmission. COVID-19 forecasts have played an important role in capturing the probability of infection and the basic reproduction rate. In this study, we predicted some trajectories of trajectories associated with COVID-19 in the coming days in India using an Auto-regression integrated moving average model (ARIMA) and Richards model. By the end of April 2020, the incidence of new cases is predicted to be 5200 (95% CI: 4650 to 6002) through the ARIMA model versus be 6378 (95% CI: 4904 to 7851) Richard model. We estimated that there would be a total of 197 (95% CI: 118 to 277) deaths and drop down in the recovery rates will reach around 501 (95% CI: 245 to 758) by the end of April 2020. These estimates can help to strengthen the implementation of strategies to increase the health system capacity and enactment of social distancing measures all over India.
b9p5tqhl
b9p5tqhl
2020-04-02
10.1101/2020.03.30.20047803
1
SARS Coronavirus Redux
As an atypical pneumonia began to appear in December 2019, Zhou et al . worked with remarkable speed to identify the associated virus, determine its relationship to animal viruses, and evaluate factors conferring infection susceptibility and resistance. These foundational results are being advanced to control the current worldwide human coronavirus epidemic.
ba8zx73b
ba8zx73b
2020-04-30
10.1016/j.it.2020.02.007
1
The modelling of COVID19 pathways sheds light on mechanisms, opportunities and on controversial interpretations of medical treatments. v2
The new coronavirus (2019-nCoV or SARS-CoV2), inducing the current pandemic disease (COVID-19) and causing pneumoniae in humans, is dramatically increasing in epidemic scale since its first appearance in Wuhan, China, in December 2019. The first infection from epidemic coronaviruses in 2003 fostered the spread of an overwhelming amount of related scientific efforts. The manifold aspects that have been raised, as well as their redundancy offer precious information that has been underexploited and needs to be critically re-evaluated, appropriately used and offered to the whole community, from scientists, to medical doctors, stakeholders and common people. These efforts will favour a holistic view on the comprehension, prevention and development of strategies (pharmacological, clinical etc) as well as common intervention against the new coronavirus spreading. Here we describe a model that emerged from our analysis that was focused on the Renin Angiotensin System (RAS) and the possible routes linking it to the viral infection. because the infection is mediated by the viral receptor on human cell membranes Angiotensin Converting Enzyme (ACE2), which is a key component in RAS signalling. The model depicts the main pathways determining the disease and the molecular framework for its establishment, and can help to shed light on mechanisms involved in the infection. It promptly gives an answer to some of the controversial, and still open, issues concerning predisposing conditions and medical treatments that protect from or favour the severity of the disease (such as the use of ACE inhibitors or ARBs/sartans), or to the sex related biases in the affected population. The model highlights novel opportunities for further investigations, diagnosis and appropriate intervention to understand and fight COVID19.
bayj4dtg
bayj4dtg
2020-03-25
2.5
Characterization of neutralizing monoclonal antibodies recognizing a 15-residues epitope on the spike protein HR2 region of severe acute respiratory syndrome coronavirus (SARS-CoV)
The spike (S) glycoprotein is thought to play a complex and central role in the biology and pathogenesis of SARS coronavirus infection. In this study, a recombinant protein (rS268, corresponding to residues 268–1255 of SARS-CoV S protein) was expressed in Escherichia coli and was purified to near homogeneity. After immunization with rS268, S protein-specific BALB/c antisera and mAbs were induced and confirmed using ELISA, Western blot and IFA. Several BALB/c mAbs were found to be effectively to neutralize the infection of Vero E6 cells by SARS-CoV in a dose-dependent manner. Systematic epitope mapping showed that all these neutralizing mAbs recognized a 15-residues peptide (CB-119) corresponding to residues 1143–1157 (SPDVDLGDISGINAS) that was located to the second heptad repeat (HR2) region of the SARS-CoV spike protein. The peptide CB-119 could specifically inhibit the interaction of neutralizing mAbs and spike protein in a dose-dependent manner. Further, neutralizing mAbs, but not control mAbs, could specifically interact with CB-119 in a dose-dependent manner. Results implicated that the second heptad repeat region of spike protein could be a good target for vaccine development against SARS-CoV.
bbn16uf1
bbn16uf1
2005-08-19
10.1007/s11373-005-9004-3
1
Drug Development and Medicinal Chemistry Efforts toward SARS‐Coronavirus and Covid‐19 Therapeutics
The COVID‐19 pandemic caused by SARS‐CoV‐2 infection is spreading at an alarming rate and has created an unprecedented health emergency around the globe. There is no effective vaccine or approved drug treatment against COVID‐19 and other pathogenic coronaviruses. The development of antiviral agents is an urgent priority. Biochemical events critical to the coronavirus replication cycle provided a number of attractive targets for drug development. These include, spike protein for binding to host cell‐surface receptors, proteolytic enzymes that are essential for processing polyproteins into mature viruses, and RNA‐dependent RNA polymerase for RNA replication. There has been a lot of ground work for drug discovery and development against these targets. Also, high‐throughput screening efforts have led to the identification of diverse lead structures, including natural product‐derived molecules. This review highlights past and present drug discovery and medicinal‐chemistry approaches against SARS‐CoV, MERS‐CoV and COVID‐19 targets. The review hopes to stimulate further research and will be a useful guide to the development of effective therapies against COVID‐19 and other pathogenic coronaviruses.
bcgbdf84
bcgbdf84
2020-05-07
10.1002/cmdc.202000223
3
Hypertension prevalence in human coronavirus disease: the role of ACE system in infection spread and severity
The prevalence of hypertension is high in patients affected by coronavirus disease 2019 (COVID-2019) and it appears to be related to an increased risk of mortality, as shown in many epidemiological studies. The angiotensin-converting enzyme (ACE) system is not uniformly expressed in all of the human races, and current differences could explain some of the geographical discrepancies in infection around the world. Furthermore, animal studies have shown that the ACE2 receptor is a potential pathway for host infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of COVID-19. As two-thirds of hypertensive patients take ACE inhibitors/angiotensin receptor blockers, several concerns have been raised about the detrimental role of current antihypertensive drugs in COVID-19. This report summarizes the recent evidence for and against the administration of ACE blockade in the COVID-19 era.
bchar8ky
bchar8ky
2020
4.5
Potent and persistent antibody responses against the receptor-binding domain of SARS-CoV spike protein in recovered patients
BACKGROUND: The spike (S) protein of SARS-CoV not only mediates receptor-binding but also induces neutralizing antibodies. We previously identified the receptor-binding domain (RBD) of S protein as a major target of neutralizing antibodies in animal models and thus proposed a RBD-based vaccine. However, the antigenicity and immunogenicity of RBD in humans need to be characterized. RESULTS: Two panels of serum samples from recovered SARS patients were included and the antibody responses against the RBD were measured by ELISA and micro-neutralization assays. We found that the RBD of S protein induced potent antibody responses in the recovered SARS patients and RBD-specific antibodies could persist at high titers over three year follow-up. Furthermore, affinity purified anti-RBD antibodies possessed robust neutralizing activity. CONCLUSION: The RBD of SARS-CoV is highly immunogenic in humans and mediates protective responses and RBD-based vaccines and diagnostic approaches can be further developed.
bd2ndoug
bd2ndoug
2010-11-04
10.1186/1743-422x-7-299
1.5
Analysis of Women’s Health Online News Articles Using Topic Modeling
OBJECTIVES: This research aimed to understand the popularity of topics in the field of women’s health through analysis of online news articles which were chronologically classified and examined to determine how women’s health and diseases had changed over time. METHODS: Women’s health and disease news articles were collated from a popular news website between 1993 to 2015 and preprocessed using gynecological medical terminology, Korean words and nouns (excluding general nouns not related to women’s healthcare topics). The resultant articles (N = 7,710) were analyzed using the Latent Dirichlet Allocation algorithm and major topics were extracted. Topic trends were analyzed by year and period for women’s health. RESULTS: It was observed that most of the women’s health articles were focused on “Healthcare”, and 9 other topics were identified that represented a relatively small proportion in 1993–2000. In 2001–2005, most of the articles were focused on “Medical Services” and “Dietary Supplements” with some specific topics that peaked people’s interest, as compared to those focused on “Healthcare” in the 1990s. It was also observed that differences in the proportion of each topic was small after 2011. CONCLUSION: Changes in topics related to women’s disease were not clearly distinguished in the 1990s but this changed from 2001where articles related to “women disease” appeared as articles on the topics of various diseases.
bfm4w84r
bfm4w84r
2019-06-16
10.24171/j.phrp.2019.10.3.07
3
Updated Approaches against SARS-CoV-2
Novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) lies behind the ongoing outbreak of coronavirus disease 2019 (COVID-19). There is a growing understanding of SARS-CoV-2 in virology, epidemiology, and clinical management strategies. However, no anti-SARS-CoV-2 drug or vaccine has been officially approved due to the absence of adequate evidence. Scientists are racing to develop a treatment for COVID-19. Recent studies have revealed many attractive therapeutic options, even if some of them remain to be further confirmed in rigorous preclinical models and clinical trials. In this minireview, we aim to summarize the updated potential approaches against SARS-CoV-2. We emphasize that further efforts are warranted to develop the safest and most effective approach.
bgm4dlwz
bgm4dlwz
2020
4.5
Medication for COVID-19-an Overview of Approaches Currently Under Study
BACKGROUND: With the worldwide spread of SARS-CoV-2 infection, it is becoming increasingly urgent to develop a vaccine to prevent COVID-19, as well as effective drugs to treat it. METHODS: This article is based on a selective literature search in PubMed and ClinicalTrials.gov, followed by an assessment of the ongoing clinical trials that were revealed by the search. RESULTS: A number of substances have been found to prevent the reproduction of SARS-CoV-2 in vitro. These include virustatic agents that have already been approved for the treatment of other types of viral infection, as well as drugs that are currently used for entirely different purposes. High in vitro activity has been found for the nucleotide analogue remdesivir, for the antimalarial drug chloroquine, and for nitazoxanide, a drug used to treat protozoan infections. Because the virus enters human cells by way of the membrane-associated angiotensin converting enzyme 2 (ACE2), keeping the virus from docking to this receptor is a conceivable treatment approach. Transmembrane protease serine 2 (TMPRSS2) plays a role in the fusion of the virus with cells; inhibitors of this enzyme are known as well. The potential therapeutic efficacy and tolerability of these and other active substances remain to be investigated in clinical trials. At present, more than 80 trials on COVID-10 have already been registered with Clinical- Trials.gov. Some initial findings should already be available in late April 2020. CONCLUSION: Clinical trials are now indispensable in order to determine the true clinical benefits and risks of the substances that have been found to be active against SARSCoV- 2 in vitro. There is not yet any recommendation for the therapeutic use of any particular agent beyond standard supportive treatment.
bht3pc5f
bht3pc5f
2020
5
Non-invasive bioluminescence imaging of HCoV-OC43 infection and therapy in the central nervous system of live mice
Abstract Human coronaviruses (HCoVs) are important pathogens that cause upper respiratory tract infections and have neuroinvasive abilities; however, little is known about the dynamic infection process of CoVs in vivo, and there are currently no specific antiviral drugs to prevent or treat HCoV infection. Here, we verified the replication ability and pathogenicity of a reporter HCoV-OC43 strain expressing Renilla luciferase (Rluc; rOC43-ns2DelRluc) in mice with different genetic backgrounds (C57BL/6 and BALB/c). Additionally, we monitored the spatial and temporal progression of HCoV-OC43 through the central nervous system (CNS) of live BALB/c mice after intranasal or intracerebral inoculation with rOC43-ns2DelRluc. We found that rOC43-ns2DelRluc was fatal to suckling mice after intranasal inoculation, and that viral titers and Rluc expression were detected in the brains and spinal cords of mice infected with rOC43-ns2DelRluc. Moreover, viral replication was initially observed in the brain by non-invasive bioluminescence imaging before the infection spread to the spinal cord of BALB/c mice, consistent with its tropism in the CNS. Furthermore, the Rluc readout correlated with the HCoV replication ability and protein expression, which allowed quantification of antiviral activity in live mice. Additionally, we validated that chloroquine strongly inhibited rOC43-ns2DelRluc replication in vivo. These results provide new insights into the temporal and spatial dissemination of HCoV-OC43 in the CNS, and our methods provide an extremely sensitive platform for evaluating the efficacy of antiviral therapies to treat neuroinvasive HCoVs in live mice.
bhu20y2d
bhu20y2d
2020-01-31
10.1016/j.antiviral.2019.104646
4.5
Small molecules targeting severe acute respiratory syndrome human coronavirus.
Severe acute respiratory syndrome (SARS) is an infectious disease caused by a novel human coronavirus. Currently, no effective antiviral agents exist against this type of virus. A cell-based assay, with SARS virus and Vero E6 cells, was developed to screen existing drugs, natural products, and synthetic compounds to identify effective anti-SARS agents. Of >10,000 agents tested, approximately 50 compounds were found active at 10 microM; among these compounds, two are existing drugs (Reserpine 13 and Aescin 5) and several are in clinical development. These 50 active compounds were tested again, and compounds 2-6, 10, and 13 showed active at 3 microM. The 50% inhibitory concentrations for the inhibition of viral replication (EC(50)) and host growth (CC(50)) were then measured and the selectivity index (SI = CC(50)/EC(50)) was determined. The EC(50), based on ELISA, and SI for Reserpine, Aescim, and Valinomycin are 3.4 microM (SI = 7.3), 6.0 microM (SI = 2.5), and 0.85 microM (SI = 80), respectively. Additional studies were carried out to further understand the mode of action of some active compounds, including ELISA, Western blot analysis, immunofluorescence and flow cytometry assays, and inhibition against the 3CL protease and viral entry. Of particular interest are the two anti-HIV agents, one as an entry blocker and the other as a 3CL protease inhibitor (K(i) = 0.6 microM).
biu8slfv
biu8slfv
2004
3.5
Repurposing of FDA-approved antivirals, antibiotics, anthelmintics, antioxidants, and cell protectives against SARS-CoV-2 papain-like protease
SARS-CoV-2 or Coronavirus disease 19 (COVID-19) is a rapidly spreading, highly contagious, and sometimes fatal disease for which drug discovery and vaccine development are critical. SARS-CoV-2 papain-like protease (PLpro) was used to virtually screen 1697 clinical FDA-approved drugs. Among the top results expected to bind with SARS-CoV-2 PLpro strongly were three cell protectives and antioxidants (NAD+, quercitrin, and oxiglutatione), three antivirals (ritonavir, moroxydine, and zanamivir), two antimicrobials (doripenem and sulfaguanidine), two anticancer drugs, three benzimidazole anthelmintics, one antacid (famotidine), three anti-hypertensive ACE receptor blockers (candesartan, losartan, and valsartan) and other miscellaneous systemically or topically acting drugs. The binding patterns of these drugs were superior to the previously identified SARS CoV PLpro inhibitor, 6-mercaptopurine (6-MP), suggesting a potential for repurposing these drugs to treat COVID-19. The objective of drug repurposing is the rapid relocation of safe and approved drugs by bypassing the lengthy pharmacokinetic, toxicity, and preclinical phases. The ten drugs with the highest estimated docking scores with favorable pharmacokinetics were subjected to molecular dynamics (MD) simulations followed by molecular mechanics/generalized Born surface area (MM/GBSA) binding energy calculations. Phenformin, quercetin, and ritonavir all demonstrated prospective binding affinities for COVID-19 PLpro over 50 ns MD simulations, with binding energy values of -56.6, -40.9, and -37.6 kcal/mol, respectively. Energetic and structural analyses showed phenformin was more stable than quercetin and ritonavir. The list of the drugs provided herein constitutes a primer for clinical application in COVID-19 patients and guidance for further antiviral studies.Communicated by Ramaswamy H. Sarma.
bkh2reye
bkh2reye
2020
5
Modeling the molecular impact of the SARS-CoV-2 infection on the renin-angiotensin system
Infection by the SARS-CoV-2 virus is mediated by the binding of its spike protein to the membrane-bound angiotensin converting enzyme 2 (ACE2), which plays a pivotal role in the renin-angiotensin system (RAS). The understanding of RAS dysregulation due to this viral infection is of fundamental importance to better understand the pathogenic mechanisms and risk factors of the coronavirus disease COVID-19, and to design effective therapeutic strategies. To address this issue, we built a mathematical model of RAS based on data about protein and peptide concentrations in normotensive and hypertensive individuals. We first tested our model on clinical data on the action of antihypertensive RAS-blocking drugs in control individuals. Despite the simplicity of our model, it reproduces very well, without any fitting of additional parameters, the impact of a series of drugs, i.e. angiotensin-converting enzyme inhibitors (ACE-I), direct renin inhibitors (DRI) and angiotensin II receptor blockers (ARB). We applied our model to analyze the impact of SARS-CoV-2 infection on the RAS system, which we modeled through a downregulation of ACE2 related to viral load. Moreover, we analyzed the effect of RAS-blockers and other RAS-targeting drugs, i.e. human recombinant ACE2 (rhACE2) and angiotensin 1-7 peptide (Ang1-7), on the RAS system of normotensive and hypertensive COVID-19 patients. We found that while ACE-I, DRI, rhACE2 and Ang1-7 tend to improve the clinical outcomes in a tension-dependent manner, the use of ARB appears to worsen it. The mathematical model that we developed offers the interesting possibility of testing in silico the RAS dysregulation upon SARS-CoV-2 infection and of predicting how risk factors as well as different drugs, alone or in combination, impact on RAS and disease severity.
ble3xfa3
ble3xfa3
2020-06-04
4.5
COVID-19: Transmission, prevention, and potential therapeutic opportunities
The novel coronavirus disease (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), remains a global challenge. Despite intense research efforts worldwide, an effective vaccine and viable treatment options have eluded investigators. Therefore, infection prevention, early viral detection and identification of successful treatment protocols provide the best approach in controlling disease spread. In this review, current therapeutic options, preventive methods and transmission routes of COVID-19 are discussed.
blxlmb9z
blxlmb9z
2020-05-29
10.1016/j.cca.2020.05.044
4
COVID-19 from veterinary medicine and one health perspectives: What animal coronaviruses have taught us
bnuda70x
bnuda70x
2020-08-31
10.1016/j.rvsc.2020.04.009
1
Emerging WuHan (COVID-19) coronavirus: glycan shield and structure prediction of spike glycoprotein and its interaction with human CD26
The recent outbreak of pneumonia-causing COVID-19 in China is an urgent global public health issue with an increase in mortality and morbidity. Here we report our modelled homo-trimer structure of COVID-19 spike glycoprotein in both closed (ligand-free) and open (ligand-bound) conformation, which is involved in host cell adhesion. We also predict the unique N- and O-linked glycosylation sites of spike glycoprotein that distinguish it from the SARS and underlines shielding and camouflage of COVID-19 from the host the defence system. Furthermore, our study also highlights the key finding that the S1 domain of COVID-19 spike glycoprotein potentially interacts with the human CD26, a key immunoregulatory factor for hijacking and virulence. These findings accentuate the unique features of COVID-19 and assist in the development of new therapeutics.
boqygpow
boqygpow
2020-03-17
10.1080/22221751.2020.1739565
1
COVID-19: the gendered impacts of the outbreak
brteb985
brteb985
2020-03-20
10.1016/s0140-6736(20)30526-2
1
Vaccine Efficacy in Senescent Mice Challenged with Recombinant SARS-CoV Bearing Epidemic and Zoonotic Spike Variants
BACKGROUND: In 2003, severe acute respiratory syndrome coronavirus (SARS-CoV) was identified as the etiological agent of severe acute respiratory syndrome, a disease characterized by severe pneumonia that sometimes results in death. SARS-CoV is a zoonotic virus that crossed the species barrier, most likely originating from bats or from other species including civets, raccoon dogs, domestic cats, swine, and rodents. A SARS-CoV vaccine should confer long-term protection, especially in vulnerable senescent populations, against both the 2003 epidemic strains and zoonotic strains that may yet emerge from animal reservoirs. We report the comprehensive investigation of SARS vaccine efficacy in young and senescent mice following homologous and heterologous challenge. METHODS AND FINDINGS: Using Venezuelan equine encephalitis virus replicon particles (VRP) expressing the 2003 epidemic Urbani SARS-CoV strain spike (S) glycoprotein (VRP-S) or the nucleocapsid (N) protein from the same strain (VRP-N), we demonstrate that VRP-S, but not VRP-N vaccines provide complete short- and long-term protection against homologous strain challenge in young and senescent mice. To test VRP vaccine efficacy against a heterologous SARS-CoV, we used phylogenetic analyses, synthetic biology, and reverse genetics to construct a chimeric virus (icGDO3-S) encoding a synthetic S glycoprotein gene of the most genetically divergent human strain, GDO3, which clusters among the zoonotic SARS-CoV. icGD03-S replicated efficiently in human airway epithelial cells and in the lungs of young and senescent mice, and was highly resistant to neutralization with antisera directed against the Urbani strain. Although VRP-S vaccines provided complete short-term protection against heterologous icGD03-S challenge in young mice, only limited protection was seen in vaccinated senescent animals. VRP-N vaccines not only failed to protect from homologous or heterologous challenge, but resulted in enhanced immunopathology with eosinophilic infiltrates within the lungs of SARS-CoV–challenged mice. VRP-N–induced pathology presented at day 4, peaked around day 7, and persisted through day 14, and was likely mediated by cellular immune responses. CONCLUSIONS: This study identifies gaps and challenges in vaccine design for controlling future SARS-CoV zoonosis, especially in vulnerable elderly populations. The availability of a SARS-CoV virus bearing heterologous S glycoproteins provides a robust challenge inoculum for evaluating vaccine efficacy against zoonotic strains, the most likely source of future outbreaks.
bs3j3nss
bs3j3nss
2006-12-26
10.1371/journal.pmed.0030525
1
Severe Acute Respiratory Syndrome Coronavirus -2 (SARS-CoV-2): A global pandemic and treatments strategies
The emergence and rapid spread of novel coronavirus disease (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) as a potentially fatal disease is swiftly evolving public health crises worldwide. The origin of SARS-CoV-2 infection was first reported in people exposed to wet animal market in Wuhan City, China in December 2019. It was suggested that the infection is likely to be of zoonotic origin and transmitted to human through yet unknown intermediary. As of (22/05/2020), there are around 4,995,996 confirmed cases reported by WHO with 327,821 deaths. SARS-CoV-2 infection is transmitted via inhalation or direct contact of infected people's droplets. It has an incubation period ranging from 2 to 14 days or more. The rate of spread of SARS-CoV-2 is more than partially resembled coronavirus (SARS-CoV and MERS). The symptoms are similar to influenza like, breathlessness, sore throat and fatigue therefore, infected person is isolated and administrated with effective treatments. Infection is mild in most but in elderly (>50 years) and those with cardiac and respiratory disorder, it may progress to pneumonia, acute respiratory distress syndrome, and multi organ failure. People with strong immunity or those developed herd immunity are asymptomatic. Fatality rate ranges to 3-4% on case basis. Diagnosis of SARS-CoV-2 is recommended in respiratory secretions by special molecular tests like PCR, chest scan and common laboratory diagnosis. Currently, the existing treatment is essentially supportive and role of antiviral agents is yet to be established as there is no vaccination or therapy available. This review focuses on epidemiology, symptoms, transmission, pathogenesis, ongoing available treatments and future perspectives of SARS-CoV-2.
btiy6jhr
btiy6jhr
2020-06-10
10.1016/j.ijantimicag.2020.106054
4.5
Evolution of the novel coronavirus from the ongoing Wuhan outbreak and modeling of its spike protein for risk of human transmission
btwrjr87
btwrjr87
2020-01-21
10.1007/s11427-020-1637-5
1
Potential Therapeutic Targets and Promising Drugs for Combating SARS‐CoV‐2
As of April 9, 2020, a novel coronavirus (SARS‐CoV‐2) had caused 89,931 deaths and 1,503,900 confirmed cases worldwide, which indicates an increasingly severe and uncontrollable situation. Initially, little was known about the virus. As research continues, we have learned the genome structure, epidemiological and clinical characteristics and pathogenic mechanisms of SARS‐CoV‐2. Based on these discoveries, identifying potential targets involved in the processes of virus pathogenesis is urgently needed, and discovering or developing promising drugs based on potential targets is the most pressing need. Therefore, we summarize the potential therapeutic targets involved in virus pathogenesis and discuss the advancements, possibilities and significance of promising drugs based on these targets for treating SARS‐CoV‐2. This review will facilitate the identification of potential targets and provide promising clues for drug development that can be translated into clinical applications for combating SARS‐CoV‐2.
bv6xa8v8
bv6xa8v8
2020-05-05
10.1111/bph.15092
4.5
Animal models of mechanisms of SARS‐CoV‐2 infection and COVID‐19 pathology
The coronavirus disease 2019 (COVID‐19) pandemic caused by SARS‐CoV‐2 infections has led to substantial unmet need for treatments, many of which will require testing in appropriate animal models of this disease. Vaccine trials are already underway, but there remains an urgent need to find other therapeutic approaches to either target SARS‐CoV‐2 or the complications arising from viral infection, particularly the dysregulated immune response and systemic complications which have been associated with progression to severe COVID‐19. At the time of writing, in vivo studies of SARS‐CoV‐2 infection have been described using macaques, cats, ferrets, hamsters, and transgenic mice expressing human angiotensin I converting enzyme 2 (ACE2). These infection models have already been useful for studies of transmission and immunity, but to date only partially model the mechanisms implicated in human severe COVID‐19. There is therefore an urgent need for development of animal models for improved evaluation of efficacy of drugs identified as having potential in the treatment of severe COVID‐19. These models need to recapitulate key mechanisms of COVID‐19 severe acute respiratory distress syndrome and reproduce the immunopathology and systemic sequelae associated with this disease. Here, we review the current models of SARS‐CoV‐2 infection and COVID‐19‐related disease mechanisms and suggest ways in which animal models can be adapted to increase their usefulness in research into COVID‐19 pathogenesis and for assessing potential treatments.
bvociyg2
bvociyg2
2020-05-27
10.1111/bph.15143
4
Characterization and treatment of SARS-CoV-2 in nasal and bronchial human airway epithelia
In the current COVID-19 pandemic context, proposing and validating effective treatments represents a major challenge. However, the lack of biologically relevant pre-clinical experimental models of SARS-CoV-2 infection as a complement of classic cell lines represents a major barrier for scientific and medical progress. Here, we advantageously used human reconstituted airway epithelial models of nasal or bronchial origin to characterize viral infection kinetics, tissue-level remodeling of the cellular ultrastructure and transcriptional immune signatures induced by SARS-CoV-2. Our results underline the relevance of this model for the preclinical evaluation of antiviral candidates. Foremost, we provide evidence on the antiviral efficacy of remdesivir and the therapeutic potential of the remdesivir-diltiazem combination as a rapidly available option to respond to the current unmet medical need imposed by COVID-19. One Sentence Summary New insights on SARS-CoV-2 biology and drug combination therapies against COVID-19.
bw9lbzvt
bw9lbzvt
2020-04-02
10.1101/2020.03.31.017889
1
COVID-19, hypertension and cardiovascular diseases: Should we change the therapy?
The coronavirus disease (COVID-19) has spread all around the world in a very short period of time. Recent data are showing significant prevalence of arterial hypertension and cardiovascular diseases (CVD) among patients with COVID-19, which raised many questions about higher susceptibility of patients with these comorbidities to the novel coronavirus, as well as the role of hypertension and CVD in progression and the prognosis of COVID-19 patients. There is a very limited amount of data, usually obtained from a small population, regarding the effect of the underlying disease on the outcome in patients with COVID-19. The evaluation of the treatment of these comorbidities at baseline and during COVID-19 is scarce and the results are conflicting. Hypertension and CVD, after the adjustment for other clinical and demographic parameters, primarily age, did not remain independent predictors of the lethal outcome in COVID-19 patients. Some investigations speculated about the association between the renin-angiotensin-aldosterone system (RAAS) and susceptibility to COVID-19, as well as the relationship between RAAS inhibitors and the adverse outcome in these patients. Withdrawing or switching RAAS inhibitors would have uncertain benefits, but it would definitely have many disadvantages such as uncontrolled hypertension, cardiac function deterioration and renal function impairment, which could potentially induce more complications in patients with COVID-19 than the infection of coronavirus itself. The aim of this review article was to summarize the prevalence of hypertension and CVD in patients with COVID-19, their influence on the outcome and the effect of treatment of hypertension and CVD in COVID-19 patients.
bwkad2s0
bwkad2s0
2020-05-13
10.1016/j.phrs.2020.104906
4.5
Optimizing high-yield production of SARS-CoV-2 soluble spike trimers for serology assays
The SARS-CoV-2 spike trimer is the primary antigen for several serology assays critical to determining the extent of SARS-CoV-2 exposure in the population. Until stable cell lines are developed to increase the titer of this secreted protein in mammalian cell culture, the low yield of spike protein produced from transient transfection of HEK293 cells will be a limiting factor for these assays. To improve the yield of spike protein and support the high demand for antigens in serology assays, we investigated several recombinant protein expression variables by altering the incubation temperature, harvest time, chromatography strategy, and final protein manipulation. Through this investigation, we developed a simplified and robust purification strategy that consistently yields 5 mg of protein per liter of expression culture for two commonly used forms of the SARS-CoV-2 spike protein. We show that these proteins form well-behaved stable trimers and are consistently functional in serology assays across multiple protein production lots. Highlights Improved yields of SARS-CoV-2 spike protein through modification of expression and purification parameters Yields of greater than 5 mg/l obtained for VRC spike under optimal conditions Spike protein quality was validated by QC methods to ensure utility in serology assays
bx87ajje
bx87ajje
2020-05-28
10.1101/2020.05.27.120204
5
Why Are Lopinavir and Ritonavir Effective against the Newly Emerged Coronavirus 2019? Atomistic Insights into the Inhibitory Mechanisms
Since the emergence of a novel coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was first reported from Wuhan, China, neither a specific vaccine nor an antiviral drug against SARS-CoV-2 has become available. However, a combination of two HIV-1 protease inhibitors, lopinavir and ritonavir, has been found to be effective against SARS-CoV, and both drugs could bind well to the SARS-CoV 3C-like protease (SARS-CoV 3CLpro). In this work, molecular complexation between each inhibitor and SARS-CoV-2 3CLpro was studied using all-atom molecular dynamics simulations, free energy calculations, and pair interaction energy analyses based on MM/PB(GB)SA and FMO-MP2/PCM/6-31G* methods. Both anti-HIV drugs interacted well with the residues at the active site of SARS-CoV-2 3CLpro. Ritonavir showed a somewhat higher number atomic contacts, a somewhat higher binding efficiency, and a somewhat higher number of key binding residues compared to lopinavir, which correspond with the slightly lower water accessibility at the 3CLpro active site. In addition, only ritonavir could interact with the oxyanion hole residues N142 and G143 via the formation of two hydrogen bonds. The interactions in terms of electrostatics, dispersion, and charge transfer played an important role in the drug binding. The obtained results demonstrated how repurposed anti-HIV drugs could be used to combat COVID-19.
bxw5pnjy
bxw5pnjy
2020
3
Pharmacological Therapeutics Targeting RNA-Dependent RNA Polymerase, Proteinase and Spike Protein: From Mechanistic Studies to Clinical Trials for COVID-19
An outbreak of novel coronavirus-related pneumonia COVID-19, that was identified in December 2019, has expanded rapidly, with cases now confirmed in more than 211 countries or areas. This constant transmission of a novel coronavirus and its ability to spread from human to human have prompted scientists to develop new approaches for treatment of COVID-19. A recent study has shown that remdesivir and chloroquine effectively inhibit the replication and infection of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2, 2019-nCov) in vitro. In the United States, one case of COVID-19 was successfully treated with compassionate use of remdesivir in January of 2020. In addition, a clinically proven protease inhibitor, camostat mesylate, has been demonstrated to inhibit Calu-3 infection with SARS-CoV-2 and prevent SARS-2-spike protein (S protein)-mediated entry into primary human lung cells. Here, we systemically discuss the pharmacological therapeutics targeting RNA-dependent RNA polymerase (RdRp), proteinase and S protein for treatment of SARS-CoV-2 infection. This review should shed light on the fundamental rationale behind inhibition of SARS-CoV-2 enzymes RdRp as new therapeutic approaches for management of patients with COVID-19. In addition, we will discuss the viability and challenges in targeting RdRp and proteinase, and application of natural product quinoline and its analog chloroquine for treatment of coronavirus infection. Finally, determining the structural-functional relationships of the S protein of SARS-CoV-2 will provide new insights into inhibition of interactions between S protein and angiotensin-converting enzyme 2 (ACE2) and enable us to develop novel therapeutic approaches for novel coronavirus SARS-CoV-2.
byjd8w4c
byjd8w4c
2020-04-15
10.3390/jcm9041131
4
Remdesivir in adults with severe COVID-19: a randomised, double-blind, placebo-controlled, multicentre trial
Summary Background No specific antiviral drug has been proven effective for treatment of patients with severe coronavirus disease 2019 (COVID-19). Remdesivir (GS-5734), a nucleoside analogue prodrug, has inhibitory effects on pathogenic animal and human coronaviruses, including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in vitro, and inhibits Middle East respiratory syndrome coronavirus, SARS-CoV-1, and SARS-CoV-2 replication in animal models. Methods We did a randomised, double-blind, placebo-controlled, multicentre trial at ten hospitals in Hubei, China. Eligible patients were adults (aged ≥18 years) admitted to hospital with laboratory-confirmed SARS-CoV-2 infection, with an interval from symptom onset to enrolment of 12 days or less, oxygen saturation of 94% or less on room air or a ratio of arterial oxygen partial pressure to fractional inspired oxygen of 300 mm Hg or less, and radiologically confirmed pneumonia. Patients were randomly assigned in a 2:1 ratio to intravenous remdesivir (200 mg on day 1 followed by 100 mg on days 2–10 in single daily infusions) or the same volume of placebo infusions for 10 days. Patients were permitted concomitant use of lopinavir–ritonavir, interferons, and corticosteroids. The primary endpoint was time to clinical improvement up to day 28, defined as the time (in days) from randomisation to the point of a decline of two levels on a six-point ordinal scale of clinical status (from 1=discharged to 6=death) or discharged alive from hospital, whichever came first. Primary analysis was done in the intention-to-treat (ITT) population and safety analysis was done in all patients who started their assigned treatment. This trial is registered with ClinicalTrials.gov, NCT04257656. Findings Between Feb 6, 2020, and March 12, 2020, 237 patients were enrolled and randomly assigned to a treatment group (158 to remdesivir and 79 to placebo); one patient in the placebo group who withdrew after randomisation was not included in the ITT population. Remdesivir use was not associated with a difference in time to clinical improvement (hazard ratio 1·23 [95% CI 0·87–1·75]). Although not statistically significant, patients receiving remdesivir had a numerically faster time to clinical improvement than those receiving placebo among patients with symptom duration of 10 days or less (hazard ratio 1·52 [0·95–2·43]). Adverse events were reported in 102 (66%) of 155 remdesivir recipients versus 50 (64%) of 78 placebo recipients. Remdesivir was stopped early because of adverse events in 18 (12%) patients versus four (5%) patients who stopped placebo early. Interpretation In this study of adult patients admitted to hospital for severe COVID-19, remdesivir was not associated with statistically significant clinical benefits. However, the numerical reduction in time to clinical improvement in those treated earlier requires confirmation in larger studies. Funding Chinese Academy of Medical Sciences Emergency Project of COVID-19, National Key Research and Development Program of China, the Beijing Science and Technology Project.
bzeqs5oh
bzeqs5oh
2020-04-29
10.1016/s0140-6736(20)31022-9
2
Virtual screening and repurposing of FDA approved drugs against COVID-19 main protease
Abstract Aims In December 2019, the Coronavirus disease-2019 (COVID-19) virus has emerged in Wuhan, China. In this research, the first resolved COVID-19 crystal structure (main protease) was targeted in a virtual screening study by of FDA approved drugs dataset. In addition, a knowledge gap in relations of COVID-19 with the previously known fatal Coronaviruses (CoVs) epidemics, SARS and MERS CoVs, was covered by investigation of sequence statistics and phylogenetics. Materials and methods Molecular modeling, virtual screening, docking, sequence comparison statistics and phylogenetics of the COVID-19 main protease were investigated. Key findings COVID-19 Mpro formed a phylogenetic group with SARS CoV that was distant from MERS CoV. The identity% was 96.061 and 51.61 for COVID-19/SARS and COVID-19/MERS CoV sequence comparisons, respectively. The top 20 drugs in the virtual screening studies comprised a broad-spectrum antiviral (ribavirin), anti-hepatitis B virus (telbivudine), two vitamins (vitamin B12 and nicotinamide) and other miscellaneous systemically acting drugs. Of special interest, ribavirin had been used in treating cases of SARS CoV. Significance The present study provided a comprehensive targeting of the first resolved COVID+19 structure of Mpro and found a suitable save drugs for repurposing against the viral Mpro. Ribavirin, telbivudine, vitamin B12 and nicotinamide can be combined and used for COVID treatment. This initiative relocates already marketed and approved safe drugs for potential use in COVID-treatment.
c0r2nbzo
c0r2nbzo
2020-06-15
10.1016/j.lfs.2020.117627
3
Interaction between heptad repeat 1 and 2 regions in spike protein of SARS-associated coronavirus: implications for virus fusogenic mechanism and identification of fusion inhibitors
Summary Background Studies on the fusion-inhibitory peptides derived from the heptad repeat 1 and 2 (HR1 and HR2) regions of the HIV-1 envelope glycoprotein gp41 provided crucial information on the viral fusogenic mechanism. We used a similar approach to study the fusogenic mechanism of severe-acute-respiratory-syndrome-associated coronavirus (SARS-CoV). Methods We tested the inhibitory activity against infection of two sets of peptides corresponding to sequences of SARS-CoV spike protein HR1 and HR2 regions and investigated the interactions between the HR1 and HR2 peptides by surface plasmon resonance, sedimentation equilibration analysis, circular dichroism, native polyacrylamide-gel electrophoresis, size exclusion high-performance liquid chromatography, and computer-aided homology modelling and molecule docking analysis. Findings One peptide, CP-1, derived from the HR2 region, inhibited SARS-CoV infection in the micromolar range. CP-1 bound with high affinity to a peptide from the HR1 region, NP-1. CP-1 alone had low -helicity and self-associated to form a trimer in phosphate buffer (pH 7·2). CP-1 and NP-1 mixed in equimolar concentrations formed a six-helix bundle, similar to the fusogenic core structure of HIV-1 gp41. Interpretation After binding to the target cell, the transmembrane spike protein might change conformation by association between the HR1 and HR2 regions to form an oligomeric structure, leading to fusion between the viral and target-cell membranes. At the prefusion intermediate state, CP-1 could bind to the HR1 region and interfere with the conformational changes, resulting in inhibition of SARS-CoV fusion with the target cells. CP-1 might be modifiable to increase its anti-SARS-CoV activity and could be further developed as an antiviral agent for treatment or prophylaxis of SARS-CoV infection.
c1ragbqw
c1ragbqw
2004-03-20
10.1016/s0140-6736(04)15788-7
1
Evaluation of a safe and sensitive Spike protein-based immunofluorescence assay for the detection of antibody responses to SARS-CoV
Abstract Previously, we have identified a truncated antigenic fragment named protein C [441 to 700 amino acids (a.a.)] as the immunodominant fragment of Spike (S) protein of severe acute respiratory syndrome (SARS) coronavirus (SARS-CoV). We have now successfully expressed protein C using the baculovirus system in S. frugiperda (Sf-9) cells. This recombinant baculovirus expressing protein C was first characterized using five SARS convalescent human sera and five normal human sera. The results showed that protein C is an authentic antigen against SARS-CoV antibody. Our Spike protein-based immunoflourescence assay (IFA) based on this recombinant baculovirus-Sf-9 system was further assessed with a panel of 163 clinical samples collected during the SARS epidemic in Singapore, which include samples from 21 clinically confirmed SARS, 42 non-SARS patient sera, and 100 normal sera. The results were compared to a commercial SARS IFA kit (EUROIMMUN, Germany) and a conventional IFA test performed in Singapore General Hospital. All of the 21 SARS-positive serum samples could be recognized by our IFA, giving a specificity and sensitivity of 100%, which was compatible with both whole virus-based IFA assays. No cross-reactivity with serum samples against infectious bronchitis virus (IBV) and transmissible gastroenteritis virus (TGEV) were detected in our assays. Thus, our Spike protein-based IFA could offer a safer procedure which can be performed in a BSL-2 laboratory as it could mimic the whole virus based-IFA without any loss of sensitivity and specificity. It is also more user-friendly and cost-effective than the whole virus-based IFA.
c2nymio9
c2nymio9
2005-01-31
10.1016/j.jim.2004.10.012
2.5
Traditional Chinese Medicine in the Treatment of Patients Infected with 2019-New Coronavirus (SARS-CoV-2): A Review and Perspective
Currently, Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2, formerly known as 2019-nCoV, the causative pathogen of Coronavirus Disease 2019 (COVID-19)) has rapidly spread across China and around the world, causing an outbreak of acute infectious pneumonia. No specific anti-virus drugs or vaccines are available for the treatment of this sudden and lethal disease. The supportive care and non-specific treatment to ameliorate the symptoms of the patient are the only options currently. At the top of these conventional therapies, greater than 85% of SARS-CoV-2 infected patients in China are receiving Traditional Chinese Medicine (TCM) treatment. In this article, relevant published literatures are thoroughly reviewed and current applications of TCM in the treatment of COVID-19 patients are analyzed. Due to the homology in epidemiology, genomics, and pathogenesis of the SARS-CoV-2 and SARS-CoV, and the widely use of TCM in the treatment of SARS-CoV, the clinical evidence showing the beneficial effect of TCM in the treatment of patients with SARS coronaviral infections are discussed. Current experiment studies that provide an insight into the mechanism underlying the therapeutic effect of TCM, and those studies identified novel naturally occurring compounds with anti-coronaviral activity are also introduced.
c3geck81
c3geck81
2020-03-15
10.7150/ijbs.45538
0.5
Origin, Potential Therapeutic Targets and Treatment for Coronavirus Disease (COVID-19)
The ongoing episode of coronavirus disease 19 (COVID-19) has imposed a serious threat to global health and the world economy. The disease has rapidly acquired a pandemic status affecting almost all populated areas of the planet. The causative agent of COVID-19 is a novel coronavirus known as SARS-CoV-2. The virus has an approximate 30 kb single-stranded positive-sense RNA genome, which is 74.5% to 99% identical to that of SARS-CoV, CoV-pangolin, and the coronavirus the from horseshoe bat. According to available information, SARS-CoV-2 is inferred to be a recombinant virus that originated from bats and was transmitted to humans, possibly using the pangolin as the intermediate host. The interaction of the SARS-CoV-2 spike protein with the human ACE2 (angiotensin-converting enzyme 2) receptor, and its subsequent cleavage by serine protease and fusion, are the main events in the pathophysiology. The serine protease inhibitors, spike protein-based vaccines, or ACE2 blockers may have therapeutic potential in the near future. At present, no vaccine is available against COVID-19. The disease is being treated with antiviral, antimalarial, anti-inflammatory, herbal medicines, and active plasma antibodies. In this context, the present review article provides a cumulative account of the recent information regarding the viral characteristics, potential therapeutic targets, treatment options, and prospective research questions.
c3ikb81g
c3ikb81g
2020-04-22
10.3390/pathogens9040307
3
An Animal Model of MERS Produced by Infection of Rhesus Macaques With MERS Coronavirus
In 2012, a novel coronavirus (CoV) associated with severe respiratory disease, Middle East respiratory syndrome (MERS-CoV; previously known as human coronavirus–Erasmus Medical Center or hCoV-EMC), emerged in the Arabian Peninsula. To date, 114 human cases of MERS-CoV have been reported, with 54 fatalities. Animal models for MERS-CoV infection of humans are needed to elucidate MERS pathogenesis and to develop vaccines and antivirals. In this study, we developed rhesus macaques as a model for MERS-CoV using intratracheal inoculation. The infected monkeys showed clinical signs of disease, virus replication, histological lesions, and neutralizing antibody production, indicating that this monkey model is suitable for studies of MERS-CoV infection.
c3s5n5vo
c3s5n5vo
2014-01-15
10.1093/infdis/jit590
1.5
The outbreak of COVID-19: An overview
In late December 2019, a previous unidentified coronavirus, currently named as the 2019 novel coronavirus#, emerged from Wuhan, China, and resulted in a formidable outbreak in many cities in China and expanded globally, including Thailand, Republic of Korea, Japan, United States, Philippines, Viet Nam, and our country (as of 2/6/2020 at least 25 countries). The disease is officially named as Coronavirus Disease-2019 (COVID-19, by WHO on February 11, 2020). It is also named as Severe Pneumonia with Novel Pathogens on January 15, 2019 by the Taiwan CDC, the Ministry of Health and is a notifiable communicable disease of the fifth category. COVID-19 is a potential zoonotic disease with low to moderate (estimated 2%–5%) mortality rate. Person-to-person transmission may occur through droplet or contact transmission and if there is a lack of stringent infection control or if no proper personal protective equipment available, it may jeopardize the first-line healthcare workers. Currently, there is no definite treatment for COVID-19 although some drugs are under investigation. To promptly identify patients and prevent further spreading, physicians should be aware of the travel or contact history of the patient with compatible symptoms.
c4u0gxp5
c4u0gxp5
2020-02-12
10.1097/jcma.0000000000000270
1.5
Maternal immunity enhances Mycoplasma hyopneumoniae vaccination induced cell-mediated immune responses in piglets
BACKGROUND: Passively acquired maternal derived immunity (MDI) is a double-edged sword. Maternal derived antibody-mediated immunity (AMI) and cell-mediated immunity (CMI) are critical immediate defenses for the neonate; however, MDI may interfere with the induction of active immunity in the neonate, i.e. passive interference. The effect of antigen-specific MDI on vaccine-induced AMI and CMI responses to Mycoplasma hyopneumoniae (M. hyopneumoniae) was assessed in neonatal piglets. To determine whether CMI and AMI responses could be induced in piglets with MDI, piglets with high and low levels of maternal M. hyopneumoniae-specific immunity were vaccinated against M. hyopneumoniae at 7 d of age. Piglet M. hyopneumoniae-specific antibody, lymphoproliferation, and delayed type hypersensitivity (DTH) responses were measured 7 d and 14 d post vaccination. RESULTS: Piglets with M. hyopneumoniae-specific MDI failed to show vaccine-induced AMI responses; there was no rise in M. hyopneumoniae antibody levels following vaccination of piglets in the presence of M. hyopneumoniae-specific MDI. However, piglets with M. hyopneumoniae-specific MDI had primary (antigen-specific lymphoproliferation) and secondary (DTH) M. hyopneumoniae-specific CMI responses following vaccination. CONCLUSIONS: In this study neonatal M. hyopneumoniae-specific CMI was not subject to passive interference by MDI. Further, it appears that both maternal derived and endogenous CMI contribute to M. hyopneumoniae-specific CMI responses in piglets vaccinated in the face of MDI.
c5t38hgo
c5t38hgo
2014-06-05
10.1186/1746-6148-10-124
2
Developing animal models for polymicrobial diseases
Polymicrobial diseases involve two or more microorganisms that act synergistically, or in succession, to mediate complex disease processes. Although polymicrobial diseases in animals and humans can be caused by similar organisms, these diseases are often also caused by organisms from different kingdoms, genera, species, strains, substrains and even by phenotypic variants of a single species. Animal models are often required to understand the mechanisms of pathogenesis, and to develop therapies and prevention regimes. However, reproducing polymicrobial diseases of humans in animal hosts presents significant challenges.
c66xm2n4
c66xm2n4
2004
10.1038/nrmicro928
5
Multidrug treatment with nelfinavir and cepharanthine against COVID-19
Antiviral treatments targeting the emerging coronavirus disease 2019 (COVID-19) are urgently required. We screened a panel of already-approved drugs in a cell culture model of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and identified two new antiviral agents: the HIV protease inhibitor Nelfinavir and the anti-inflammatory drug Cepharanthine. In silico modeling shows Nelfinavir binds the SARS-CoV-2 main protease consistent with its inhibition of viral replication, whilst Cepharanthine inhibits viral attachment and entry into cells. Consistent with their different modes of action, in vitro assays highlight a synergistic effect of this combined treatment to limit SARS-CoV-2 proliferation. Mathematical modeling in vitro antiviral activity coupled with the known pharmacokinetics for these drugs predicts that Nelfinavir will facilitate viral clearance. Combining Nelfinavir/Cepharanthine enhanced their predicted efficacy to control viral proliferation, to ameliorate both the progression of disease and risk of transmission. In summary, this study identifies a new multidrug combination treatment for COVID-19.
c6pbr3nn
c6pbr3nn
2020-04-15
10.1101/2020.04.14.039925
2
Remdesivir in adults with severe COVID-19: a randomised, double-blind, placebo-controlled, multicentre trial
BACKGROUND: No specific antiviral drug has been proven effective for treatment of patients with severe coronavirus disease 2019 (COVID-19). Remdesivir (GS-5734), a nucleoside analogue prodrug, has inhibitory effects on pathogenic animal and human coronaviruses, including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in vitro, and inhibits Middle East respiratory syndrome coronavirus, SARS-CoV-1, and SARS-CoV-2 replication in animal models. METHODS: We did a randomised, double-blind, placebo-controlled, multicentre trial at ten hospitals in Hubei, China. Eligible patients were adults (aged &#8805;18 years) admitted to hospital with laboratory-confirmed SARS-CoV-2 infection, with an interval from symptom onset to enrolment of 12 days or less, oxygen saturation of 94% or less on room air or a ratio of arterial oxygen partial pressure to fractional inspired oxygen of 300 mm Hg or less, and radiologically confirmed pneumonia. Patients were randomly assigned in a 2:1 ratio to intravenous remdesivir (200 mg on day 1 followed by 100 mg on days 2-10 in single daily infusions) or the same volume of placebo infusions for 10 days. Patients were permitted concomitant use of lopinavir-ritonavir, interferons, and corticosteroids. The primary endpoint was time to clinical improvement up to day 28, defined as the time (in days) from randomisation to the point of a decline of two levels on a six-point ordinal scale of clinical status (from 1=discharged to 6=death) or discharged alive from hospital, whichever came first. Primary analysis was done in the intention-to-treat (ITT) population and safety analysis was done in all patients who started their assigned treatment. This trial is registered with ClinicalTrials.gov, NCT04257656. FINDINGS: Between Feb 6, 2020, and March 12, 2020, 237 patients were enrolled and randomly assigned to a treatment group (158 to remdesivir and 79 to placebo); one patient in the placebo group who withdrew after randomisation was not included in the ITT population. Remdesivir use was not associated with a difference in time to clinical improvement (hazard ratio 1·23 [95% CI 0·87-1·75]). Although not statistically significant, patients receiving remdesivir had a numerically faster time to clinical improvement than those receiving placebo among patients with symptom duration of 10 days or less (hazard ratio 1·52 [0·95-2·43]). Adverse events were reported in 102 (66%) of 155 remdesivir recipients versus 50 (64%) of 78 placebo recipients. Remdesivir was stopped early because of adverse events in 18 (12%) patients versus four (5%) patients who stopped placebo early. INTERPRETATION: In this study of adult patients admitted to hospital for severe COVID-19, remdesivir was not associated with statistically significant clinical benefits. However, the numerical reduction in time to clinical improvement in those treated earlier requires confirmation in larger studies. FUNDING: Chinese Academy of Medical Sciences Emergency Project of COVID-19, National Key Research and Development Program of China, the Beijing Science and Technology Project.
c74zdtnn
c74zdtnn
2020
5
RNA genome conservation and secondary structure in SARS-CoV-2 and SARS-related viruses
As the COVID-19 outbreak spreads, there is a growing need for a compilation of conserved RNA genome regions in the SARS-CoV-2 virus along with their structural propensities to guide development of antivirals and diagnostics. Using sequence alignments spanning a range of betacoronaviruses, we rank genomic regions by RNA sequence conservation, identifying 79 regions of length at least 15 nucleotides as exactly conserved over SARS-related complete genome sequences available near the beginning of the COVID-19 outbreak. We then confirm the conservation of the majority of these genome regions across 739 SARS-CoV-2 sequences reported to date from the current COVID-19 outbreak, and we present a curated list of 30 ‘SARS-related-conserved’ regions. We find that known RNA structured elements curated as Rfam families and in prior literature are enriched in these conserved genome regions, and we predict additional conserved, stable secondary structures across the viral genome. We provide 106 ‘SARS-CoV-2-conserved-structured’ regions as potential targets for antivirals that bind to structured RNA. We further provide detailed secondary structure models for the 5’ UTR, frame-shifting element, and 3’ UTR. Last, we predict regions of the SARS-CoV-2 viral genome have low propensity for RNA secondary structure and are conserved within SARS-CoV-2 strains. These 59 ‘SARS-CoV-2-conserved-unstructured’ genomic regions may be most easily targeted in primer-based diagnostic and oligonucleotide-based therapeutic strategies.
c8f7a9bq
c8f7a9bq
2020-04-06
10.1101/2020.03.27.012906
1.5
Synthetic antibodies neutralize SARS-CoV-2 infection of mammalian cells
Coronaviruses (CoV) are a large family of enveloped, RNA viruses that circulate in mammals and birds. Three highly pathogenic strains have caused zoonotic infections in humans that result in severe respiratory syndromes including the Middle East Respiratory Syndrome CoV (MERS), Severe Acute Respiratory Syndrome CoV (SARS), and the ongoing Coronavirus Disease 2019 (COVID-19) pandemic. Here, we describe a panel of synthetic monoclonal antibodies, built on a human IgG framework, that bind to the spike protein of SARS-CoV-2 (the causative agent of COVID-19), compete for ACE2 binding, and potently inhibit SARS-CoV-2. All antibodies that exhibited neutralization potencies at sub-nanomolar concentrations against SARS-CoV-2/USA/WA1 in Vero E6 cells, also bound to the receptor binding domain (RBD), suggesting competition for the host receptor ACE2. These antibodies represent strong immunotherapeutic candidates for treatment of COVID-19.
c9bj38gn
c9bj38gn
2020-06-10
10.1101/2020.06.05.137349
4.5
SARS-CoV-2 infection protects against rechallenge in rhesus macaques
An understanding of protective immunity to SARS-CoV-2 is critical for vaccine and public health strategies aimed at ending the global COVID-19 pandemic. A key unanswered question is whether infection with SARS-CoV-2 results in protective immunity against re-exposure. We developed a rhesus macaque model of SARS-CoV-2 infection and observed that macaques had high viral loads in the upper and lower respiratory tract, humoral and cellular immune responses, and pathologic evidence of viral pneumonia. Following initial viral clearance, animals were rechallenged with SARS-CoV-2 and showed 5 log(10) reductions in median viral loads in bronchoalveolar lavage and nasal mucosa compared with primary infection. Anamnestic immune responses following rechallenge suggested that protection was mediated by immunologic control. These data show that SARS-CoV-2 infection induced protective immunity against re-exposure in nonhuman primates.
car394ou
car394ou
2020-05-20
10.1126/science.abc4776
5
RNAi therapeutics: Can siRNAs conquer SARS?
caxb9ob9
caxb9ob9
2005-11-10
10.1038/sj.gt.3302682
5
The hunt for covid-19 drugs
Many drugs and vaccines are now being developed and tested
cdctlduc
cdctlduc
2020-03-14
10.1016/s0262-4079(20)30525-x
2.5
Repurposing of clinically approved drugs for treatment of coronavirus disease 2019 in a 2019-novel coronavirus-related coronavirus model
BACKGROUND: Medicines for the treatment of 2019-novel coronavirus (2019-nCoV) infections are urgently needed. However, drug screening using live 2019-nCoV requires high-level biosafety facilities, which imposes an obstacle for those institutions without such facilities or 2019-nCoV. This study aims to repurpose the clinically approved drugs for the treatment of coronavirus disease 2019 (COVID-19) in a 2019-nCoV-related coronavirus model. METHODS: A 2019-nCoV-related pangolin coronavirus GX_P2V/pangolin/2017/Guangxi was described. Whether GX_P2V uses angiotensin-converting enzyme 2 (ACE2) as the cell receptor was investigated by using small interfering RNA (siRNA)-mediated silencing of ACE2. The pangolin coronavirus model was used to identify drug candidates for treating 2019-nCoV infection. Two libraries of 2406 clinically approved drugs were screened for their ability to inhibit cytopathic effects on Vero E6 cells by GX_P2V infection. The anti-viral activities and anti-viral mechanisms of potential drugs were further investigated. Viral yields of RNAs and infectious particles were quantified by quantitative real-time polymerase chain reaction (qRT-PCR) and plaque assay, respectively. RESULTS: The spike protein of coronavirus GX_P2V shares 92.2% amino acid identity with that of 2019-nCoV isolate Wuhan-hu-1, and uses ACE2 as the receptor for infection just like 2019-nCoV. Three drugs, including cepharanthine (CEP), selamectin, and mefloquine hydrochloride, exhibited complete inhibition of cytopathic effects in cell culture at 10 µmol/L. CEP demonstrated the most potent inhibition of GX_P2V infection, with a concentration for 50% of maximal effect [EC50] of 0.98 µmol/L. The viral RNA yield in cells treated with 10 µmol/L CEP was 15,393-fold lower than in cells without CEP treatment ([6.48â±â0.02]â×â10vs. 1.00â±â0.12, tâ=â150.38, Pâ<â0.001) at 72 h post-infection (p.i.). Plaque assays found no production of live viruses in media containing 10 µmol/L CEP at 48 h p.i. Furthermore, we found CEP had potent anti-viral activities against both viral entry (0.46â±â0.12, vs.1.00â±â0.37, tâ=â2.42, Pâ<â0.05) and viral replication ([6.18â±â0.95]â×â10vs. 1.00â±â0.43, tâ=â3.98, Pâ<â0.05). CONCLUSIONS: Our pangolin coronavirus GX_P2V is a workable model for 2019-nCoV research. CEP, selamectin, and mefloquine hydrochloride are potential drugs for treating 2019-nCoV infection. Our results strongly suggest that CEP is a wide-spectrum inhibitor of pan-betacoronavirus, and further study of CEP for treatment of 2019-nCoV infection is warranted.
cej0guuc
cej0guuc
2020
3
Machine learning using intrinsic genomic signatures for rapid classification of novel pathogens: COVID-19 case study
As of February 20, 2020, the 2019 novel coronavirus (renamed to COVID-19) spread to 30 countries with 2130 deaths and more than 75500 confirmed cases. COVID-19 is being compared to the infamous SARS coronavirus, which resulted, between November 2002 and July 2003, in 8098 confirmed cases worldwide with a 9.6% death rate and 774 deaths. Though COVID-19 has a death rate of 2.8% as of 20 February, the 75752 confirmed cases in a few weeks (December 8, 2019 to February 20, 2020) are alarming, with cases likely being under-reported given the comparatively longer incubation period. Such outbreaks demand elucidation of taxonomic classification and origin of the virus genomic sequence, for strategic planning, containment, and treatment. This paper identifies an intrinsic COVID-19 genomic signature and uses it together with a machine learning-based alignment-free approach for an ultra-fast, scalable, and highly accurate classification of whole COVID-19 genomes. The proposed method combines supervised machine learning with digital signal processing for genome analyses, augmented by a decision tree approach to the machine learning component, and a Spearman’s rank correlation coefficient analysis for result validation. These tools are used to analyze a large dataset of over 5000 unique viral genomic sequences, totalling 61.8 million bp. Our results support a hypothesis of a bat origin and classify COVID-19 as Sarbecovirus, within Betacoronavirus. Our method achieves high levels of classification accuracy and discovers the most relevant relationships among over 5,000 viral genomes within a few minutes, ab initio, using raw DNA sequence data alone, and without any specialized biological knowledge, training, gene or genome annotations. This suggests that, for novel viral and pathogen genome sequences, this alignment-free whole-genome machine-learning approach can provide a reliable real-time option for taxonomic classification.
cetdqgff
cetdqgff
2020-02-04
10.1101/2020.02.03.932350
1.5
Allelic Variation in the Toll-Like Receptor Adaptor Protein Ticam2 Contributes to SARS-Coronavirus Pathogenesis in Mice
Host genetic variation is known to contribute to differential pathogenesis following infection. Mouse models allow direct assessment of host genetic factors responsible for susceptibility to Severe Acute Respiratory Syndrome coronavirus (SARS-CoV). Based on an assessment of early stage lines from the Collaborative Cross mouse multi-parent population, we identified two lines showing highly divergent susceptibilities to SARS-CoV: the resistant CC003/Unc and the susceptible CC053/Unc. We generated 264 F2 mice between these strains, and infected them with SARS-CoV. Weight loss, pulmonary hemorrhage, and viral load were all highly correlated disease phenotypes. We identified a quantitative trait locus of major effect on chromosome 18 (27.1–58.6 Mb) which affected weight loss, viral titer and hemorrhage. Additionally, each of these three phenotypes had distinct quantitative trait loci [Chr 9 (weight loss), Chrs 7 and 12 (virus titer), and Chr 15 (hemorrhage)]. We identified Ticam2, an adaptor protein in the TLR signaling pathways, as a candidate driving differential disease at the Chr 18 locus. Ticam2(−/−) mice were highly susceptible to SARS-CoV infection, exhibiting increased weight loss and more pulmonary hemorrhage than control mice. These results indicate a critical role for Ticam2 in SARS-CoV disease, and highlight the importance of host genetic variation in disease responses.
cf453xqa
cf453xqa
2017-06-05
10.1534/g3.117.041434
2
TUBERCULOUS SARCOIDOSIS: DOES IT EXIST?
cge5uve3
cge5uve3
2008
10.4103/0970-2113.44140
4.5
An innovative approach to induce cross-protective immunity against porcine reproductive and respiratory syndrome virus in the lungs of pigs through adjuvanted nanotechnology-based vaccination
Porcine reproductive and respiratory syndrome (PRRS) is an economically devastating respiratory disease of pigs. The disease is caused by the PRRS virus (PRRSV), an Arterivirus which is a highly mutating RNA virus. Widely used modified live PRRSV vaccines have failed to prevent PRRS outbreaks and reinfections; moreover, safety of the live virus vaccines is questionable. Though poorly immunogenic, inactivated PRRSV vaccine is safe. The PRRSV infects primarily the lung macrophages. Therefore, we attempted to strengthen the immunogenicity of inactivated/killed PRRSV vaccine antigens (KAg), especially in the pig respiratory system, through: 1) entrapping the KAg in biodegradable poly(lactic-co-glycolic acid) nanoparticles (NP-KAg); 2) coupling the NP-KAg with a potent mucosal adjuvant, whole cell lysate of Mycobacterium tuberculosis (M. tb WCL); and 3) delivering the vaccine formulation twice intranasally to growing pigs. We have previously shown that a single dose of NP-KAg partially cleared the challenged heterologous PRRSV. Recently, we reported that NP-KAg coupled with unentrapped M. tb WCL significantly cleared the viremia of challenged heterologous PRRSV. Since PRRSV is primarily a lung disease, our goal in this study was to investigate lung viral load and various immune correlates of protection at the lung mucosal surfaces and its parenchyma in vaccinated heterologous PRRSV-challenged pigs. Our results indicated that out of five different vaccine-adjuvant formulations, the combination of NP-KAg and unentrapped M. tb WCL significantly cleared detectable replicating infective PRRSV with a tenfold reduction in viral RNA load in the lungs, associated with substantially reduced gross and microscopic lung pathology. Immunologically, strong humoral (enhanced virus neutralization titers by high avidity antibodies) and cell-mediated immune responses (augmented population of interferon-γ secreting CD4(+) and CD8(+) lymphocytes and reduced secretion of immunosuppressive cytokines) in the lungs were observed. In conclusion, combination of NP-KAg and soluble M. tb WCL elicits broadly cross-protective anti-PRRSV immunity in the pig respiratory system.
cgiok0ce
cgiok0ce
2014-03-24
10.2147/ijn.s59924
4
Prophylactic and therapeutic efficacy of mAb treatment against MERS-CoV in common marmosets
Abstract The high case-fatality rate of confirmed MERS-CoV infections underlines the urgent need for an effective treatment to reduce the disease severity and mortality. REGN3051 and REGN3048 are two fully human neutralizing monoclonal antibodies (mAb) against MERS-CoV that reduced virus replication in mice expressing human DPP4 upon prophylactic and therapeutic treatment. Here, we evaluated the prophylactic and therapeutic efficacy of REGN3048 and REGN3051 in the common marmoset model of MERS-CoV infection. Intravenous administration of mAb resulted in high levels of MERS-CoV-neutralizing activity in circulating blood. When animals were treated with mAbs one day before challenge, respiratory disease was less severe and, in animals treated with both REGN3048 and REGN3051, viral loads in the lungs were reduced. However, therapeutic treatment on day one after challenge was less efficacious as it did not prevent the development of severe respiratory disease and all treated animals developed bronchointerstitial pneumonia of similar severity as the control animals. Thus, mAb administration may be more effective in a prophylactic treatment regimen rather than treatment of MERS.
ch1omeec
ch1omeec
2018-08-31
10.1016/j.antiviral.2018.06.006
2.5
Severe COVID-19 and aging: are monocytes the key?
The ongoing pandemic severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) causes a disproportionate number of severe cases and deaths in older adults. Severe SARS-CoV-2-associated disease (coronavirus disease 2019 (COVID-19)) was declared a pandemic by the World Health Organization in March 2020 and is characterized by cytokine storm, acute respiratory distress syndrome, and in some cases by systemic inflammation–related pathology. Currently, our knowledge of the determinants of severe COVID-19 is primarily observational. Here, I review emerging evidence to argue that monocytes, a circulating innate immune cell, are principal players in cytokine storm and associated pathologies in COVID-19. I also describe changes in monocyte function and phenotype that are characteristic of both aging and severe COVID-19, which suggests a potential mechanism underlying increased morbidity and mortality due to SARS-CoV-2 infection in older adults. The innate immune system is therefore a potentially important target for therapeutic treatment of COVID-19, but experimental studies are needed, and SARS-CoV-2 presents unique challenges for pre-clinical and mechanistic studies in vivo. The immediate establishment of colonies of SARS-CoV-2-susceptible animal models for aging studies, as well as strong collaborative efforts in the geroscience community, will be required in order to develop the therapies needed to combat severe COVID-19 in older adult populations.
ch7pjb70
ch7pjb70
2020-06-15
10.1007/s11357-020-00213-0
5
The risk of SARS-CoV-2 transmission to pets and other wild and domestic animals strongly mandates a one-health strategy to control the COVID-19 pandemic
chbegdex
chbegdex
2020-04-13
10.1016/j.onehlt.2020.100133
3.5
The Novel Coronavirus: A Bird's Eye View
The novel coronavirus (2019-nCoV) outbreak, which initially began in China, has spread to many countries around the globe, with the number of confirmed cases increasing every day. With a death toll exceeding that of the SARS-CoV outbreak back in 2002 and 2003 in China, 2019-nCoV has led to a public health emergency of international concern, putting all health organizations on high alert. Herein, we present on an overview of the currently available information on the pathogenesis, epidemiology, clinical presentation, diagnosis, and treatment of this virus.
cja8i0hw
cja8i0hw
2020-02-05
10.15171/ijoem.2020.1921
2.5
Inhibition of SARS-CoV-2 (previously 2019-nCoV) infection by a highly potent pan-coronavirus fusion inhibitor targeting its spike protein that harbors a high capacity to mediate membrane fusion
The recent outbreak of coronavirus disease (COVID-19) caused by SARS-CoV-2 infection in Wuhan, China has posed a serious threat to global public health. To develop specific anti-coronavirus therapeutics and prophylactics, the molecular mechanism that underlies viral infection must first be defined. Therefore, we herein established a SARS-CoV-2 spike (S) protein-mediated cell-cell fusion assay and found that SARS-CoV-2 showed a superior plasma membrane fusion capacity compared to that of SARS-CoV. We solved the X-ray crystal structure of six-helical bundle (6-HB) core of the HR1 and HR2 domains in the SARS-CoV-2 S protein S2 subunit, revealing that several mutated amino acid residues in the HR1 domain may be associated with enhanced interactions with the HR2 domain. We previously developed a pan-coronavirus fusion inhibitor, EK1, which targeted the HR1 domain and could inhibit infection by divergent human coronaviruses tested, including SARS-CoV and MERS-CoV. Here we generated a series of lipopeptides derived from EK1 and found that EK1C4 was the most potent fusion inhibitor against SARS-CoV-2 S protein-mediated membrane fusion and pseudovirus infection with IC50s of 1.3 and 15.8 nM, about 241- and 149-fold more potent than the original EK1 peptide, respectively. EK1C4 was also highly effective against membrane fusion and infection of other human coronavirus pseudoviruses tested, including SARS-CoV and MERS-CoV, as well as SARSr-CoVs, and potently inhibited the replication of 5 live human coronaviruses examined, including SARS-CoV-2. Intranasal application of EK1C4 before or after challenge with HCoV-OC43 protected mice from infection, suggesting that EK1C4 could be used for prevention and treatment of infection by the currently circulating SARS-CoV-2 and other emerging SARSr-CoVs.
cl2pny3w
cl2pny3w
2020
4.5
Searching inhibitors for three important proteins of COVID-19 through molecular docking studies
After the first infected patient detected in Wuhan, China in December, 2019 with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus, the COVID-19 (CO means corona, VI is virus, D is disease, 19 is the year of discovery) disease spread globally due to its high contagious nature and became an ongoing pandemic. Also, the lack of vaccines and efficacious drugs to treat infected patients is a great problem to cope this pandemic. The approved drugs for similar health problems, reported potential drugs but not yet approved clinically or under clinical trial, and molecules from medicinal plants extracts are investigated randomly to deal with the COVID-19 infection. Molecular docking, one of the best approach to search therapeutically potent drugs/molecules in real time with possible hope to apply on COVID-19. In this communication, molecular docking studies of 18 ligands were carried out with the three important proteins of SARS-CoV-2, i.e., RNA-dependent RNA polymerase (RdRp), angiotensin-converting enzyme 2 (ACE2) and spike glycoprotein (SGp). From the obtained results, we observed that all the tested molecules showed better dock score in compared to the hydroxychloroquine claimed to be effective against COVID-19. Combining the dock score and other medicinal properties, we believe the limonin can be further explored for potential use against COVID-19.
cloeomqq
cloeomqq
2020-04-17
3
Comparison of risk factors for viral and nonviral asthma exacerbations
cmqo0nkb
cmqo0nkb
2015-07-17
10.1016/j.jaci.2015.05.038
4.5
Nonhuman Primate Quarantine: Its Evolution and Practice
Nonhuman primates (NHPs) are imported to the United States for use in research, domestic breeding, and propagation of endangered populations in zoological gardens. During the past 60 years, individuals responsible for NHP importation programs have observed morbidity and mortality typically associated with infectious disease outbreaks. These outbreaks have included infectious agents such as tuberculosis, Herpesvirus sp., simian hemorrhagic fever, and filovirus infections such as the Ebola and Marburg viruses. Some outbreaks have affected both animal and human populations. These epizootics are attributable to a variety of factors, including increased population density, exposure of naïve populations to new infectious agents, and stress. The practice of quarantining animals arriving in the United States was first applied by individual research programs to improve animal health and ensure the quality of animals entering research programs. The development of government regulations for nonhuman primate quarantine accompanied the recognition that imported NHPs could pose a risk to public health. This article briefly reviews the history of US NHP importation and the factors behind the development of NHP quarantine regulations. The focus is on regulations concerned with infectious disease, public health, and the health of domestic primate colonies. These regulations have had the dual benefit of protecting public health as well as reducing animal morbidity and mortality during importation and quarantine. We review current practices and facilities for nonhuman primate quarantine and identify challenges for the future.
cnislmpo
cnislmpo
2008-01-01
10.1093/ilar.49.2.145
1
COVID-19: Viral-host interactome analyzed by network based-approach model to study pathogenesis of SARS-CoV-2 infection
Background Epidemiological, virological and pathogenetic characteristics of SARS-CoV-2 infection are under evaluation. A better understanding of the pathophysiology associated with COVID-19 is crucial to improve treatment modalities and to develop effective prevention strategies. Transcriptomic and proteomic data on the host response against SARS-CoV-2 still have anecdotic character; currently available data from other coronavirus infections are therefore a key source of information. Methods We investigated selected molecular aspects of three human coronavirus (HCoV) infections, namely SARS-CoV, MERS-CoV and HCoV-229E, through a network based-approach. A functional analysis of HCoV-host interactome was carried out in order to provide a theoretic host-pathogen interaction model for HCoV infections and in order to translate the results in prediction for SARS-CoV-2 pathogenesis. The 3D model of S-glycoprotein of SARS-CoV-2 was compared to the structure of the corresponding SARS-CoV, HCoV-229E and MERS-CoV S-glycoprotein. SARS-CoV, MERS-CoV, HCoV-229E and the host interactome were inferred through published protein-protein interactions (PPI) as well as gene co-expression, triggered by HCoV S-glycoprotein in host cells. Results Although the amino acid sequences of the S-glycoprotein were found to be different between the various HCoV, the structures showed high similarity, but the best 3D structural overlap shared by SARS-CoV and SARS-CoV-2, consistent with the shared ACE2 predicted receptor. The host interactome, linked to the S-glycoprotein of SARS-CoV and MERS-CoV, mainly highlighted innate immunity pathway components, such as Toll Like receptors, cytokines and chemokines. Conclusions In this paper, we developed a network-based model with the aim to define molecular aspects of pathogenic phenotypes in HCoV infections. The resulting pattern may facilitate the process of structure-guided pharmaceutical and diagnostic research with the prospect to identify potential new biological targets.
co81fi08
co81fi08
2020-05-07
10.1101/2020.05.07.082487
3.5
Design of potent membrane fusion inhibitors against SARS-CoV-2, an emerging coronavirus with high fusogenic activity
The coronavirus disease COVID-19, caused by emerging SARS-CoV-2, has posed serious threats to global public health, economic and social stabilities, calling for the prompt development of therapeutics and prophylactics. In this study, we firstly verified that SARS-CoV-2 uses human ACE2 as a cell receptor and its spike (S) protein mediates high membrane fusion activity. Comparing to that of SARS-CoV, the heptad repeat 1 (HR1) sequence in the S2 fusion protein of SARS-CoV-2 possesses markedly increased α-helicity and thermostability, as well as a higher binding affinity with its corresponding heptad repeat 2 (HR1) site. Then, we designed a HR2 sequence-based lipopeptide fusion inhibitor, termed IPB02, which showed highly poent activities in inibibiting the SARS-CoV-2 S protein-mediated cell-cell fusion and pseudovirus infection. IPB02 also inhibited the SARS-CoV pseudovirus efficiently. Moreover, the strcuture and activity relationship (SAR) of IPB02 were characterzized with a panel of truncated lipopeptides, revealing the amino acid motifs critical for its binding and antiviral capacities. Therefore, the presented results have provided important information for understanding the entry pathway of SARS-CoV-2 and the design of antivirals that target the membrane fusion step.
cogk5kig
cogk5kig
2020-03-28
10.1101/2020.03.26.009233
1.5
Broad spectrum antiviral remdesivir inhibits human endemic and zoonotic deltacoronaviruses with a highly divergent RNA dependent RNA polymerase
Abstract The genetically diverse Orthocoronavirinae (CoV) family is prone to cross species transmission and disease emergence in both humans and livestock. Viruses similar to known epidemic strains circulating in wild and domestic animals further increase the probability of emergence in the future. Currently, there are no approved therapeutics for any human CoV presenting a clear unmet medical need. Remdesivir (RDV, GS-5734) is a monophosphoramidate prodrug of an adenosine analog with potent activity against an array of RNA virus families including Filoviridae, Paramyxoviridae, Pneumoviridae, and Orthocoronavirinae, through the targeting of the viral RNA dependent RNA polymerase (RdRp). We developed multiple assays to further define the breadth of RDV antiviral activity against the CoV family. Here, we show potent antiviral activity of RDV against endemic human CoVs OC43 (HCoV-OC43) and 229E (HCoV-229E) with submicromolar EC50 values. Of known CoVs, the members of the deltacoronavirus genus have the most divergent RdRp as compared to SARS- and MERS-CoV and both avian and porcine members harbor a native residue in the RdRp that confers resistance in beta-CoVs. Nevertheless, RDV is highly efficacious against porcine deltacoronavirus (PDCoV). These data further extend the known breadth and antiviral activity of RDV to include both contemporary human and highly divergent zoonotic CoV and potentially enhance our ability to fight future emerging CoV.
coryaz2s
coryaz2s
2019-09-30
10.1016/j.antiviral.2019.104541
3.5
“Teaching old drugs to kill new bugs”: structure-based discovery of anti-SARS drugs
Abstract Severe acute respiratory syndrome (SARS) main protease or 3C-like protease (3CLpro) is essential for the propagation of the coronaviral life cycle and is regarded as one of the main targets for structure-based anti-SARS drug design. It is an attractive approach to find new uses for old drugs as they have already been through extensive clinical testing and could easily be accelerated for clinical approval. Briefly, we performed virtual screening of a database of small molecules against SARS 3CLpro, analyzed inhibitor–protease complexes, and identified several covalent and non-covalent inhibitors. Several old drugs that bind to SARS 3CLpro active site were selected and in silico derivatized to generate covalent irreversible inhibitors with enhanced affinity. Furthermore, we show that pharmacophores derived from clusters of compounds resulting out of virtual screening could be useful probes for future structure–activity relationship studies (SARs) and fine-tune the lead molecules identified.
cqbayzat
cqbayzat
2004-08-20
10.1016/j.bbrc.2004.06.155
1
Development of a dynamic model for ventral hernia mesh repair.
INTRODUCTION The adequate way of mesh fixation in laparoscopic ventral hernia repair is still subject to debate. So far, simulation has only been carried out in a static way, thereby omitting dynamic effects of coughing or vomiting. We developed a dynamic model of the anterior abdominal wall. MATERIALS AND METHODS An aluminium cylinder was equipped with a pressure controlled, fluid-filled plastic bag, simulating the abdominal viscera. A computer-controlled system allowed the control of influx and efflux, thus creating pressure peaks of up to 200 mmHg to simulate coughing and 290 mmHg to simulate vomiting. We tested fixation with tacks (Absorbatack, Covidien Deutschland, Neustadt a. D., Germany). The model was controlled for the friction coefficient of the tissue against the mesh and the physiologic elasticity of the abdominal wall surrogate. RESULTS The model was able to create pressure peaks equivalent to physiologic coughs or vomiting. Physiologic elasticity was thereby maintained. We could show that the friction coefficient is crucial to achieve a physiologic situation. The meshes showed a tendency to dislocate with an increasing number of coughs (Fig. 4). Nevertheless, when applied in a plain manner, the meshes withstood more cough cycles than when applied with a bulge as in laparoscopic surgery. CONCLUSIONS The dynamic movement of the abdominal wall, the friction between tissue and mesh and the way of mesh application are crucial factors that have to be controlled for in simulation of ventral abdominal hernia closure. We could demonstrate that patient specific factors such as the frequency of coughing as well as the application technique influence the long term stability of the mesh.
cry2jfco
cry2jfco
2014
10.1007/s00423-014-1239-x
3.5
A nanoluciferase SARS-CoV-2 for rapid neutralization testing and screening of anti-infective drugs for COVID-19
A high-throughput platform would greatly facilitate COVID-19 serological testing and antiviral screening. Here we report a nanoluciferase SARS-CoV-2 (SARS-CoV-2-Nluc) that is genetically stable and replicates similarly to the wild-type virus in cell culture. We demonstrate that the optimized reporter virus assay in Vero E6 cells can be used to measure neutralizing antibody activity in patient sera and produces results in concordance with a plaque reduction neutralization test (PRNT). Compared with the low-throughput PRNT (3 days), the SARS-CoV-2-Nluc assay has substantially shorter turnaround time (5 hours) with a high-throughput testing capacity. Thus, the assay can be readily deployed for large-scale vaccine evaluation and neutralizing antibody testing in humans. Additionally, we developed a high-throughput antiviral assay using SARS-CoV-2-Nluc infection of A549 cells expressing human ACE2 receptor (A549-hACE2). When tested against this reporter virus, remdesivir exhibited substantially more potent activity in A549-hACE2 cells compared to Vero E6 cells (EC50 0.115 vs 1.28 μM), while this difference was not observed for chloroquine (EC50 1.32 vs 3.52 μM), underscoring the importance of selecting appropriate cells for antiviral testing. Using the optimized SARS-CoV-2-Nluc assay, we evaluated a collection of approved and investigational antivirals and other anti-infective drugs. Nelfinavir, rupintrivir, and cobicistat were identified as the most selective inhibitors of SARS-CoV-2-Nluc (EC50 0.77 to 2.74 μM). In contrast, most of the clinically approved antivirals, including tenofovir alafenamide, emtricitabine, sofosbuvir, ledipasvir, and velpatasvir were inactive at concentrations up to 10 μM. Collectively, this high-throughput platform represents a reliable tool for rapid neutralization testing and antiviral screening for SARS-CoV-2.
ct2esfmo
ct2esfmo
2020-06-23
10.1101/2020.06.22.165712
5
Relative rates of non-pneumonic SARS coronavirus infection and SARS coronavirus pneumonia
Summary Background Although the genome of severe acute respiratory syndrome coronavirus (SARS-CoV) has been sequenced and a possible animal reservoir identified, seroprevalence studies and mass screening for detection of subclinical and non-pneumonic infections are still lacking. Methods We cloned and purified the nucleocapsid protein and spike polypeptide of SARS-CoV and examined their immunogenicity with serum from patients with SARS-CoV pneumonia. An ELISA based on recombinant nucleocapsid protein for IgG detection was tested with serum from 149 healthy blood donors who donated 3 years previously and with serum positive for antibodies against SARS-CoV (by indirect immunofluorescence assay) from 106 patients with SARS-CoV pneumonia. The seroprevalence of SARS-CoV was studied with the ELISA in healthy blood donors who donated during the SARS outbreak in Hong Kong, non-pneumonic hospital inpatients, and symptom-free health-care workers. All positive samples were confirmed by two separate western-blot assays (with recombinant nucleocapsid protein and recombinant spike polypeptide). Findings Western-blot analysis showed that the nucleocapsid protein and spike polypeptide of SARS-CoV are highly immunogenic. The specificity of the IgG antibody test (ELISA with positive samples confirmed by the two western-blot assays) was 100%, and the sensitivity was 94·3%. Three of 400 healthy blood donors who donated during the SARS outbreak and one of 131 non-pneumonic paediatric inpatients were positive for IgG antibodies, confirmed by the two western-blot assays (total, 0·48% of our study population). Interpretation Our findings support the existence of subclinical or non-pneumonic SARS-CoV infections. Such infections are more common than SARS-CoV pneumonia in our locality.
ctx39vhi
ctx39vhi
2004-03-13
10.1016/s0140-6736(04)15729-2
2.5
Structure, Function, and Evolution of Coronavirus Spike Proteins.
The coronavirus spike protein is a multifunctional molecular machine that mediates coronavirus entry into host cells. It first binds to a receptor on the host cell surface through its S1 subunit and then fuses viral and host membranes through its S2 subunit. Two domains in S1 from different coronaviruses recognize a variety of host receptors, leading to viral attachment. The spike protein exists in two structurally distinct conformations, prefusion and postfusion. The transition from prefusion to postfusion conformation of the spike protein must be triggered, leading to membrane fusion. This article reviews current knowledge about the structures and functions of coronavirus spike proteins, illustrating how the two S1 domains recognize different receptors and how the spike proteins are regulated to undergo conformational transitions. I further discuss the evolution of these two critical functions of coronavirus spike proteins, receptor recognition and membrane fusion, in the context of the corresponding functions from other viruses and host cells.
cvp10nx0
cvp10nx0
2016
1.5
COVID-19 Drug Discovery Using Intensive Approaches
Since the infectious disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was reported in China during December 2019, the coronavirus disease 2019 (COVID-19) has spread on a global scale, causing the World Health Organization (WHO) to issue a warning. While novel vaccines and drugs that target SARS-CoV-2 are under development, this review provides information on therapeutics which are under clinical trials or are proposed to antagonize SARS-CoV-2. Based on the information gained from the responses to other RNA coronaviruses, including the strains that cause severe acute respiratory syndrome (SARS)-coronaviruses and Middle East respiratory syndrome (MERS), drug repurposing might be a viable strategy. Since several antiviral therapies can inhibit viral replication cycles or relieve symptoms, mechanisms unique to RNA viruses will be important for the clinical development of antivirals against SARS-CoV-2. Given that several currently marketed drugs may be efficient therapeutic agents for severe COVID-19 cases, they may be beneficial for future viral pandemics and other infections caused by RNA viruses when standard treatments are unavailable.
cw3ci2yk
cw3ci2yk
2020-04-18
10.3390/ijms21082839
5
Infection and Rapid Transmission of SARS-CoV-2 in Ferrets
The outbreak of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged in China and rapidly spread worldwide. To prevent SARS-CoV-2 dissemination, understanding the in vivo characteristics of SARS-CoV-2 is a high priority. We report a ferret model of SARS-CoV-2 infection and transmission that recapitulates aspects of human disease. SARS-CoV-2-infected ferrets exhibit elevated body temperatures and virus replication. Although fatalities were not observed, SARS-CoV-2-infected ferrets shed virus in nasal washes, saliva, urine, and feces up to 8 days post-infection. At 2 days post-contact, SARS-CoV-2 was detected in all naive direct contact ferrets. Furthermore, a few naive indirect contact ferrets were positive for viral RNA, suggesting airborne transmission. Viral antigens were detected in nasal turbinate, trachea, lungs, and intestine with acute bronchiolitis present in infected lungs. Thus, ferrets represent an infection and transmission animal model of COVID-19 that may facilitate development of SARS-CoV-2 therapeutics and vaccines.
cx4slb0x
cx4slb0x
2020
3.5
Updated Approaches against SARS-CoV-2
Novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) lies behind the ongoing outbreak of coronavirus disease 2019 (COVID-19). There is a growing understanding of SARS-CoV-2 in virology, epidemiology, and clinical management strategies. However, no anti-SARS-CoV-2 drug or vaccine has been officially approved due to the absence of adequate evidence. Scientists are racing to develop a treatment for COVID-19. Recent studies have revealed many attractive therapeutic options, even if some of them remain to be further confirmed in rigorous preclinical models and clinical trials. In this minireview, we aim to summarize the updated potential approaches against SARS-CoV-2. We emphasize that further efforts are warranted to develop the safest and most effective approach.
cx6u4qx8
cx6u4qx8
2020-05-21
10.1128/aac.00483-20
4
Comparison of SARS-CoV-2 infections among 3 species of non-human primates
COVID-19, caused by SARS-CoV-2 infection, has recently been announced as a pandemic all over the world. Plenty of diagnostic, preventive and therapeutic knowledges have been enriched from clinical studies since December 2019. However, animal models, particularly non-human primate models, are urgently needed for critical questions that could not be answered in clinical patients, evaluations of anti-viral drugs and vaccines. In this study, two families of non-human primates, old world monkeys (12 Macaca mulatta, 6 Macaca fascicularis) and new world monkeys (6 Callithrix jacchus), were experimentally inoculated with SARS-CoV-2. Clinical signs were recorded. Samples were collected for analysis of viral shedding, viremia and histopathological examination. Increased body temperature was observed in 100% (12/12) M. mulatta, 33.3% (2/6) M. fascicularis and none (0/6) of C. jacchus post inoculation of SARS-CoV-2. All of M. mulatta and M. fascicularis showed chest radiographic abnormality. Viral genomes were detected in nasal swabs, throat swabs, anal swabs and blood from all 3 species of monkeys. Viral shedding from upper respiratory reached the peak between day 6 and day 8 post inoculation. From necropsied M. mulatta and M. fascicularis, tissues showing virus positive were mainly lung, weasand, bronchus and spleen. No viral genome was seen in any of tissues from 2 necropsied C. jacchus. Severe gross lesions and histopathological changes were observed in lung, heart and stomach of SARS-CoV-2 infected animals. In summary, we have established a NHP model for COVID-19, which could be used to evaluate drugs and vaccines, and investigate viral pathogenesis. M. mulatta is the most susceptible to SARS-CoV2 infection, followed by M. fascicularis and C. jacchus. One Sentence Summary M. mulatta is the most susceptible to SARS-CoV-2 infection as compared to M. fascicularis and C. jacchus.
czh3zfb3
czh3zfb3
2020-04-11
10.1101/2020.04.08.031807
2
Enantiomers of Chloroquine and Hydroxychloroquine Exhibit Different Activities Against SARS-CoV-2 in vitro, Evidencing S-Hydroxychloroquine as a Potentially Superior Drug for COVID-19
In all of the clinical trials for COVID-19 conducted thus far and among those ongoing involving chloroquine or hydroxychloroquine, the drug substance used has invariably been chloroquine (CQ) diphosphate or hydroxychloroquine (HCQ) sulfate, i.e., the phosphoric or sulfuric acid salt of a racemic mixture of R- and S-enantiomer (50/50), respectively. As a result, the clinical outcome from previous CQ or HCQ trials were, in fact, the collective manifestation of both R and S-enantiomers with inherent different pharmacodynamic and pharmacokinetic properties, and toxicity liabilities. Our data for the first time demonstrated the stereoselective difference of CQ and HCQ against live SARS-CoV-2 virus in a Biosafety Level 3 laboratory. S-chloroquine (S-CQ) and S-hydroxychloroquine (S-HCQ) were found to be 27% and 60% more active against SARS-CoV-2, as compared to R-CQ and R-HCQ, respectively. With these data and previous work on stereoselective metabolism of CQ and HCQ, we recommend that future clinical studies should employ S-HCQ as a potentially superior drug substance for the treatment of COVID-19 for improved therapeutic index.
cztp457w
cztp457w
2020-05-30
10.1101/2020.05.26.114033
4
Deep-COVID: Predicting COVID-19 From Chest X-Ray Images Using Deep Transfer Learning
The COVID-19 pandemic is causing a major outbreak in more than 150 countries around the world, having a severe impact on the health and life of many people globally. One of the crucial step in fighting COVID-19 is the ability to detect the infected patients early enough, and put them under special care. Detecting this disease from radiography and radiology images is perhaps one of the fastest way to diagnose the patients. Some of the early studies showed specific abnormalities in the chest radiograms of patients infected with COVID-19. Inspired by earlier works, we study the application of deep learning models to detect COVID-19 patients from their chest radiography images. We first prepare a dataset of 5,000 Chest X-rays from the publicly available datasets. Images exhibiting COVID-19 disease presence were identified by board-certified radiologist. Transfer learning on a subset of 2,000 radiograms was used to train four popular convolutional neural networks, including ResNet18, ResNet50, SqueezeNet, and DenseNet-121, to identify COVID-19 disease in the analyzed chest X-ray images. We evaluated these models on the remaining 3,000 images, and most of these networks achieved a sensitivity rate of 97\%($\pm$ 5\%), while having a specificity rate of around 90\%. While the achieved performance is very encouraging, further analysis is required on a larger set of COVID-19 images, to have a more reliable estimation of accuracy rates. Besides sensitivity and specificity rates, we also present the receiver operating characteristic (ROC), area under the curve (AUC), and confusion matrix of each model. The dataset, model implementations (in PyTorch), and evaluations, are all made publicly available for research community, here: https://github.com/shervinmin/DeepCovid.git
czu0bga0
czu0bga0
2020-04-20
2
How many are at increased risk of severe COVID-19 disease? Rapid global, regional and national estimates for 2020
Background The risk of severe COVID-19 disease is known to be higher in older individuals and those with underlying health conditions. Understanding the number of individuals at increased risk of severe COVID-19 illness, and how this varies between countries may inform the design of possible strategies to shield those at highest risk. Methods We estimated the number of individuals at increased risk of severe COVID-19 disease by age (5-year age groups), sex and country (n=188) based on prevalence data from the Global Burden of Disease (GBD) study for 2017 and United Nations population estimates for 2020. We also calculated the number of individuals without an underlying condition that could be considered at-risk because of their age, using thresholds from 50-70 years. The list of underlying conditions relevant to COVID-19 disease was determined by mapping conditions listed in GBD to the guidelines published by WHO and public health agencies in the UK and US. We analysed data from two large multimorbidity studies to determine appropriate adjustment factors for clustering and multimorbidity. Results We estimate that 1.7 (1.0 - 2.4) billion individuals (22% [15-28%] of the global population) are at increased risk of severe COVID-19 disease. The share of the population at increased risk ranges from 16% in Africa to 31% in Europe. Chronic kidney disease (CKD), cardiovascular disease (CVD), diabetes and chronic respiratory disease (CRD) were the most prevalent conditions in males and females aged 50+ years. African countries with a high prevalence of HIV/AIDS and Island countries with a high prevalence of diabetes, also had a high share of the population at increased risk. The prevalence of multimorbidity (>1 underlying conditions) was three times higher in Europe than in Africa (10% vs 3%). Conclusion Based on current guidelines and prevalence data from GBD, we estimate that one in five individuals worldwide has a condition that is on the list of those at increased risk of severe COVID-19 disease. However, for many of these individuals the underlying condition will be undiagnosed or not severe enough to be captured in health systems, and in some cases the increase in risk may be quite modest. There is an urgent need for robust analyses of the risks associated with different underlying conditions so that countries can identify the highest risk groups and develop targeted shielding policies to mitigate the effects of the COVID-19 pandemic.
czuq8rw5
czuq8rw5
2020-04-22
10.1101/2020.04.18.20064774
2
A facile Q-RT-PCR assay for monitoring SARS-CoV-2 growth in cell culture
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the etiological agent of the ongoing COVID-19 pandemic, has infected millions within just a few months and is continuing to spread around the globe causing immense respiratory disease and mortality. Assays to monitor SARS-CoV-2 growth depend on time-consuming and costly RNA extraction steps, hampering progress in basic research and drug development efforts. Here we developed a facile Q-RT-PCR assay that bypasses viral RNA extraction steps and can monitor SARS-CoV-2 replication kinetics from a small amount of cell culture supernatants. Using this assay, we screened the activities of a number of entry, SARS-CoV-2- and HIV-1-specific inhibitors in a proof of concept study. In line with previous studies which has shown that processing of the viral Spike protein by cellular proteases and endosomal fusion are required for entry, we found that E64D and apilimod potently decreased the amount of SARS-CoV-2 RNA in cell culture supernatants with minimal cytotoxicity. Surprisingly, we found that macropinocytosis inhibitor EIPA similarly decreased viral RNA in supernatants suggesting that entry may additionally be mediated by an alternative pathway. HIV-1-specific inhibitors nevirapine (an NNRTI), amprenavir (a protease inhibitor), and ALLINI-2 (an allosteric integrase inhibitor) modestly inhibited SARS-CoV-2 replication, albeit the IC(50) values were much higher than that required for HIV-1. Taken together, this facile assay will undoubtedly expedite basic SARS-CoV-2 research, be amenable to mid-throughput screens to identify chemical inhibitors of SARS-CoV-2, and be applicable to a broad number of RNA and DNA viruses.
d0hu681v
d0hu681v
2020-06-28
10.1101/2020.06.26.174698
5
What’s new in the renin-angiotensin system?: Angiotensin-converting enzyme 2: a functional receptor for SARS coronavirus
Cellular entry of enveloped viruses is often dependent on attachment proteins expressed on the host cell surface. Viral envelope proteins bind these receptors, and, in an incompletely understood process, facilitate fusion of the cellular and viral membranes so as to introduce the viral core into the cytoplasm. Only a small fraction of viral receptors have been identified so far. Recently, a novel coronavirus was identified as the etiological agent of severe acute respiratory syndrome (SARS). The fusion protein gene of SARS coronavirus (SARS-CoV) was cloned and characterized, and shortly thereafter, angiotensin-converting enzyme 2 (ACE2) was shown to be its functional receptor. Identification of ACE2 as a receptor for SARS-CoV will likely contribute to the development of antivirals and vaccines. It may also contribute to the development of additional animal models for studying SARS pathogenesis, and could help identify the animal reservoir of SARS-CoV.
d11ua0oh
d11ua0oh
2004
10.1007/s00018-004-4242-5
0.5
Structure of mouse coronavirus spike protein complexed with receptor reveals mechanism for viral entry
Coronaviruses recognize a variety of receptors using different domains of their envelope-anchored spike protein. How these diverse receptor recognition patterns affect viral entry is unknown. Mouse hepatitis coronavirus (MHV) is the only known coronavirus that uses the N-terminal domain (NTD) of its spike to recognize a protein receptor, CEACAM1a. Here we determined the cryo-EM structure of MHV spike complexed with mouse CEACAM1a. The trimeric spike contains three receptor-binding S1 heads sitting on top of a trimeric membrane-fusion S2 stalk. Three receptor molecules bind to the sides of the spike trimer, where three NTDs are located. Receptor binding induces structural changes in the spike, weakening the interactions between S1 and S2. Using protease sensitivity and negative-stain EM analyses, we further showed that after protease treatment of the spike, receptor binding facilitated the dissociation of S1 from S2, allowing S2 to transition from pre-fusion to post-fusion conformation. Together these results reveal a new role of receptor binding in MHV entry: in addition to its well-characterized role in viral attachment to host cells, receptor binding also induces the conformational change of the spike and hence the fusion of viral and host membranes. Our study provides new mechanistic insight into coronavirus entry and highlights the diverse entry mechanisms used by different viruses.
d1o2oeyr
d1o2oeyr
2020
3
Susceptibility of tree shrew to SARS-CoV-2 infection
Since SARS-CoV-2 became a pandemic event in the world, it has not only caused huge economic losses, but also a serious threat to global public health. Many scientific questions about SARS-CoV-2 and COVID-19 were raised and urgently need to be answered, including the susceptibility of animals to SARS-CoV-2 infection. Here we tested whether tree shrew, an emerging experimental animal domesticated from wild animal, is susceptible to SARS-CoV-2 infection. No clinical signs were observed in SARS-CoV-2 inoculated tree shrews during this experiment except the increasing body temperature (above 39° C) particular in female animals during infection. Low levels of virus shedding and replication in tissues occurred in all three age groups, each of which showed his own characteristics. Histopathological examine revealed that pulmonary abnormalities were mild but the main changes although slight lesions were also observed in other tissues. In summary, tree shrew is not susceptible to SARS-CoV-2 infection and may not be a suitable animal for COVID-19 related researches.
d1stzy8w
d1stzy8w
2020-04-30
10.1101/2020.04.30.029736
3
A small nonhuman primate model for filovirus-induced disease
Abstract Ebolavirus and Marburgvirus are members of the filovirus family and induce a fatal hemorrhagic disease in humans and nonhuman primates with 90% case fatality. To develop a small nonhuman primate model for filovirus disease, common marmosets (Callithrix jacchus) were intramuscularly inoculated with wild type Marburgvirus Musoke or Ebolavirus Zaire. The infection resulted in a systemic fatal disease with clinical and morphological features closely resembling human infection. Animals experienced weight loss, fever, high virus titers in tissue, thrombocytopenia, neutrophilia, high liver transaminases and phosphatases and disseminated intravascular coagulation. Evidence of a severe disseminated viral infection characterized principally by multifocal to coalescing hepatic necrosis was seen in EBOV animals. MARV-infected animals displayed only moderate fibrin deposition in the spleen. Lymphoid necrosis and lymphocytic depletion observed in spleen. These findings provide support for the use of the common marmoset as a small nonhuman primate model for filovirus induced hemorrhagic fever.
d212h4bp
d212h4bp
2011-11-25
10.1016/j.virol.2011.08.022
1.5
What about COVID-19 and arachidonic acid pathway?
BACKGROUND AND OBJECTIVE: COVID-19 is a highly contagious viral disease. In this study, we tried to define and discuss all the findings on the potential association between arachidonic acid (AA) pathway and COVID-19 pathophysiology. METHODS: A literature search across PubMed, Scopus, Embase, and Cochrane database was conducted. A total of 25 studies were identified. RESULTS: The data elucidated that COX-2 and prostaglandins (PGs), particularly PGE(2), have pro-inflammatory action in COVID-19 pathophysiology. Arachidonic acid can act as endogenous antiviral compound. A deficiency in AA can make humans more susceptible to COVID-19. Targeting these pro-inflammatory mediators may help in decreasing the mortality and morbidity rate in COVID-19 patients. CONCLUSIONS: PGE(2) levels and other PGs levels should be measured in patients with COVID-19. Lowering the PGE(2) levels through inhibition of human microsomal prostaglandin E synthase-1 (mPGES-1) can enhance the host immune response against COVID-19. In addition, the hybrid compounds, such as COX-2 inhibitors/TP antagonists, can be an innovative treatment to control the overall balance between AA mediators in patients with COVID-19.
d2qffjji
d2qffjji
2020-06-25
10.1007/s00228-020-02941-w
5
Old drugs as lead compounds for a new disease? Binding analysis of SARS coronavirus main proteinase with HIV, psychotic and parasite drugs
Abstract The SARS-associated coronavirus (SARS-CoV) main proteinase is a key enzyme in viral polyprotein processing. To allow structure-based design of drugs directed at SARS-CoV main proteinase, we predicted its binding pockets and affinities with existing HIV, psychotic and parasite drugs (lopinavir, ritonavir, niclosamide and promazine), which show signs of inhibiting the replication of SARS-CoV. Our results suggest that these drugs and another two HIV inhibitors (PNU and UC2) could be used as templates for designing SARS-CoV proteinase inhibitors.
d4loia11
d4loia11
2004-05-15
10.1016/j.bmc.2004.03.035
3
Glycosylation of the severe acute respiratory syndrome coronavirus triple-spanning membrane proteins 3a and M.
The severe acute respiratory syndrome coronavirus (SARS-CoV) open reading frame 3a protein has recently been shown to be a structural protein. The protein is encoded by one of the so-called group-specific genes and has no sequence homology with any of the known structural or group-specific proteins of coronaviruses. It does, however, have several similarities to the coronavirus M proteins; (i) they are triple membrane spanning with the same topology, (ii) they have similar intracellular localizations (predominantly Golgi), (iii) both are viral structural proteins, and (iv) they appear to interact with the E and S proteins, as well as with each other. The M protein plays a crucial role in coronavirus assembly and is glycosylated in all coronaviruses, either by N-linked or by O-linked oligosaccharides. The conserved glycosylation of the coronavirus M proteins and the resemblance of the 3a protein to them led us to investigate the glycosylation of these two SARS-CoV membrane proteins. The proteins were expressed separately using the vaccinia virus T7 expression system, followed by metabolic labeling. Pulse-chase analysis showed that both proteins were modified, although in different ways. While the M protein acquired cotranslationally oligosaccharides that could be removed by PNGaseF, the 3a protein acquired its modifications posttranslationally, and they were not sensitive to the N-glycosidase enzyme. The SARS-CoV 3a protein, however, was demonstrated to contain sialic acids, indicating the presence of oligosaccharides. O-glycosylation of the 3a protein was indeed confirmed using an in situ O-glycosylation assay of endoplasmic reticulum-retained mutants. In addition, we showed that substitution of serine and threonine residues in the ectodomain of the 3a protein abolished the addition of the O-linked sugars. Thus, the SARS-CoV 3a protein is an O-glycosylated glycoprotein, like the group 2 coronavirus M proteins but unlike the SARS-CoV M protein, which is N glycosylated.
d56ed4hw
d56ed4hw
2006
2.5
The FDA-approved gold drug auranofin inhibits novel coronavirus (SARS-COV-2) replication and attenuates inflammation in human cells
SARS-COV-2 has recently emerged as a new public health threat. Herein, we report that the FDA-approved drug, auranofin, inhibits SARS-COV-2 replication in human cells at low micro molar concentration. Treatment of cells with auranofin resulted in a 95% reduction in the viral RNA at 48 h after infection. Auranofin treatment dramatically reduced the expression of SARS-COV-2-induced cytokines in human cells. These data indicate that auranofin could be a useful drug to limit SARS-CoV-2 infection and associated lung injury due to its antiviral, anti-inflammatory and anti-reactive oxygen species (ROS) properties. Further animal studies are warranted to evaluate the safety and efficacy of auranofin for the management of SARS-COV-2 associated disease.
d59dck5t
d59dck5t
2020
4
Molekulare Struktur eukaryotischer Chromosomen
Die Chromosomen sind die lichtmikroskopisch sichtbaren, materiellen Träger der Gene. Bedeutet das aber, dass sie lediglich eine Ansammlung kettenartig aneinandergefügter Gene sind? Aus cytologischen Beobachtungen wissen wir, dass die Chromosomen, und damit die Gene, in Mitose und Meiose gleichmäßig auf die Tochterzellen verteilt werden. In den Centromerbereichen der Chromosomen dienen die Kinetochore als Ansatzpunkte für die Mikrotubuli des Spindelapparates. So werden die Chromosomen bzw. deren Untereinheiten, die Chromatiden, bei der Zellteilung auf die Tochterzellen aufgeteilt. Besondere terminale Domänen, die Telomere, gewährleisten, dass die freien Enden der DNA im Chromosom nicht von Exonukleasen abgebaut werden oder durch Reparaturenzyme mit den freien Enden der DNA eines anderen Chromosoms verschmelzen.
d69ta408
d69ta408
2010-12-01
10.1007/978-3-642-04999-6_6
3
Emergence of a Novel Coronavirus, Severe Acute Respiratory Syndrome Coronavirus 2: Biology and Therapeutic Options
The new decade of the 21(st) century (2020) started with the emergence of a novel coronavirus known as SARS-CoV-2 that caused an epidemic of coronavirus disease (COVID-19) in Wuhan, China. It is the third highly pathogenic and transmissible coronavirus after severe acute respiratory syndrome coronavirus (SARS-CoV) and Middle East respiratory syndrome coronavirus (MERS-CoV) emerged in humans. The source of origin, transmission to humans, and mechanisms associated with the pathogenicity of SARS-CoV-2 are not yet clear, however, its resemblance to SARS-CoV and several other bat coronaviruses was recently confirmed through genome sequencing-related studies. The development of therapeutic strategies is necessary in order to prevent further epidemics and cure infections. In this review, we summarize current information about the emergence, origin, diversity, and epidemiology of three pathogenic coronaviruses with a specific focus on the current outbreak in Wuhan, China. Furthermore, we discuss the clinical features and potential therapeutic options that may be effective against SARS-CoV-2.
d6by9p41
d6by9p41
2020-04-23
10.1128/jcm.00187-20
2
Anti-HCV, nucleotide inhibitors, repurposing against COVID-19
Abstract Aims A newly emerged Human Coronavirus (HCoV) is reported two months ago in Wuhan, China (COVID-19). Until today >2700 deaths from the 80,000 confirmed cases reported mainly in China and 40 other countries. Human to human transmission is confirmed for COVID-19 by China a month ago. Based on the World Health Organization (WHO) reports, SARS HCoV is responsible for >8000 cases with confirmed 774 deaths. Additionally, MERS HCoV is responsible for 858 deaths out of about 2500 reported cases. The current study aims to test anti-HCV drugs against COVID-19 RNA dependent RNA polymerase (RdRp). Materials and methods In this study, sequence analysis, modeling, and docking are used to build a model for Wuhan COVID-19 RdRp. Additionally, the newly emerged Wuhan HCoV RdRp model is targeted by anti-polymerase drugs, including the approved drugs Sofosbuvir and Ribavirin. Key findings The results suggest the effectiveness of Sofosbuvir, IDX-184, Ribavirin, and Remidisvir as potent drugs against the newly emerged HCoV disease. Significance The present study presents a perfect model for COVID-19 RdRp enabling its testing in silico against anti-polymerase drugs. Besides, the study presents some drugs that previously proved its efficiency against the newly emerged viral infection.
d7n1zy0b
d7n1zy0b
2020-05-01
10.1016/j.lfs.2020.117477
1
Screening of FDA-Approved Drugs for Inhibitors of Japanese Encephalitis Virus Infection
Japanese encephalitis virus (JEV), an arthropod-borne flavivirus, is a major cause of acute viral encephalitis in humans. No approved drug is available for the specific treatment of JEV infections, and the available vaccines are not effective against all clinical JEV isolates. In the study described here, a high-throughput screening of an FDA-approved drug library for inhibitors of JEV was performed. Five hit drugs that inhibited JEV infection with a selective index of >10 were identified. The antiviral activities of these five hit drugs against other flavivirus, including Zika virus, were also validated. As three of the five hit drugs were calcium inhibitors, additional types of calcium inhibitors that confirmed that calcium is essential for JEV infection, most likely during viral replication, were utilized. Adaptive mutant analysis uncovered that replacement of Q130, located in transmembrane domain 3 of the nonstructural NS4B protein, which is relatively conserved in flaviviruses, with R or K conferred JEV resistance to manidipine, a voltage-gated Ca(2+) channel (VGCC) inhibitor, without an apparent loss of the viral growth profile. Furthermore, manidipine was indicated to protect mice against JEV-induced lethality by decreasing the viral load in the brain, while it abrogated the histopathological changes associated with JEV infection. This study provides five antiflavivirus candidates and identifies cytoplasmic calcium to be a novel antiviral target for the treatment of JEV infection. The findings reported here provide therapeutic possibilities for combating infections caused by flaviviruses. IMPORTANCE No approved therapy for the treatment of Japanese encephalitis virus infection is currently available. Repurposing of approved drugs would accelerate the development of a therapeutic stratagem. In this study, we screened a library of FDA-approved drugs and identified five hit drugs, especially calcium inhibitors, exerting antiflavivirus activity that blocked viral replication. The in vivo efficacy and toxicity of manidipine were investigated with a mouse model of JEV infection, and the viral target was identified by generating an adaptive mutant.
d8p7mgqt
d8p7mgqt
2017-10-13
10.1128/jvi.01055-17
1
New insights on the antiviral effects of chloroquine against coronavirus: what to expect for COVID-19?
ABSTRACT Recently, a novel coronavirus (2019-nCoV), officially known as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), emerged in China. Despite drastic containment measures, the spread of this virus is ongoing. SARS-CoV-2 is the aetiological agent of coronavirus disease 2019 (COVID-19) characterised by pulmonary infection in humans. The efforts of international health authorities have since focused on rapid diagnosis and isolation of patients as well as the search for therapies able to counter the most severe effects of the disease. In the absence of a known efficient therapy and because of the situation of a public-health emergency, it made sense to investigate the possible effect of chloroquine/hydroxychloroquine against SARS-CoV-2 since this molecule was previously described as a potent inhibitor of most coronaviruses, including SARS-CoV-1. Preliminary trials of chloroquine repurposing in the treatment of COVID-19 in China have been encouraging, leading to several new trials. Here we discuss the possible mechanisms of chloroquine interference with the SARS-CoV-2 replication cycle.
da61tfr9
da61tfr9
2020-03-12
10.1016/j.ijantimicag.2020.105938
0.5
Potential host range of multiple SARS-like coronaviruses and an improved ACE2-Fc variant that is potent against both SARS-CoV-2 and SARS-CoV-1
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a currently uncontrolled pandemic and the etiological agent of coronavirus disease 2019 (COVID-19). It is important to study the host range of SARS-CoV-2 because some domestic species might harbor the virus and transmit it back to humans. In addition, insight into the ability of SARS-CoV-2 and SARS-like viruses to utilize animal orthologs of the SARS-CoV-2 receptor ACE2 might provide structural insight into improving ACE2-based viral entry inhibitors. Here we show that ACE2 orthologs of a wide range of domestic and wild animals support entry of SARS-CoV-2, as well as that of SARS-CoV-1, bat coronavirus RaTG13, and a coronavirus isolated from pangolins. Some of these species, including camels, cattle, horses, goats, sheep, pigs, cats, and rabbits may serve as potential intermediate hosts for new human transmission, and rabbits in particular may serve as a useful experimental model of COVID-19. We show that SARS-CoV-2 and SARS-CoV-1 entry could be potently blocked by recombinant IgG Fc-fusion proteins of viral spike protein receptor-binding domains (RBD-Fc) and soluble ACE2 (ACE2-Fc). Moreover, an ACE2-Fc variant, which carries a D30E mutation and has ACE2 truncated at its residue 740 but not 615, outperforms all the other ACE2-Fc variants on blocking entry of both viruses. Our data suggest that RBD-Fc and ACE2-Fc could be used to treat and prevent infection of SARS-CoV-2 and any new viral variants that emerge over the course of the pandemic.
dblrxlt1
dblrxlt1
2020-04-11
10.1101/2020.04.10.032342
2
Cathepsin L-selective inhibitors: A potentially promising treatment for COVID-19 patients
The widespread coronavirus SARS-CoV-2 has already infected over 4 million people worldwide, with a death toll over 280,000. Current treatment of COVID-19 patients relies mainly on antiviral drugs lopinavir/ritonavir, arbidol, and remdesivir, the anti-malarial drugs hydroxychloroquine and chloroquine, and traditional Chinese medicine. There are over 2118 on-going clinical trials underway, but to date none of these drugs have consistently proven effective. Cathepsin L (CatL) is an endosomal cysteine protease. It mediates the cleavage of the S1 subunit of the coronavirus surface spike glycoprotein. This cleavage is necessary for coronavirus entry into human host cells, virus and host cell endosome membrane fusion, and viral RNA release for next round of replication. Here we summarize data regarding seven CatL-selective inhibitors that block coronavirus entry into cultured host cells and provide a mechanism to block SARS-CoV-2 infection in humans. Given the rapid growth of the SARS-CoV-2-positive population worldwide, ready-to-use CatL inhibitors should be explored as a treatment option. We identify ten US FDA-approved drugs that have CatL inhibitory activity. We provide evidence that supports the combined use of serine protease and CatL inhibitors as a possibly safer and more effective therapy than other available therapeutics to block coronavirus host cell entry and intracellular replication, without compromising the immune system.
dc8x2v49
dc8x2v49
2020-05-26
10.1016/j.pharmthera.2020.107587
4.5
Serum albumin-mediated strategy for the effective targeting of SARS-CoV-2
Abstract Novel coronavirus (NCoV-19), also known as SARS CoV-2, is a pathogen causing an emerging infection that rapidly increases in incidence and geographic range, is associated with the ever-increasing morbidity and mortality rates, and shows sever economic impact worldwide. The WHO declares the NCoV-19 infection disease (COVID-19) a Public Health Emergency of International Concern on 30 January 2020 and subsequently, on March 11, 2020, declared it a Global Pandemic. Although some people infected with SARS CoV-2 have no symptoms, the spectrum of symptomatic infection ranges from mild to critical, with most COVID-19 infections being not severe. The common mild symptoms include body aches, dry cough, fatigue, low-grade fever, nasal congestion, and sore throat. More severe COVID-19 symptoms are typical of pneumonia, and upon progression, the patient’s condition can worsen with severe respiratory and cardiac problems. Currently, there is no drug or vaccine for curing patients. It has been observed that people with challenged immunity are highly prone to SARS CoV-2 infection and least likely to recover. Also, older adults and people of any age with serious underlying medical conditions might be at higher risk for severe forms of COVID-19. We are suggesting here a strategy for the COVID-19 treatment that could be effective in curing the patients in the current scenario when no efficient medicine or Vaccine is currently available, and Clinicians solely depend upon the performing trials with drugs with known antiviral activities. Our proposed strategy is based on the compilation of published scientific research and concepts. The different published research indicates the success of a similar strategy in different physiological conditions, and such a strategy is widely studied at the cellular level and in animal models.
dcs1rgd0
dcs1rgd0
2020-07-31
10.1016/j.mehy.2020.109790
3
Maladies respiratoires, allergies et infections à COVID-19. Premières nouvelles de Wuhan
ddg87zxv
ddg87zxv
2020-04-01
10.1016/j.reval.2020.03.003
1.5
A descriptive study of on-farm biosecurity and management practices during the incursion of porcine epidemic diarrhea into Canadian swine herds, 2014
Porcine epidemic diarrhea virus (PEDV) emerged into Canada in January 2014, primarily affecting sow herds. Subsequent epidemiological analyses suggested contaminated feed was the most likely transmission pathway. The primary objective of this study was to describe general biosecurity and management practices implemented in PEDV-positive sow herds and matched control herds at the time the virus emerged. The secondary objective was to determine if any of these general biosecurity and farm management practices were important in explaining PEDV infection status from January 22, 2014 to March 1, 2014. A case herd was defined as a swine herd with clinical signs and a positive test result for PEDV. A questionnaire was used to a gather 30-day history of herd management practices, animal movements on/off site, feed management practices, semen deliveries and biosecurity practices for case (n = 8) and control (n = 12) herds, primarily located in Ontario. Data was analyzed using descriptive statistics and random forests (RFs). Case herds were larger in size than control herds. Case herds had more animal movements and non-staff movements onto the site. Also, case herds had higher quantities of pigs delivered, feed deliveries and semen deliveries on-site. The biosecurity practices of case herds were considered more rigorous based on herd management, feed deliveries, transportation and truck driver practices than control herds. The RF model found that the most important variables for predicting herd status were related to herd size and feed management variables. Nonetheless, predictive accuracy of the final RF model was 72%.
ddp9swag
ddp9swag
2020-01-17
10.4142/jvs.2020.21.e25
2
Molecular targets for COVID-19 drug development: Enlightening Nigerians about the pandemic and future treatment
There is little or no research initiated on enlightening Nigerians about the pathogenesis, targets for drug development, and drug repositioning for SARS-CoV-2 infection. COVID-19 is a viral infection causing symptoms like dry cough, sore throat, nasal congestion, tiredness, fever, loss of taste and smell etc. Th disease was first reported in Wuhan, China, in December 2019. The infection is caused by SARS-CoV-2, which is the third introduction of a highly pathogenic coronavirus into the human population. Coronaviruses are viruses with a positive RNA envelope assigned to α, β, γ, and δ genera. Moreover, SARS-CoV-2 belongs to the β genus. The four structural proteins of β coronavirus are membrane (M), envelope (E), spike (S), and nucleocapsid (N) protein, mediation of coronavirus host infection is established by spike (S) protein. Therefore, the search for drug development targets and repositioning of existing therapeutics is essential for fighting the present pandemic. It was reviewed that therapeutics targeting SARS-CoV-2 binding to ACE2 receptor, viral RNA synthesis and replication, 3CLpro, RdRp, and helicase will play a crucial role in the development of treatment for SARS-CoV-2 infection. Furthermore, the RdRp and spike protein of SARS-CoV-2 are the most promising targets for drug development and repositioning and vaccine development. Remdesivir combination with chloroquine/hydroxychloroquine are promising drug repositioning for the treatment of COVID-19, and mRNA-1273 targeting spike protein is the promising vaccine. However, as patient management and drug repositioning are taking place, it is imperative to identify other promising targets used by SARS-CoV-2 to establish infection, to develop novel therapeutics.
ddt5qmls
ddt5qmls
2020-07-09
10.1016/j.bsheal.2020.07.002
5
Host Factors in Coronavirus Replication
Coronaviruses are pathogens with a serious impact on human and animal health. They mostly cause enteric or respiratory disease, which can be severe and life threatening, e.g., in the case of the zoonotic coronaviruses causing severe acute respiratory syndrome (SARS) and Middle East Respiratory Syndrome (MERS) in humans. Despite the economic and societal impact of such coronavirus infections, and the likelihood of future outbreaks of additional pathogenic coronaviruses, our options to prevent or treat coronavirus infections remain very limited. This highlights the importance of advancing our knowledge on the replication of these viruses and their interactions with the host. Compared to other +RNA viruses, coronaviruses have an exceptionally large genome and employ a complex genome expression strategy. Next to a role in basic virus replication or virus assembly, many of the coronavirus proteins expressed in the infected cell contribute to the coronavirus-host interplay. For example, by interacting with the host cell to create an optimal environment for coronavirus replication, by altering host gene expression or by counteracting the host’s antiviral defenses. These coronavirus–host interactions are key to viral pathogenesis and will ultimately determine the outcome of infection. Due to the complexity of the coronavirus proteome and replication cycle, our knowledge of host factors involved in coronavirus replication is still in an early stage compared to what is known for some other +RNA viruses. This review summarizes our current understanding of coronavirus–host interactions at the level of the infected cell, with special attention for the assembly and function of the viral RNA-synthesising machinery and the evasion of cellular innate immune responses.
ddza1x3z
ddza1x3z
2017-06-23
10.1007/82_2017_25
2.5
Comprehensive analysis of drugs to treat SARS-CoV-2 infection: Mechanistic insights into current COVID-19 therapies (Review)
The major impact produced by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) focused many researchers attention to find treatments that can suppress transmission or ameliorate the disease. Despite the very fast and large flow of scientific data on possible treatment solutions, none have yet demonstrated unequivocal clinical utility against coronavirus disease 2019 (COVID-19). This work represents an exhaustive and critical review of all available data on potential treatments for COVID-19, highlighting their mechanistic characteristics and the strategy development rationale. Drug repurposing, also known as drug repositioning, and target based methods are the most used strategies to advance therapeutic solutions into clinical practice. Current in silico, in vitro and in vivo evidence regarding proposed treatments are summarized providing strong support for future research efforts.
de3mqy2d
de3mqy2d
2020-05-18
10.3892/ijmm.2020.4608
5
SARS-like cluster of circulating bat coronavirus pose threat for human emergence
The emergence of Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV) and Middle East Respiratory Syndrome (MERS)-CoV underscores the threat of cross-species transmission events leading to outbreaks in humans. In this study, we examine the disease potential for SARS-like CoVs currently circulating in Chinese horseshoe bat populations. Utilizing the SARS-CoV infectious clone, we generated and characterized a chimeric virus expressing the spike of bat coronavirus SHC014 in a mouse adapted SARS-CoV backbone. The results indicate that group 2b viruses encoding the SHC014 spike in a wild type backbone can efficiently utilize multiple ACE2 receptor orthologs, replicate efficiently in primary human airway cells, and achieve in vitro titers equivalent to epidemic strains of SARS-CoV. Additionally, in vivo experiments demonstrate replication of the chimeric virus in mouse lung with notable pathogenesis. Evaluation of available SARS-based immune-therapeutic and prophylactic modalities revealed poor efficacy; both monoclonal antibody and vaccine approaches failed to neutralize and protect from CoVs utilizing the novel spike protein. Importantly, based on these findings, we synthetically rederived an infectious full length SHC014 recombinant virus and demonstrate robust viral replication both in vitro and in vivo. Together, the work highlights a continued risk of SARS-CoV reemergence from viruses currently circulating in bat populations.
dfl69g4f
dfl69g4f
2015-11-09
10.1038/nm.3985
2.5
Insights into SARS-CoV-2 genome, structure, evolution, pathogenesis and therapies: Structural genomics approach
The sudden emergence of severe respiratory disease, caused by a novel severe acute respiratory syndrome coronavirus (SARS-CoV-2), has recently become a public health emergency. Genome sequence analysis of SARS-CoV-2 revealed its close resemblance to the earlier reported SARS-CoV and Middle East respiratory syndrome coronavirus (MERS-CoV). However, initial testing of the drugs used against SARS-CoV and MERS-CoV has been ineffective in controlling SARS-CoV-2. The present review looks to highlight the differences in genomic, proteomic, pathogenesis, and therapeutic strategies of SARS-CoV-2. We have carried out sequence analysis of potential drug target proteins in SARS-CoV-2 and, compared them with SARS-CoV-1 and MERS viruses. Analysis of mutations in the coding and non-coding regions, genetic diversity, and pathogenicity of SARS-CoV-2 has also been done. A detailed structural analysis of drug target proteins was performed to gain insights into the mechanism of pathogenesis, structure-function relationships, and the development of structure-guided therapeutic approaches. The cytokine profiling and inflammatory signalling are different in the case of SARS-CoV-2 infection. We also highlighted possible therapies and their mechanism of action followed by clinical manifestation. Our analysis suggests a minimal variation in the genome sequence of SARS-CoV-2, may be responsible for a drastic change in the structures of target proteins, makes available drugs ineffective.
dfydh7sf
dfydh7sf
2020-06-13
10.1016/j.bbadis.2020.165878
4
Chloroquine is a potent inhibitor of SARS coronavirus infection and spread
BACKGROUND: Severe acute respiratory syndrome (SARS) is caused by a newly discovered coronavirus (SARS-CoV). No effective prophylactic or post-exposure therapy is currently available. RESULTS: We report, however, that chloroquine has strong antiviral effects on SARS-CoV infection of primate cells. These inhibitory effects are observed when the cells are treated with the drug either before or after exposure to the virus, suggesting both prophylactic and therapeutic advantage. In addition to the well-known functions of chloroquine such as elevations of endosomal pH, the drug appears to interfere with terminal glycosylation of the cellular receptor, angiotensin-converting enzyme 2. This may negatively influence the virus-receptor binding and abrogate the infection, with further ramifications by the elevation of vesicular pH, resulting in the inhibition of infection and spread of SARS CoV at clinically admissible concentrations. CONCLUSION: Chloroquine is effective in preventing the spread of SARS CoV in cell culture. Favorable inhibition of virus spread was observed when the cells were either treated with chloroquine prior to or after SARS CoV infection. In addition, the indirect immunofluorescence assay described herein represents a simple and rapid method for screening SARS-CoV antiviral compounds.
dgnddq80
dgnddq80
2005-08-22
10.1186/1743-422x-2-69
4.5
Inhibition of NF-κB-mediated inflammation in severe acute respiratory syndrome coronavirus-infected mice increases survival.
Severe acute respiratory syndrome coronavirus (SARS-CoV) is the etiological agent of a respiratory disease that has a 10% mortality rate. We previously showed that SARS-CoV lacking the E gene (SARS-CoV-ΔE) is attenuated in several animal model systems. Here, we show that absence of the E protein resulted in reduced expression of proinflammatory cytokines, decreased numbers of neutrophils in lung infiltrates, diminished lung pathology, and increased mouse survival, suggesting that lung inflammation contributed to SARS-CoV virulence. Further, infection with SARS-CoV-ΔE resulted in decreased activation of NF-κB compared to levels for the wild-type virus. Most important, treatment with drugs that inhibited NF-κB activation led to a reduction in inflammation and lung pathology in both SARS-CoV-infected cultured cells and mice and significantly increased mouse survival after SARS-CoV infection. These data indicated that activation of the NF-κB signaling pathway represents a major contribution to the inflammation induced after SARS-CoV infection and that NF-κB inhibitors are promising antivirals in infections caused by SARS-CoV and potentially other pathogenic human coronaviruses.
dgwektka
dgwektka
2014
10.1128/jvi.02576-13
4
In silico studies on the comparative characterization of the interactions of SARS-CoV-2 spike glycoprotein with ACE-2 receptor homologs and human TLRs
Coronavirus disease-2019 (COVID-19) outbreak due to novel coronavirus or severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has come out as a major threat for mankind in recent times. It is continually taking an enormous toll on mankind by means of increasing number of deaths, associated comorbidities, and socioeconomic loss around the globe. Unavailability of chemotherapeutics/vaccine has posed tremendous challenges to scientists and doctors for developing an urgent therapeutic strategy. In this connection, the present in silico study aims to understand the sequence divergence of spike protein (the major infective protein of SARS-CoV-2), its mode of interaction with the angiotensin-converting enzyme-2 receptor (ACE2) receptor of human and related animal hosts/reservoir. Moreover, the involvement of the human Toll-like receptors (TLRs) against the spike protein has also been demonstrated. Our data indicated that the spike glycoprotein of SARS-CoV-2 is phylogenetically close to bat coronavirus and strongly binds with ACE2 receptor protein from both human and bat origin. We have also found that cell surface TLRs, especially TLR4 is most likely to be involved in recognizing molecular patterns from SARS-CoV-2 to induce inflammatory responses. The present study supported the zoonotic origin of SARS-CoV-2 from a bat and also revealed that TLR4 may have a crucial role in the virus-induced inflammatory consequences associated with COVID-19. Therefore, selective targeting of TLR4-spike protein interaction by designing competitive TLR4-antagonists could pave a new way to treat COVID-19. Finally, this study is expected to improve our understanding on the immunobiology of SARS-CoV-2 and could be useful in adopting spike protein, ACE2, or TLR-guided intervention strategy against COVID-19 shortly.
dir0jtyb
dir0jtyb
2020
3.5
NSAIDs in patients with viral infections, including Covid-19: victims or perpetrators?
Abstract Taking anti-inflammatory drugs, including non-steroidal (NSAIDs), during Covid-19 infection, how much is risky? The French Minister of Health, who has raised an alarm on a possible risk deriving from the use of ibuprofen for the control of fever and other symptoms during the disease, opened the debate a few days ago. In this paper we examine available evidence from preclinical and clinical studies that had analysed the role of COX in the inflammatory process and the effects of NSAIDs in patients with infections. Most of the published studies that suggested not protective effects of NSAIDs were mainly performed in vitro or on animals. Therefore, their meaning in humans is to be considered with great caution. Based also on data suggesting protective effects of NSAIDs, we concluded that currently there is no evidence suggesting a correlation between NSAIDs and a worsening of infections. Further studies will be certainly needed to better define the role of NSAIDs and particularly COX2 inhibitors in patients with infections. In the meantime, we must wait for results of the revision started by the PRAC on May 2019 on the association ibuprofen/ketoprofen​​​​​​ and worsening of infections. Since nowadays no scientific evidence establishes a correlation between NSAIDS and worsening of COVID-19, patients should be advice against any NSAIDs self-medication when COVID-19 like symptoms are present.
dl2irtdy
dl2irtdy
2020-04-29
10.1016/j.phrs.2020.104849
2
Reversal of Infected Host Gene Expression Identifies Repurposed Drug Candidates for COVID-19
Repurposing existing drugs is a timely option to cope with COVID-19. We predicted therapeutic candidates that could reverse the gene expression of coronavirus-infected host cells. Thirteen expression signatures computed from various experimental conditions and preclinical models could be reversed by those compounds known to be effective against SARS- or MERS-CoV, as well as the drug candidates recently shown to be effective against SARS-CoV-2. We selected ten novel candidates to further evaluate their in vitro efficacy against SARS-CoV-2 infection. Four compounds bortezomib, dactolisib, alvocidib and methotrexate inhibited the formation of virus infection-induced cytopathic effect in Vero E6 cells at 1 μM, yet such a concentration seems toxic to the cells as well. While the evaluation in other permissive cells and the prediction of toxicity are needed to optimize and minimize their antiviral activity and cytotoxicity, respectively, this computational approach has the potential to rapidly and rationally identify drug candidates against COVID-19.
dl6rbqxp
dl6rbqxp
2020-04-09
10.1101/2020.04.07.030734
2
Susceptibility of ferrets, cats, dogs, and other domesticated animals to SARS–coronavirus 2
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes the infectious disease COVID-19, which was first reported in Wuhan, China in December, 2019. Despite the tremendous efforts to control the disease, COVID-19 has now spread to over 100 countries and caused a global pandemic. SARS-CoV-2 is thought to have originated in bats; however, the intermediate animal sources of the virus are completely unknown. Here, we investigated the susceptibility of ferrets and animals in close contact with humans to SARS-CoV-2. We found that SARS-CoV-2 replicates poorly in dogs, pigs, chickens, and ducks, but ferrets and cats are permissive to infection. We found experimentally that cats are susceptible to airborne infection. Our study provides important insights into the animal models for SARS-CoV-2 and animal management for COVID-19 control.
dlpgq0rm
dlpgq0rm
2020-04-08
10.1126/science.abb7015
2
Vaccination strategies to combat novel corona virus SARS-CoV-2
The 2019-novel coronavirus disease (COVID-19) is caused by SARS-CoV-2 is transmitted from human to human has recently reported in China. Now COVID-19 has been spread all over the world and declared epidemics by WHO. It has caused a Public Health Emergency of International Concern. The elderly and people with underlying diseases are susceptible to infection and prone to serious outcomes, which may be associated with acute respiratory distress syndrome (ARDS) and cytokine storm. Due to the rapid increase of SARS-CoV-2 infections and unavailability of antiviral therapeutic agents, developing an effective SAR-CoV-2 vaccine is urgently required. SARS-CoV-2 which is genetically similar to SARS-CoV and Middle East respiratory syndrome coronavirus (MERS-CoV) is an enveloped, single and positive-stranded RNA virus with a genome comprising 29,891 nucleotides, which encode the 12 putative open reading frames responsible for the synthesis of viral structural and nonstructural proteins which are very similar to SARS-CoV and MERS-CoV proteins. In this review we have summarized various vaccine candidates i.e., nucleotide, subunit and vector based as well as attenuated and inactivated forms, which have already been demonstrated their prophylactic efficacy against MERS-CoV and SARS-CoV, so these candidates could be used as a potential tool for the development of a safe and effective vaccine against SARS-CoV-2.
dm7rysvj
dm7rysvj
2020-06-12
10.1016/j.lfs.2020.117956
4.5
Pulmonary fibrosis and COVID-19: the potential role for antifibrotic therapy
In December, 2019, reports emerged from Wuhan, China, of a severe acute respiratory disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). By the end of April, 2020, over 3 million people had been confirmed infected, with over 1 million in the USA alone, and over 215 000 deaths. The symptoms associated with COVID-19 are diverse, ranging from mild upper respiratory tract symptoms to severe acute respiratory distress syndrome. The major risk factors for severe COVID-19 are shared with idiopathic pulmonary fibrosis (IPF), namely increasing age, male sex, and comorbidities such as hypertension and diabetes. However, the role of antifibrotic therapy in patients with IPF who contract SARS-CoV-2 infection, and the scientific rationale for their continuation or cessation, is poorly defined. Furthermore, several licensed and potential antifibrotic compounds have been assessed in models of acute lung injury and viral pneumonia. Data from previous coronavirus infections such as severe acute respiratory syndrome and Middle East respiratory syndrome, as well as emerging data from the COVID-19 pandemic, suggest there could be substantial fibrotic consequences following SARS-CoV-2 infection. Antifibrotic therapies that are available or in development could have value in preventing severe COVID-19 in patients with IPF, have the potential to treat severe COVID-19 in patients without IPF, and might have a role in preventing fibrosis after SARS-CoV-2 infection.
dmh2j6n3
dmh2j6n3
2020-05-15
10.1016/s2213-2600(20)30225-3
3.5
TMPRSS2 Contributes to Virus Spread and Immunopathology in the Airways of Murine Models after Coronavirus Infection
Transmembrane serine protease TMPRSS2 activates the spike protein of highly pathogenic human coronaviruses such as severe acute respiratory syndrome-related coronavirus (SARS-CoV) and Middle East respiratory syndrome-related coronavirus (MERS-CoV). In vitro, activation induces virus-cell membrane fusion at the cell surface. However, the roles of TMPRSS2 during coronavirus infection in vivo are unclear. Here, we used animal models of SARS-CoV and MERS-CoV infection to investigate the role of TMPRSS2. Th1-prone C57BL/6 mice and TMPRSS2-knockout (KO) mice were used for SARS-CoV infection, and transgenic mice expressing the human MERS-CoV receptor DPP4 (hDPP4-Tg mice) and TMPRSS2-KO hDPP4-Tg mice were used for MERS-CoV infection. After experimental infection, TMPRSS2-deficient mouse strains showed reduced body weight loss and viral kinetics in the lungs. Lack of TMPRSS2 affected the primary sites of infection and virus spread within the airway, accompanied by less severe immunopathology. However, TMPRSS2-KO mice showed weakened inflammatory chemokine and/or cytokine responses to intranasal stimulation with poly(I·C), a Toll-like receptor 3 agonist. In conclusion, TMPRSS2 plays a crucial role in viral spread within the airway of murine models infected by SARS-CoV and MERS-CoV and in the resulting immunopathology. IMPORTANCE Broad-spectrum antiviral drugs against highly pathogenic coronaviruses and other emerging viruses are desirable to enable a rapid response to pandemic threats. Transmembrane protease serine type 2 (TMPRSS2), a protease belonging to the type II transmembrane serine protease family, cleaves the coronavirus spike protein, making it a potential therapeutic target for coronavirus infections. Here, we examined the role of TMPRSS2 using animal models of SARS-CoV and MERS-CoV infection. The results suggest that lack of TMPRSS2 in the airways reduces the severity of lung pathology after infection by SARS-CoV and MERS-CoV. Taken together, the results will facilitate development of novel targets for coronavirus therapy.
dp2t735t
dp2t735t
2019-01-09
10.1128/jvi.01815-18
0.5
Shedding Light on the Effect of Natural Anti-Herpesvirus Alkaloids on SARS-CoV-2: A Treatment Option for COVID-19
The whole world is currently facing an unseen enemy, called coronavirus disease 2019 (COVID-19), which is causing a global pandemic. This disease is caused by a novel single-stranded enveloped RNA virus, known as the Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2). Although huge efforts are being made to produce effective therapies to combat this disease, it continues to be one of the greatest challenges in medicine. There is no doubt that herpesviruses are one of the most important viruses that infect humans and animals, and infections induced by these pathogens have developed into a great threat to public health. According to the currently available evidence, the correlation between herpesviruses and coronaviruses is limited to the induced complications following the infections. For instance, the inflammation that is induced at the sites of infection could tie these viruses to each other in a relationship. Another example, bovine herpesvirus 1, which is an important pathogen of cattle, can cause a severe respiratory infection; the same way in which SARS-CoV-2 affects humans. Considering the current circumstances related to the COVID-19 crisis, this editorial paper, which belongs to the Special Issue “Recent Advances in Herpesviruses Research: What’s in the Pipeline?” aims to draw attention to some natural anti-herpesvirus alkaloid compounds, which have recently been proven to have excellent inhibitory efficacy against SARS-CoV-2 replication. Thus, this special focus is an attempt to hunt down various treatment options to combat COVID-19 based on repurposing drugs that are known to have multiple antiviral properties, including against herpesvirus.
dp4umo8l
dp4umo8l
2020-04-23
10.3390/v12040476
4.5
A review on the cleavage priming of the spike protein on coronavirus by angiotensin-converting enzyme-2 and furin
The widespread antigenic changes lead to the emergence of a new type of coronavirus (CoV) called as severe acute respiratory syndrome (SARS)-CoV-2 that is immunologically different from the previous circulating species. Angiotensin-converting enzyme-2 (ACE-2) is one of the most important receptors on the cell membrane of the host cells (HCs) which its interaction with spike protein (SP) with a furin-cleavage site results in the SARS-CoV-2 invasion. Hence, in this review, we presented an overview on the interaction of ACE-2 and furin with SP. As several kinds of CoVs, from various genera, have at their S1/S2 binding site a preserved site, we further surveyed the role of furin cleavage site (FCS) on the life cycle of the CoV. Furthermore, we discussed that the small molecular inhibitors can limit the interaction of ACE-2 and furin with SP and can be used as potential therapeutic platforms to combat the spreading CoV epidemic. Finally, some ongoing challenges and future prospects for the development of potential drugs to promote targeting specific activities of the CoV were reviewed. In conclusion, this review may pave the way for providing useful information about different compounds involved in improving the effectiveness of CoV vaccine or drugs with minimum toxicity against human health. Communicated by Ramaswamy H. Sarma
dq2empne
dq2empne
2020-04-22
10.1080/07391102.2020.1754293
4.5
Characterization of spike glycoprotein of SARS-CoV-2 on virus entry and its immune cross-reactivity with SARS-CoV
Since 2002, beta coronaviruses (CoV) have caused three zoonotic outbreaks, SARS-CoV in 2002–2003, MERS-CoV in 2012, and the newly emerged SARS-CoV-2 in late 2019. However, little is currently known about the biology of SARS-CoV-2. Here, using SARS-CoV-2 S protein pseudovirus system, we confirm that human angiotensin converting enzyme 2 (hACE2) is the receptor for SARS-CoV-2, find that SARS-CoV-2 enters 293/hACE2 cells mainly through endocytosis, that PIKfyve, TPC2, and cathepsin L are critical for entry, and that SARS-CoV-2 S protein is less stable than SARS-CoV S. Polyclonal anti-SARS S1 antibodies T62 inhibit entry of SARS-CoV S but not SARS-CoV-2 S pseudovirions. Further studies using recovered SARS and COVID-19 patients’ sera show limited cross-neutralization, suggesting that recovery from one infection might not protect against the other. Our results present potential targets for development of drugs and vaccines for SARS-CoV-2.
dqour5jr
dqour5jr
2020-03-27
10.1038/s41467-020-15562-9
0.5
Molecular structure analyses suggest strategies to therapeutically target SARS-CoV-2
Amid the COVID-19 pandemic, scientists around the globe have been working resolutely to find therapies to treat patients and avert the spreading of the SARS-CoV-2 virus. In this commentary, we highlight some of the latest studies that provide atomic-resolution structural details imperative for the development of vaccines and antiviral therapeutics.
dqtnj3y3
dqtnj3y3
2020-06-10
10.1038/s41467-020-16779-4
4
Spike protein binding prediction with neutralizing antibodies of SARS-CoV-2
Coronavirus disease 2019 (COVID-19) is a new emerging human infectious disease caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2, also previously known as 2019-nCoV), originated in Wuhan seafood and animal market, China. Since December 2019, more than 69,000 cases of COVID-19 have been confirmed in China and quickly spreads to other counties. Currently, researchers put their best efforts to identify effective drugs for COVID-19. The neutralizing antibody, which binds to viral capsid in a manner that inhibits cellular entry of virus and uncoating of the genome, is the specific defense against viral invaders. In this study, we investigate to identify neutralizing antibodies that can bind to SARS-CoV-2 Sipke (S) protein and interfere with the interaction between viral S protein and a host receptor by bioinformatic methods. The sequence analysis of S protein showed two major differences in the RBD region of the SARS-CoV-2 S protein compared to SARS-CoV and SARS-CoV related bat viruses (btSARS-CoV). The insertion regions were close to interacting residues with the human ACE2 receptor. Epitope analysis of neutralizing antibodies revealed that SARS-CoV neutralizing antibodies used conformational epitopes, whereas MERS-CoV neutralizing antibodies used a common linear epitope region, which contributes to form the β-sheet structure in MERS-CoV S protein and deleted in SARS-CoV-2 S protein. To identify effective neutralizing antibodies for SARS-CoV-2, the binding affinities of neutralizing antibodies with SARS-CoV-2 S protein were predicted and compared by antibody-antigen docking simulation. The result showed that CR3022 neutralizing antibody from human may have higher binding affinity with SARS-CoV-2 S protein than SARS-CoV S protein. We also found that F26G19 and D12 mouse antibodies could bind to SARS-CoV S protein with high affinity. Our findings provide crucial clues towards the development of antigen diagnosis, therapeutic antibody, and the vaccine against SARS-CoV-2.
dqxfcwyu
dqxfcwyu
2020-02-27
10.1101/2020.02.22.951178
0.5
COVID-19 and veterinarians for one health, zoonotic- and reverse-zoonotic transmissions
A novel coronavirus emerged in human populations and spread rapidly to cause the global coronavirus disease 2019 pandemic. Although the origin of the associated virus (severe acute respiratory syndrome coronavirus 2 [SARS-CoV-2]) remains unclear, genetic evidence suggests that bats are a reservoir host of the virus, and pangolins are a probable intermediate. SARS-CoV-2 has crossed the species barrier to infect humans and other animal species, and infected humans can facilitate reverse-zoonotic transmission to animals. Considering the rapidly changing interconnections among people, animals, and ecosystems, traditional roles of veterinarians should evolve to include transdisciplinary roles.
dr7cz1jo
dr7cz1jo
2020
4.5
Inhibitory effect of mizoribine and ribavirin on the replication of severe acute respiratory syndrome (SARS)-associated coronavirus
Abstract The activity of inosine-5′-monophosphate dehydrogenase (IMPDH) inhibitors, mizoribine and ribavirin, against severe acute respiratory syndrome (SARS)-associated coronavirus (SARS-CoV) was determined by plaque reduction and yield reduction assays. Mizoribine and ribavirin selectively inhibited replication of SARS-CoV. The 50% inhibitory concentration (IC50) of mizoribine for SARS-CoV Frankfurt-1 and SARS-CoV HKU39849, as determined by plaque reduction was 3.5μg/ml and 16μg/ml, respectively, and the IC50 of ribavirin for SARS-CoV Frankfurt-1 and SARS-CoV HKU39849 was 20μg/ml and 80μg/ml, while the 50% cytotoxic concentration of mizoribine and ribavirin for Vero E6 cells exceeded 200μg/ml. In a yield reduction assay, mizoribine (10μg/ml) and ribavirin (40μg/ml) inhibited the replication of SARS-CoV and reduced the infectious SARS-CoV titers to one-tenth or less. Mizoribine inhibited replication of SARS-CoV more strongly than ribavirin. However, neither drug could completely inhibit replication of SARS-CoV even at concentrations up to 100μg/ml.
drrs2tc1
drrs2tc1
2005-06-30
10.1016/j.antiviral.2005.01.003
2.5
SARS-COV-2 infection (coronavirus disease 2019) for the gastrointestinal consultant
The current pandemic due to the severe acute respiratory syndrome coronavirus 2 has caused an extreme burden for health care systems globally, and the number of cases is expected to continue to increase, at least in the immediate future. The virus is estimated to have infected more than 1.5 million individuals. The available reports suggest that gastrointestinal (GI) involvement in coronavirus disease 2019 (COVID-19) is common and in some cases the GI symptoms may precede the respiratory symptoms. In addition to direct effects of severe acute respiratory syndrome coronavirus 2, the infected patients remain at risk for the complications commonly managed by gastroenterology and hepatology consultants. The most commonly reported GI manifestation of COVID-19 is diarrhea, which is reported in a third to up to more than half of the patients. Mild to moderate elevation of the liver enzymes are also common, although no case of acute liver failure has been reported so far. Many of the medications used for treatment of COVID-19 can also be associated with GI symptoms or liver injury and can be included in the differential diagnosis in these patients. Although the diagnosis of the infection is currently based on RNA analysis in respiratory samples, the available literature on fecal shedding of this virus suggests that fecal RNA testing might prove to be a useful diagnostic test. It is reasonable to delay all non-urgent endoscopic procedures during the peak of the pandemic and use additional protective equipment such as N95 respirators during endoscopy while most patients can be considered high risk for having been exposed to the virus.
dtkh2ljm
dtkh2ljm
2020-04-14
10.3748/wjg.v26.i14.1546
2.5
Interferon alfacon 1 inhibits SARS-CoV infection In human bronchial epithelial Calu-3 cells
The primary targets for SARS-CoV infection are the epithelial cells in the respiratory and intestinal tract. The angiotensin-converting enzyme 2 (ACE-2) has been identified as a functional receptor for SARS-CoV. ACE-2 has been shown to be expressed at the apical domain of polarized Calu-3 cells. In this report, interferon alfacon 1 was examined for inhibitory activities against SARS-CoV on human lung carcinoma epithelial Calu-3 cell line and the other three African green monkey kidney epithelial cell lines. Interferon alfacon 1 demonstrated significant antiviral activity in neutral red uptake assay and virus yield reduction assay. The data might provide an important insight into the mechanism of pathogenesis of SARS-CoV allowing further development of antiviral therapies for treating SARS infections.
dufsielh
dufsielh
2008-06-01
10.1016/j.bbrc.2008.04.006
2.5
Inference and forecast of H7N9 influenza in China, 2013 to 2015
The recent emergence of A(H7N9) avian influenza poses a significant challenge to public health in China and around the world; however, understanding of the transmission dynamics and progression of influenza A(H7N9) infection in domestic poultry, as well as spillover transmission to humans, remains limited. Here, we develop a mathematical model–Bayesian inference system which combines a simple epidemic model and data assimilation method, and use it in conjunction with data on observed human influenza A(H7N9) cases from 19 February 2013 to 19 September 2015 to estimate key epidemiological parameters and to forecast infection in both poultry and humans. Our findings indicate a high outbreak attack rate of 33% among poultry but a low rate of chicken-to-human spillover transmission. In addition, we generated accurate forecasts of the peak timing and magnitude of human influenza A(H7N9) cases. This work demonstrates that transmission dynamics within an avian reservoir can be estimated and that real-time forecast of spillover avian influenza in humans is possible.
dv3o8dl3
dv3o8dl3
2017-02-16
10.2807/1560-7917.es.2017.22.7.30462
2.5
Computational Prediction of the Comprehensive SARS-CoV-2 vs. Human Interactome to Guide the Design of Therapeutics
Understanding the disease pathogenesis of the novel coronavirus, denoted SARS-CoV-2, is critical to the development of anti-SARS-CoV-2 therapeutics. The global propagation of the viral disease, denoted COVID-19 (“coronavirus disease 2019”), has unified the scientific community in searching for possible inhibitory small molecules or polypeptides. Given the known interaction between the human ACE2 (“Angiotensin-converting enzyme 2”) protein and the SARS-CoV virus (responsible for the coronavirus outbreak circa. 2003), considerable focus has been directed towards the putative interaction between the SARS-CoV-2 Spike protein and ACE2. However, a more holistic understanding of the SARS-CoV-2 vs. human inter-species interactome promises additional putative protein-protein interactions (PPI) that may be considered targets for the development of inhibitory therapeutics. To that end, we leverage two state-of-the-art, sequence-based PPI predictors (PIPE4 & SPRINT) capable of generating the comprehensive SARS-CoV-2 vs. human interactome, comprising approximately 285,000 pairwise predictions. Of these, we identify the high-scoring subset of human proteins predicted to interact with each of the 14 SARS-CoV-2 proteins by both methods, comprising 279 high-confidence putative interactions involving 225 human proteins. Notably, the Spike-ACE2 interaction was the highest ranked for both the PIPE4 and SPRINT predictors, corroborating existing evidence for this PPI. Furthermore, the PIPE-Sites algorithm was used to predict the putative subsequence that might mediate each interaction and thereby inform the design of inhibitory polypeptides intended to disrupt the corresponding host-pathogen interactions. We hereby publicly release the comprehensive set of PPI predictions and their corresponding PIPE-Sites landscapes in the following DataVerse repository: 10.5683/SP2/JZ77XA. All data and metadata are released under a CC-BY 4.0 licence. The information provided represents theoretical modeling only and caution should be exercised in its use. It is intended as a resource for the scientific community at large in furthering our understanding of SARS-CoV-2.
dxabs45r
dxabs45r
2020-03-31
10.1101/2020.03.29.014381
4.5
Coronaviruses in cats and other companion animals: Where does SARS-CoV-2/COVID-19 fit?
• Coronaviruses are wide-ranging diseases in humans and animals. • SARS-CoV-2 is a bat-origin zoonotic coronavirus causing the COViD-19 pandemic. • SARS-CoV-2 can also infect cats and ferrets and has been detected in dogs. • The SARS-CoV-2 receptor ACE2 is highly similar between cats and humans.
dyhd8p8z
dyhd8p8z
2020-06-23
10.1016/j.vetmic.2020.108777
5
Broad and differential animal ACE2 receptor usage by SARS-CoV-2.
The COVID-19 pandemic has caused an unprecedented global public health and economy crisis. The origin and emergence of its causal agent, SARS-CoV-2, in the human population remains mysterious, although bat and pangolin were proposed to be the natural reservoirs. Strikingly, comparing to the SARS-CoV-2-like CoVs identified in bats and pangolins, SARS-CoV-2 harbors a polybasic furin cleavage site in its spike (S) glycoprotein. SARS-CoV-2 uses human ACE2 as its receptor to infect cells. Receptor recognition by the S protein is the major determinant of host range, tissue tropism, and pathogenesis of coronaviruses. In an effort to search for the potential intermediate or amplifying animal hosts of SARS-CoV-2, we examined receptor activity of ACE2 from 14 mammal species and found that ACE2 from multiple species can support the infectious entry of lentiviral particles pseudotyped with the wild-type or furin cleavage site deficient S protein of SARS-CoV-2. ACE2 of human/rhesus monkey and rat/mouse exhibited the highest and lowest receptor activity, respectively. Among the remaining species, ACE2 from rabbit and pangolin strongly bound to the S1 subunit of SARS-CoV-2 S protein and efficiently supported the pseudotyped virus infection. These findings have important implications for understanding potential natural reservoirs, zoonotic transmission, human-to-animal transmission, and use of animal models.IMPORTANCE SARS-CoV-2 uses human ACE2 as primary receptor for host cell entry. Viral entry mediated by the interaction of ACE2 with spike protein largely determines host range and is the major constraint to interspecies transmission. We examined the receptor activity of 14 ACE2 orthologues and found that wild type and mutant SARS-CoV-2 lacking the furin cleavage site in S protein could utilize ACE2 from a broad range of animal species to enter host cells. These results have important implications in the natural hosts, interspecies transmission, animal models and molecular basis of receptor binding for SARS-CoV-2.
dz1ikex1
dz1ikex1
2020-07-13
10.1128/jvi.00940-20
5
Clinical impact of renin-angiotensin system inhibitors on in-hospital mortality of patients with hypertension hospitalized for COVID-19
e0skv0bn
e0skv0bn
2020-04-27
10.1093/cid/ciaa492
4
In vitro and Animal Models for SARS-CoV-2 research
Abstract Basic research on SARS-CoV-2 is essential to understand its detailed pathophysiology and identify best drug targets. Models that can faithfully reproduce the viral life cycle and reproduce the pathology of COVID-19 are required. Here, we briefly review the cell lines, organoids, and animal models that are currently being used in COVID-19 research.
e16lln3f
e16lln3f
2020-05-30
10.1016/j.tips.2020.05.005
4
Middle East Respiratory Syndrome-coronavirus infection: An overview
Summary Middle East Respiratory Syndrome-coronavirus (MERS-CoV) was reported from a number of countries in the Middle East and Europe with a reported high mortality rate. MERS-CoV was initially isolated from a patient from Bisha, Saudi Arabia. A recent outbreak of MERS-CoV infection was described in a healthcare facility. Although, the recent publications on this topic had shed light on the epidemiology of the disease, many questions remain to be answered.
e2epus6x
e2epus6x
2013-10-31
10.1016/j.jiph.2013.06.001
2
Comparative Impact of Individual Quarantine vs. Active Monitoring of Contacts for the Mitigation of COVID-19: a modelling study
BACKGROUND: Voluntary individual quarantine and voluntary active monitoring of contacts are core disease control strategies for emerging infectious diseases, such as COVID-19. Given the impact of quarantine on resources and individual liberty, it is vital to assess under what conditions individual quarantine can more effectively control COVID-19 than active monitoring. As an epidemic grows, it is also important to consider when these interventions are no longer feasible, and broader mitigation measures must be implemented. METHODS: To estimate the comparative efficacy of these case-based interventions to control COVID-19, we fit a stochastic branching model to reported parameters for the dynamics of the disease. Specifically, we fit to the incubation period distribution and each of two sets of the serial interval distribution: a shorter one with a mean serial interval of 4.8 days and a longer one with a mean of 7.5 days. To assess variable resource settings, we consider two feasibility settings: a high feasibility setting with 90% of contacts traced, a half-day average delay in tracing and symptom recognition, and 90% effective isolation; and low feasibility setting with 50% of contacts traced, a two-day average delay, and 50% effective isolation. FINDINGS: Our results suggest that individual quarantine in high feasibility settings where at least three-quarters of infected contacts are individually quarantined contains an outbreak of COVID-19 with a short serial interval (4.8 days) 84% of the time. However, in settings where this performance is unrealistically high and the outbreak continues to grow, so too will the burden of the number of contacts traced for active monitoring or quarantine. When resources are prioritized for scalable interventions such as social distancing, we show active monitoring or individual quarantine of high-risk contacts can contribute synergistically to mitigation efforts. INTERPRETATION: Our model highlights the urgent need for more data on the serial interval and the extent of presymptomatic transmission in order to make data-driven policy decisions regarding the cost-benefit comparisons of individual quarantine vs. active monitoring of contacts. To the extent these interventions can be implemented they can help mitigate the spread of COVID-19.
e2p46wa8
e2p46wa8
2020-04-26
10.1101/2020.03.05.20031088
1.5
Impact of gender on extent of lung injury in COVID-19
e3i3ngmk
e3i3ngmk
2020-04-23
10.1016/j.crad.2020.04.005
2
Striding Toward Malaria Elimination in China
e4xy1huv
e4xy1huv
2015-08-05
10.4269/ajtmh.15-0391
3
Respiratory Viruses
Respiratory viruses are the most frequent causative agents of disease in humans, with significant impact on morbidity and mortality worldwide. Common respiratory agents from several virus families are well adapted to efficient person-to-person transmission and circulate in a global scale, and community-based studies conducted over the past five decades or so confirm that these viruses are the predominant etiological agents of acute respiratory infections (ARIs). The respiratory viruses that most commonly circulate in all continents as endemic or epidemic agents are influenza virus, respiratory syncytial virus, parainfluenza viruses, metapneumovirus, rhinovirus, coronaviruses, adenoviruses, and bocaviruses. Although vaccines and effective antiviral drugs are not yet available for most of these viruses, much progress has been made in the understanding of their biology and fundamental issues of host–parasite relationship. This article is a summary of the current knowledge about these viruses.
e5frjae8
e5frjae8
2009-12-31
10.1016/b978-012373944-5.00314-x
0.5
Pirfenidone: A novel hypothetical treatment for COVID-19
Cytokine storm, multiorgan failure, and particularly acute respiratory distress syndrome (ARDS) is the leading cause of mortality and morbidity in patients with COVID-19. A fulminant ARDS kills the majority of COVID-19 victims. Pirfenidone (5-methyl-1-phenyl-2-[1H]-pyridone), is a novel anti-fibrotic agent with trivial adverse effects. Pirfenidone is approved for the treatment of Idiopathic Pulmonary Fibrosis (IPF) for patients with mild to moderate disease. Pirfenidone could inhibit apoptosis, downregulate ACE receptors expression, decrease inflammation by several mechanisms and ameliorate oxidative stress and hence protect pneumocytes and other cells from COVID-19 invasion and cytokine storm simultaneously. Based on the pirfenidone mechanism of action and the known pathophysiology of COVID-19, I believe that pirfenidone has the potential for the treatment of COVID-19 patients.
e71pykjk
e71pykjk
2020-06-17
10.1016/j.mehy.2020.110005
5
Substrate specificity profiling of SARS-CoV-2 main protease enables design of activity-based probes for patient-sample imaging
In December 2019, the first cases of infection with a novel coronavirus, SARS-CoV-2, were diagnosed in Wuhan, China. Due to international travel and human-to-human transmission, the virus spread rapidly inside and outside of China. Currently, there is no effective antiviral treatment for coronavirus disease 2019 (COVID-19); therefore, research efforts are focused on the rapid development of vaccines and antiviral drugs. The SARS-CoV-2 main protease constitutes one of the most attractive antiviral drug targets. To address this emerging problem, we have synthesized a combinatorial library of fluorogenic substrates with glutamine in the P1 position. We used it to determine the substrate preferences of the SARS-CoV and SARS-CoV-2 main proteases, using natural and a large panel of unnatural amino acids. On the basis of these findings, we designed and synthesized an inhibitor and two activity-based probes, for one of which we determined the crystal structure of its complex with the SARS-CoV-2 Mpro. Using this approach we visualized SARS-CoV-2 active Mpro within nasopharyngeal epithelial cells of a patient with active COVID-19 infection. The results of our work provide a structural framework for the design of inhibitors as antiviral agents or diagnostic tests.
e8qubwha
e8qubwha
2020-06-08
10.1101/2020.03.07.981928
2.5
Identification of potent and safe antiviral therapeutic candidates against SARS-CoV-2
COVID-19 pandemic has infected millions of people with mortality exceeding 300,000. There is an urgent need to find therapeutic agents that can help clear the virus to prevent the severe disease and death. Identifying effective and safer drugs can provide with more options to treat the COVID-19 infections either alone or in combination. Here we performed a high throughput screen of approximately 1700 US FDA approved compounds to identify novel therapeutic agents that can effectively inhibit replication of coronaviruses including SARS-CoV-2. Our two-step screen first used a human coronavirus strain OC43 to identify compounds with anti-coronaviral activities. The effective compounds were then screened for their effectiveness in inhibiting SARS-CoV-2. These screens have identified 24 anti-SARS-CoV-2 drugs including previously reported compounds such as hydroxychloroquine, amlodipine, arbidol hydrochloride, tilorone 2HCl, dronedarone hydrochloride, and merfloquine hydrochloride. Five of the newly identified drugs had a safety index (cytotoxic/effective concentration) of >600, indicating wide therapeutic window compared to hydroxychloroquine which had safety index of 22 in similar experiments. Mechanistically, five of the effective compounds were found to block SARS-CoV-2 S protein-mediated cell fusion. These FDA approved compounds can provide much needed therapeutic options that we urgently need in the midst of the pandemic.
e9fjo7tl
e9fjo7tl
2020-07-06
10.1101/2020.07.06.188953
5
COVID-19 preclinical models: human angiotensin-converting enzyme 2 transgenic mice
Coronavirus disease 2019 (COVID-19) is a declared pandemic that is spreading all over the world at a dreadfully fast rate. Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), the pathogen of COVID-19, infects the human body using angiotensin-converting enzyme 2 (ACE2) as a receptor identical to the severe acute respiratory syndrome (SARS) pandemic that occurred in 2002–2003. SARS-CoV-2 has a higher binding affinity to human ACE2 than to that of other species. Animal models that mimic the human disease are highly essential to develop therapeutics and vaccines against COVID-19. Here, we review transgenic mice that express human ACE2 in the airway and other epithelia and have shown to develop a rapidly lethal infection after intranasal inoculation with SARS-CoV, the pathogen of SARS. This literature review aims to present the importance of utilizing the human ACE2 transgenic mouse model to better understand the pathogenesis of COVID-19 and develop both therapeutics and vaccines.
e9uhe5z2
e9uhe5z2
2020-06-04
10.1186/s40246-020-00272-6
4
TWIRLS, an automated topic-wise inference method based on massive literature, suggests a possible mechanism via ACE2 for the pathological changes in the human host after coronavirus infection
Faced with the current large-scale public health emergency, collecting, sorting, and analyzing biomedical information related to the “coronavirus” should be done as quickly as possible to gain a global perspective, which is a basic requirement for strengthening epidemic control capacity. However, for human researchers studying the viruses and the hosts, the vast amount of information available cannot be processed effectively and in a timely manner, particularly when the scientific understanding may be limited, which can further lower the information processing efficiency. We present TWIRLS, a method that can automatically acquire, organize, and classify information. Additionally, independent functional data sources can be added to build an inference system using a machine-based approach, which can provide relevant knowledge to help human researchers quickly establish subject cognition and to make more effective decisions. TWIRLS can automatically analyze more than three million words in more than 14,000 literature articles in only 4 hours. Combining with generalized gene interaction databases creates a data interface that can help researchers to further analyze the information. Using the TWIRLS system, we found that an important regulatory factor angiotensin-converting enzyme 2 (ACE2) may be involved in the host pathological changes on binding to the coronavirus after infection. After triggering functional changes in ACE2/AT2R, an imbalance in the steady-state cytokine regulatory axis involving the Renin-Angiotensin System and IP-10 leads to a cytokine storm.
eaglecq7
eaglecq7
2020-03-02
10.1101/2020.02.27.967588
1.5
BOARD OF DIRECTORS NOMINATIONS
eciycfpr
eciycfpr
2008-06-28
10.1111/j.1751-0813.2003.tb14599.x
3
The SARS-CoV-2 Spike protein has a broad tropism for mammalian ACE2 proteins
SARS-CoV-2 emerged in late 2019, leading to the COVID-19 pandemic that continues to cause significant global mortality in human populations. Given its sequence similarity to SARS-CoV, as well as related coronaviruses circulating in bats, SARS-CoV-2 is thought to have originated in Chiroptera species in China. However, whether the virus spread directly to humans or through an intermediate host is currently unclear, as is the potential for this virus to infect companion animals, livestock and wildlife that could act as viral reservoirs. Using a combination of surrogate entry assays and live virus we demonstrate that, in addition to human ACE2, the Spike glycoprotein of SARS-CoV-2 has a broad host tropism for mammalian ACE2 receptors, despite divergence in the amino acids at the Spike receptor binding site on these proteins. Of the twenty-two different hosts we investigated, ACE2 proteins from dog, cat and rabbit were the most permissive to SARS-CoV-2, while bat and bird ACE2 proteins were the least efficiently used receptors. The absence of a significant tropism for any of the three genetically distinct bat ACE2 proteins we examined indicates that SARS-CoV-2 receptor usage likely shifted during zoonotic transmission from bats into people, possibly in an intermediate reservoir. Interestingly, while SARS-CoV-2 pseudoparticle entry was inefficient in cells bearing the ACE2 receptor from bats or birds the live virus was still able to enter these cells, albeit with markedly lower efficiency. The apparently broad tropism of SARS-CoV-2 at the point of viral entry confirms the potential risk of infection to a wide range of companion animals, livestock and wildlife.
eecwjrdc
eecwjrdc
2020-06-18
10.1101/2020.06.17.156471
5
A model to estimate bed demand for COVID-19 related hospitalization
As of March 23, 2020 there have been over 354,000 confirmed cases of coronavirus disease 2019 (COVID-19) in over 180 countries, the World Health Organization characterized COVID-19 as a pandemic, and the United States (US) announced a national state of emergency.1, 2, 3 In parts of China and Italy the demand for intensive care (IC) beds was higher than the number of available beds.4, 5 We sought to build an accessible interactive model that could facilitate hospital capacity planning in the presence of significant uncertainty about the proportion of the population that is COVID-19+ and the rate at which COVID-19 is spreading in the population. Our approach was to design a tool with parameters that hospital leaders could adjust to reflect their local data and easily modify to conduct sensitivity analyses. We developed a model to facilitate hospital planning with estimates of the number of Intensive Care (IC) beds, Acute Care (AC) beds, and ventilators necessary to accommodate patients who require hospitalization for COVID-19 and how these compare to the available resources. Inputs to the model include estimates of the characteristics of the patient population and hospital capacity. We deployed this model as an interactive online tool.6 The model is implemented in R 3.5, RStudio, RShiny 1.4.0 and Python 3.7. The parameters used may be modified as data become available, for use at other institutions, and to generate sensitivity analyses. We illustrate the use of the model by estimating the demand generated by COVID-19+ arrivals for a hypothetical acute care medical center. The model calculated that the number of patients requiring an IC bed would equal the number of IC beds on Day 23, the number of patients requiring a ventilator would equal the number of ventilators available on Day 27, and the number of patients requiring an AC bed and coverage by the Medicine Service would equal the capacity of the Medicine service on Day 21. In response to the COVID-19 epidemic, hospitals must understand their current and future capacity to care for patients with severe illness. While there is significant uncertainty around the parameters used to develop this model, the analysis is based on transparent logic and starts from observed data to provide a robust basis of projections for hospital managers. The model demonstrates the need and provides an approach to address critical questions about staffing patterns for IC and AC, and equipment capacity such as ventilators.
eee22bzx
eee22bzx
2020-03-26
10.1101/2020.03.24.20042762
1
Consensus Summary Report for CEPI/BC March 12-13, 2020 Meeting: Assessment of Risk of Disease Enhancement with COVID-19 Vaccines
A novel coronavirus (CoV), Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), emerged in late 2019 in Wuhan, China and has since spread as a global pandemic. Safe and effective vaccines are thus urgently needed to reduce the significant morbidity and mortality of Coronavirus Disease 2019 (COVID-19) disease and ease the major economic impact. There has been an unprecedented rapid response by vaccine developers with now over one hundred vaccine candidates in development and at least six having reached clinical trials. However, a major challenge during rapid development is to avoid safety issues both by thoughtful vaccine design and by thorough evaluation in a timely manner. A syndrome of “disease enhancement” has been reported in the past for a few viral vaccines where those immunized suffered increased severity or death when they later encountered the virus or were found to have an increased frequency of infection. Animal models allowed scientists to determine the underlying mechanism for the former in the case of Respiratory Syncytial virus (RSV) vaccine and have been utilized to design and screen new RSV vaccine candidates. Because some Middle East respiratory syndrome (MERS) and SARS-CoV-1 vaccines have shown evidence of disease enhancement in some animal models, this is a particular concern for SARS-CoV-2 vaccines. To address this challenge, the Coalition for Epidemic Preparedness Innovations (CEPI) and the Brighton Collaboration (BC) Safety Platform for Emergency vACcines (SPEAC) convened a scientific working meeting on March 12 and 13, 2020 of experts in the field of vaccine immunology and coronaviruses to consider what vaccine designs could reduce safety concerns and how animal models and immunological assessments in early clinical trials can help to assess the risk. This report summarizes the evidence presented and provides considerations for safety assessment of COVID-19 vaccine candidates in accelerated vaccine development.
eeh2a0t8
eeh2a0t8
2020-05-25
10.1016/j.vaccine.2020.05.064
4.5
The SARS-CoV ferret model in an infection–challenge study
Abstract Phase I human clinical studies involving therapeutics for emerging and biodefense pathogens with low incidence, such as the severe acute respiratory syndrome coronavirus (SARS-CoV), requires at a minimum preclinical evaluation of efficacy in two well-characterized and robust animal models. Thus, a ferret SARS-CoV model was evaluated over a period of 58 days following extensive optimization and characterization of the model in order to validate clinical, histopathological, virological and immunological endpoints. Ferrets that were infected intranasally with 103 TCID50 SARS-CoV showed higher body temperature (2–6 d.p.i.), sneezing (5–10 d.p.i.), lesions (5–7 d.p.i.) and decreased WBC/lymphocytes (2–5 d.p.i.). SARS-CoV was detected up to 7 d.p.i. in various tissues and excreta, while neutralizing antibody titers rose at 7 d.p.i. and peaked at 14 d.p.i. At 29 d.p.i., one group was challenged with 103 TCID50 SARS-CoV, and an anamnestic response in neutralizing antibodies was evident with no detectable virus. This study supports the validity of the ferret model for use in evaluating efficacy of potential therapeutics to treat SARS.
eeugb4x7
eeugb4x7
2008-04-25
10.1016/j.virol.2007.12.032
2.5
The First 75 Days of Novel Coronavirus (SARS-CoV-2) Outbreak: Recent Advances, Prevention, and Treatment
The recent severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2, previously known as 2019-nCoV) outbreak has engulfed an unprepared world amidst a festive season. The zoonotic SARS-CoV-2, believed to have originated from infected bats, is the seventh member of enveloped RNA coronavirus. Specifically, the overall genome sequence of the SARS-CoV-2 is 96.2% identical to that of bat coronavirus termed BatCoV RaTG13. Although the current mortality rate of 2% is significantly lower than that of SARS (9.6%) and Middle East respiratory syndrome (MERS) (35%), SARS-CoV-2 is highly contagious and transmissible from human to human with an incubation period of up to 24 days. Some statistical studies have shown that, on average, one infected patient may lead to a subsequent 5.7 confirmed cases. Since the first reported case of coronavirus disease 2019 (COVID-19) caused by the SARS-CoV-2 on December 1, 2019, in Wuhan, China, there has been a total of 60,412 confirmed cases with 1370 fatalities reported in 25 different countries as of February 13, 2020. The outbreak has led to severe impacts on social health and the economy at various levels. This paper is a review of the significant, continuous global effort that was made to respond to the outbreak in the first 75 days. Although no vaccines have been discovered yet, a series of containment measures have been implemented by various governments, especially in China, in the effort to prevent further outbreak, whilst various medical treatment approaches have been used to successfully treat infected patients. On the basis of current studies, it would appear that the combined antiviral treatment has shown the highest success rate. This review aims to critically summarize the most recent advances in understanding the coronavirus, as well as the strategies in prevention and treatment.
efk2jj50
efk2jj50
2020-03-30
10.3390/ijerph17072323
2
Establishment of Murine Infection Models with Biological Clones of Dengue Viruses Derived from a Single Clinical Viral Isolate
Dengue virus (DENV) is a single-stranded RNA virus transmitted by mosquitoes in tropical and subtropical regions. It causes dengue fever, dengue hemorrhagic fever and dengue shock syndrome in patients. Each year, 390 million people are estimated to be infected by four serotypes of dengue virus, creating a great burden on global public health and local economy. So far, no antiviral drug is available for dengue disease, and the newly licensed vaccine is far from satisfactory. One large obstacle for dengue vaccine and drug development is the lack of suitable small animal models. Although some DENV infection models have been developed, only a small number of viral strains can infect immunodeficient mice. In this study, with biologically cloned viruses from a single clinical isolate, we have established two mouse models of DENV infection, one is severe lethal infection in immunocompromised mice, and the other resembles self-limited disease manifestations in Balb/c mice with transient blockage of type I IFN responses. This study not only offers new small animal models of dengue viral infection, but also provides new viral variants for further investigations on dengue viral pathogenesis.
eg108wcd
eg108wcd
2020-05-25
10.1007/s12250-020-00229-y
4.5
In-silico strategies for probing chloroquine based inhibitors against SARS-CoV-2
The global health emergency of novel COVID-19 is due to severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). Currently there are no approved drugs for the treatment of coronaviral disease (COVID-19), although some of the drugs have been tried. Chloroquine is being widely used in treatment of SARS-CoV-2 infection. Hydroxychloroquine, the derivative of Chloroquine shows better inhibition than Chloroquine and has in vitro activity against SARS-CoV-2 also used to treat COVID-19. To study the interactions of Chloroquine and derivatives of Chloroquine with SARS-CoV-2, series of computational approaches like pharmacophore model, molecular docking, MM_GBSA study and ADME property analysis are explored. The pharmacophore model and molecular docking study are used to explore the structural properties of the compounds and the ligand-receptor (PDB_ID: 6LU7) interactions respectively. MM_GBSA study gives the binding free energy of the protein-ligand complex and ADME property analysis explains the pharmacological property of the compounds. The resultant best molecule (CQD15) further subjected to molecular dynamics (MD) simulation study which explains the protein stability (RMSD), ligand properties as well as protein-ligand contacts. Outcomes of the present study conclude with the molecule CQD15 which shows better interactions for the inhibition of SARS-CoV-2 in comparison to Chloroquine and Hydroxychloroquine. Communicated by Ramaswamy H. Sarma
eh65jhxb
eh65jhxb
2020-06-08
10.1080/07391102.2020.1772111
4.5
Evaluating new evidence in the early dynamics of the novel coronavirus COVID-19 outbreak in Wuhan, China with real time domestic traffic and potential asymptomatic transmissions
The novel coronavirus (COVID-19), first detected in Wuhan, China in December 2019, has spread to 28 countries/regions with over 43,000 confirmed cases. Much about this outbreak is still unknown. At this early stage of the epidemic, it is important to investigate alternative sources of information to understand its dynamics and spread. With updated real time domestic traffic, this study aims to integrate recent evidence of international evacuees extracted from Wuhan between Jan. 29 and Feb. 2, 2020 to infer the dynamics of the COVD-19 outbreak in Wuhan. In addition, a modified SEIR model was used to evaluate the empirical support for the presence of asymptomatic transmissions. Based on the data examined, this study found little evidence for the presence of asymptomatic transmissions. However, it is still too early to rule out its presence conclusively due to sample size and other limitations. The updated basic reproductive number was found to be 2.12 on average with a 95% credible interval of [2.04, 2.18]. It is smaller than previous estimates probably because the new estimate factors in the social and non-pharmaceutical mitigation implemented in Wuhan through the evacuee dataset. Detailed predictions of infected individuals exported both domestically and internationally were produced. The estimated case confirmation rate has been low but has increased steadily to 23.37% on average. The findings of this study depend on the validity of the underlying assumptions, and continuing work is needed, especially in monitoring the current infection status of Wuhan residents.
ehm4fgos
ehm4fgos
2020-02-18
10.1101/2020.02.15.20023440
1.5
Arbidol: A potential antiviral drug for the treatment of SARS-CoV-2 by blocking the trimerization of viral spike glycoprotein ?
Abstract The SARS-CoV-2 pandemic is an urgent global public health emergency and warrants investigating studies on bonafide antivirals for combat. Here we report the drug target and mechanism of action of potential antiviral drug Arbidol for SARS-CoV-2 infections. Our structural and molecular dynamics studies show how Arbidol targets the SARS-CoV-2 spike glycoprotein and impede the trimerization of spike glycoprotein, which is a key for host cell adhesion and hijacking, thus placing Arbidol as a potential drug for repurposing. This study also abets in the development of other new therapeutics for COIVD-19 disease based on Arbidol binding mode and using structure-guided drug designing.
ei3kkp30
ei3kkp30
2020-04-28
10.1016/j.ijantimicag.2020.105998
2
Automated diagnosis of COVID-19 with limited posteroanterior chest X-ray images using fine-tuned deep neural networks
The novel coronavirus 2019 (COVID-19) is a respiratory syndrome that resembles pneumonia. The current diagnostic procedure of COVID-19 follows reverse-transcriptase polymerase chain reaction (RT-PCR) based approach which however is less sensitive to identify the virus at the initial stage. Hence, a more robust and alternate diagnosis technique is desirable. Recently, with the release of publicly available datasets of corona positive patients comprising of computed tomography (CT) and chest X-ray (CXR) imaging; scientists, researchers and healthcare experts are contributing for faster and automated diagnosis of COVID-19 by identifying pulmonary infections using deep learning approaches to achieve better cure and treatment. These datasets have limited samples concerned with the positive COVID-19 cases, which raise the challenge for unbiased learning. Following from this context, this article presents the random oversampling and weighted class loss function approach for unbiased fine-tuned learning (transfer learning) in various state-of-the-art deep learning approaches such as baseline ResNet, Inception-v3, Inception ResNet-v2, DenseNet169, and NASNetLarge to perform binary classification (as normal and COVID-19 cases) and also multi-class classification (as COVID-19, pneumonia, and normal case) of posteroanterior CXR images. Accuracy, precision, recall, loss, and area under the curve (AUC) are utilized to evaluate the performance of the models. Considering the experimental results, the performance of each model is scenario dependent; however, NASNetLarge displayed better scores in contrast to other architectures, which is further compared with other recently proposed approaches. This article also added the visual explanation to illustrate the basis of model classification and perception of COVID-19 in CXR images.
eici4eit
eici4eit
2020-04-23
3.5
The development and application of Laboratory Animal Science in China
ej9efiq3
ej9efiq3
2018-12-21
10.1002/ame2.12047
1
A SARS-CoV-2 protein interaction map reveals targets for drug repurposing.
The novel coronavirus SARS-CoV-2, the causative agent of COVID-19 respiratory disease, has infected over 2.3 million people, killed over 160,000, and caused worldwide social and economic disruption1,2. There are currently no antiviral drugs with proven clinical efficacy, nor are there vaccines for its prevention, and these efforts are hampered by limited knowledge of the molecular details of SARS-CoV-2 infection. To address this, we cloned, tagged and expressed 26 of the 29 SARS-CoV-2 proteins in human cells and identified the human proteins physically associated with each using affinity-purification mass spectrometry (AP-MS), identifying 332 high-confidence SARS-CoV-2-human protein-protein interactions (PPIs). Among these, we identify 66 druggable human proteins or host factors targeted by 69 compounds (29 FDA-approved drugs, 12 drugs in clinical trials, and 28 preclinical compounds). Screening a subset of these in multiple viral assays identified two sets of pharmacological agents that displayed antiviral activity: inhibitors of mRNA translation and predicted regulators of the Sigma1 and Sigma2 receptors. Further studies of these host factor targeting agents, including their combination with drugs that directly target viral enzymes, could lead to a therapeutic regimen to treat COVID-19.
eje3i558
eje3i558
2020-04-30
10.1038/s41586-020-2286-9
3
Screening and druggability analysis of some plant metabolites against SARS-CoV-2: An integrative computational approach
The sudden outbreak of novel coronavirus has caused a global concern due to its infection rate and mortality. Despite extensive research, there are still no specific drugs or vaccines to combat SARS-CoV-2 infection. Hence, this study was designed to evaluate some plant-based active compounds for drug candidacy against SARS-CoV-2 by using virtual screening methods and various computational analyses. A total of 27 plant metabolites were screened against SARS-CoV-2 main protease proteins (MPP), Nsp9 RNA binding protein, spike receptor binding domain, spike ecto-domain and HR2 domain using a molecular docking approach. Four metabolites, i.e., asiatic acid, avicularin, guajaverin, and withaferin showed maximum binding affinity with all key proteins in terms of lowest global binding energy. The crucial binding sites and drug surface hotspots were unravelled for each viral protein. The top candidates were further employed for ADME (absorption, distribution, metabolism, and excretion) analysis to investigate their drug profiles. Results suggest that none of the compounds render any undesirable consequences that could reduce their drug likeness properties. The analysis of toxicity pattern revealed no significant tumorigenic, mutagenic, irritating, or reproductive effects by the compounds. However, withaferin was comparatively toxic among the top four candidates with considerable cytotoxicity and immunotoxicity. Most of the target class by top drug candidates belonged to enzyme groups (e.g. oxidoreductases hydrolases, phosphatases). Moreover, results of drug similarity prediction revealed two approved structural analogs of Asiatic acid i.e. Hydrocortisone (DB00741) (previously used for SARS-CoV-1 and MERS) and Dinoprost-tromethamine (DB01160) from DrugBank. In addition, two other biologically active compounds, Mupirocin (DB00410) and Simvastatin (DB00641) could be an option for the treatment of viral infections. The study may pave the way to develop effective medications and preventive measure against SARS-CoV-2. Due to the encouraging results, we highly recommend further in vivo trials for the experimental validation of our findings.
ekkgcy93
ekkgcy93
2020-06-09
10.1016/j.imu.2020.100367
4
FDA-approved thiol-reacting drugs that potentially bind into the SARS-CoV-2 main protease, essential for viral replication
Emergent novel SARS-CoV-2 is responsible for the current pandemic outbreak of severe acute respiratory syndrome with high mortality among the symptomatic population worldwide. Given the absence of a current vaccine or specific antiviral treatment, it is urgent to search for FDA-approved drugs that can potentially inhibit essential viral enzymes. The inhibition of 3CLpro has potential medical application, due to the fact that it is required for processing of the first translated replicase polyproteins into a series of native proteins, which are essential for viral replication in the host cell. We employed an in silico approach to test if disulfiram, as well as its metabolites, and captopril could be used as potential antiviral drugs against COVID-19. We provide data on the potential covalent interaction of disulfiram and its metabolites with the substrate binding subsite of 3CLpro and propose a possible mechanism for the irreversible protease inactivation thought the reaction of the aforementioned compounds with the Cys145. Although, captopril is shown to be a potential ligand of 3CLpro, it is not recommended anti-COVID-19 therapy, due to the fact that it can induce the expression of the viral cellular receptor such as, angiotensin-converting enzyme ACE-2, and thus, making the patient potentially more susceptible to infection. On the other hand, disulfiram, an alcoholism-averting drug, has been previously proposed as an antimicrobial and anti-SARS and MERS agent, safe to use even at higher doses with low side effects, it is recommended to be tested for control of SARS-CoV-2 infection.Communicated by Ramaswamy H. Sarma.
elmrvpxd
elmrvpxd
2020
4
A systematic review protocol of the antiviral activity of chloroquine and hydroxychloroquine against COVID-19.
Introduction: The recent outbreak of the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), or COVID-19 with no approved medicines has led to global health threat. Currently, repositioning of old medicines seems the most responsible strategy for potential cure and prevention COVID-19. Hydroxychloroquine and chloroquine have shown promising efficacy against COVID-19 related pneumonia in clinical studies. However, the mode of drug action of chloroquine and hydroxychloroquine against SARS-CoV-2 infection is not clear. This review aims to gather evidence on antiviral activity and possible mechanism of drug action of chloroquine and hydroxychloroquine on SARS-CoV-2, including in-vitro, animal studies, and studies in humans. Method: A structured search of five bibliographic databases namely; Medline, Web of Science, PubMed, Cochrane CENTRAL, and Google Scholar will be undertaken to retrieve studies that describe the antiviral activity and possible mechanism of drug action of chloroquine and hydroxychloroquine on SARS-CoV-2. No restrictions will be placed on publication date, but studies will be limited to only publications in English. Duplication of studies will be removed using EndNote reference manager. Three authors will screen the citations independently based on inclusion criteria. Data extraction and assessment of risk of bias will be done independently. Meta-analysis of selected studies will be done wherever suitable. Ethics and dissemination: Primary data collection will not be involved in this study, hence no need for formal ethical clearance. Findings from the study will be disseminated through a peer-reviewed publication and conference meeting. Trial registration number: https://doi.org/10.17605/OSF.IO/7DJMU
em98mikz
em98mikz
2020-06-16
10.1101/2020.06.13.20130245
4
Replication-competent vesicular stomatitis virus vaccine vector protects against SARS-CoV-2-mediated pathogenesis
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused millions of human infections and hundreds of thousands of deaths. Accordingly, an effective vaccine is of critical importance in mitigating coronavirus induced disease 2019 (COVID-19) and curtailing the pandemic. We developed a replication-competent vesicular stomatitis virus (VSV)-based vaccine by introducing a modified form of the SARS-CoV-2 spike gene in place of the native glycoprotein gene (VSV-eGFP-SARS-CoV-2). Immunization of mice with VSV-eGFP-SARS-CoV-2 elicits high titers of antibodies that neutralize SARS-CoV-2 infection and target the receptor binding domain that engages human angiotensin converting enzyme-2 (ACE2). Upon challenge with a human isolate of SARS-CoV-2, mice expressing human ACE2 and immunized with VSV-eGFP-SARS-CoV-2 show profoundly reduced viral infection and inflammation in the lung indicating protection against pneumonia. Finally, passive transfer of sera from VSV-eGFP-SARS-CoV-2-immunized animals protects naïve mice from SARS-CoV-2 challenge. These data support development of VSV-eGFP-SARS-CoV-2 as an attenuated, replication-competent vaccine against SARS-CoV-2.
enli9n34
enli9n34
2020-07-10
10.1101/2020.07.09.196386
5
The epidemic of 2019-novel-coronavirus (2019-nCoV) pneumonia and insights for emerging infectious diseases in the future
Abstract At the end of December 2019, a novel coronavirus, 2019-nCoV, caused an outbreak of pneumonia spreading from Wuhan, Hubei province, to the whole country of China, which has posed great threats to public health and attracted enormous attention around the world. To date, there are no clinically approved vaccines or antiviral drugs available for these human coronavirus infections. Intensive research on the novel emerging human infectious coronaviruses is urgently needed to elucidate their route of transmission and pathogenic mechanisms, and to identify potential drug targets, which would promote the development of effective preventive and therapeutic countermeasures. Herein, we describe the epidemic and etiological characteristics of 2019-nCoV, discuss its essential biological features, including tropism and receptor usage, summarize approaches for disease prevention and treatment, and speculate on the transmission route of 2019-nCoV.
epcel2ez
epcel2ez
2020-03-31
10.1016/j.micinf.2020.02.002
1
Molecular cloning, expression, and purification of SARS-CoV nsp13
Abstract The SARS-nsp13 protein was identified as an mRNA cap1 methyltransferase. In this study, the nsp13 gene was cloned from the SARS-CoV PUMC02 strain viral RNA by RT-PCR, and inserted into the expression plasmid pET30a(+). The recombinant plasmid pET30a(+)-nsp13 was confirmed by restriction enzymes and sequencing analysis, and transformed into Escherichia coli BL21(DE3). The His-tag-fused protein was expressed by induction of 0.5mM IPTG and purified by a single Ni2+ affinity chromatography. The protein was validated by western blot and MS analysis. A large quantity of the nsp13 protein obtained with this method may be useful for further study of its structure and function.
epqbljzn
epqbljzn
2005-06-30
10.1016/j.pep.2004.08.003
1.5
Understanding the binding affinity of noscapines with protease of SARS-CoV-2 for COVID-19 using MD simulations at different temperatures
The current outbreak of a novel coronavirus, named as SARS-CoV-2 causing COVID-19 occurred in 2019, is in dire need of finding potential therapeutic agents. Recently, ongoing viral epidemic due to coronavirus (SARS-CoV-2) primarily affected mainland China that now threatened to spread to populations in most countries of the world. In spite of this, there is currently no antiviral drug/ vaccine available against coronavirus infection, COVID-19. In the present study, computer-aided drug design-based screening to find out promising inhibitors against the coronavirus (SARS-CoV-2) leads to infection, COVID-19. The lead therapeutic molecule was investigated through docking and molecular dynamics simulations. In this, binding affinity of noscapines(23B)-protease of SARS-CoV-2 complex was evaluated through MD simulations at different temperatures. Our research group has established that noscapine is a chemotherapeutic agent for the treatment of drug resistant cancers; however, noscapine was also being used as anti-malarial, anti-stroke and cough-suppressant. This study suggests for the first time that noscapine exerts its antiviral effects by inhibiting viral protein synthesis.
epr1sct6
epr1sct6
2020-05-04
10.1080/07391102.2020.1752310
4.5
Coronaviruses: Molecular Biology☆
Abstract Coronaviruses (CoVs) are enveloped, positive-strand RNA viruses with characteristic spike glycoproteins that project outward like the rays of the sun (corona – Latin for ‘crown’), when visualized by electron microscopy. CoV are classified, together with the toroviruses, in the family Coronaviridae and the order Nidovirales. All nidoviruses have a common genome organization and generate a nested set (nido – Latin for ‘nest’) of 3′ co-terminal mRNAs. CoVs have been isolated from a variety of species, including birds, livestock, domestic animals, and humans. CoV infections can cause respiratory, gastrointestinal, and neurologic disease, depending on the strain of the virus and the site of infection. Importantly, CoVs have been shown to cross species barriers and have emerged from animal reservoirs to infect humans and cause severe disease. The CoV responsible for an outbreak of severe acute respiratory disease (SARS-CoV) in 2002–03 likely originated as a bat coronavirus which, during replication in an intermediate host (such as the palm civet), evolved to be able to infect humans efficiently. SARS-CoV infected over 8000 people with approximately 10% mortality rate before it was controlled by public health measures of isolation of infected individuals and contacts. Middle East Respiratory Syndrome CoV (MERS-CoV), first reported in 2012, is likely transmitted from camels to humans with potentially fatal consequences. To date, there are no approved vaccines or direct acting antiviral drugs to combat coronavirus infections in humans. The emergence or re-emergence of CoVs from animal reservoirs is a potential concern for public health.
eqfz0wpm
eqfz0wpm
2014-12-31
10.1016/b978-0-12-801238-3.02550-2
0.5
Current Drugs with Potential for Treatment of COVID-19: A Literature Review.
PURPOSE SARS-CoV-2 first emerged in China in December 2019 and rapidly spread worldwide. No vaccine or approved drug is available to eradicate the virus, however, some drugs that are indicated for other afflictions seems to be potentially beneficial to treat the infection albeit without unequivocal evidence. The aim of this article is to review the published background on the effectiveness of these drugs against COVID-19 Methods: A thorough literature search was conducted on recently published studies which have published between January 1 to March 25, 2020. PubMed, Google Scholar and Science Direct databases were searched Results: A total 22 articles were found eligible. 8 discuss about treatment outcomes from their applied drugs during treatment of COVID-19 patients, 4 report laboratory tests, one report animal trial and other 9 articles discuss recommendations and suggestions based on the treatment process and clinical outcomes of other diseases such as malaria, ebola, severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS). The data and/or recommendations are categorized in 4 classes: (a) anti-viral and anti-inflammatory drugs, (b) anti-malaria drugs, (c) traditional Chinese drugs and (d) other treatments/drugs. CONCLUSION All examined treatments, although potentiality effective against COVID-19, need either appropriate drug development or clinical trial to be suitable for clinical use.
er8qrkz3
er8qrkz3
2020
10.18433/jpps31002
3.5
Receptor Recognition by the Novel Coronavirus from Wuhan: an Analysis Based on Decade-Long Structural Studies of SARS Coronavirus
Recently, a novel coronavirus (2019-nCoV) has emerged from Wuhan, China, causing symptoms in humans similar to those caused by severe acute respiratory syndrome coronavirus (SARS-CoV). Since the SARS-CoV outbreak in 2002, extensive structural analyses have revealed key atomic-level interactions between the SARS-CoV spike protein receptor-binding domain (RBD) and its host receptor angiotensin-converting enzyme 2 (ACE2), which regulate both the cross-species and human-to-human transmissions of SARS-CoV. Here, we analyzed the potential receptor usage by 2019-nCoV, based on the rich knowledge about SARS-CoV and the newly released sequence of 2019-nCoV. First, the sequence of 2019-nCoV RBD, including its receptor-binding motif (RBM) that directly contacts ACE2, is similar to that of SARS-CoV, strongly suggesting that 2019-nCoV uses ACE2 as its receptor. Second, several critical residues in 2019-nCoV RBM (particularly Gln493) provide favorable interactions with human ACE2, consistent with 2019-nCoV's capacity for human cell infection. Third, several other critical residues in 2019-nCoV RBM (particularly Asn501) are compatible with, but not ideal for, binding human ACE2, suggesting that 2019-nCoV has acquired some capacity for human-to-human transmission. Last, while phylogenetic analysis indicates a bat origin of 2019-nCoV, 2019-nCoV also potentially recognizes ACE2 from a diversity of animal species (except mice and rats), implicating these animal species as possible intermediate hosts or animal models for 2019-nCoV infections. These analyses provide insights into the receptor usage, cell entry, host cell infectivity and animal origin of 2019-nCoV and may help epidemic surveillance and preventive measures against 2019-nCoV.IMPORTANCE The recent emergence of Wuhan coronavirus (2019-nCoV) puts the world on alert. 2019-nCoV is reminiscent of the SARS-CoV outbreak in 2002 to 2003. Our decade-long structural studies on the receptor recognition by SARS-CoV have identified key interactions between SARS-CoV spike protein and its host receptor angiotensin-converting enzyme 2 (ACE2), which regulate both the cross-species and human-to-human transmissions of SARS-CoV. One of the goals of SARS-CoV research was to build an atomic-level iterative framework of virus-receptor interactions to facilitate epidemic surveillance, predict species-specific receptor usage, and identify potential animal hosts and animal models of viruses. Based on the sequence of 2019-nCoV spike protein, we apply this predictive framework to provide novel insights into the receptor usage and likely host range of 2019-nCoV. This study provides a robust test of this reiterative framework, providing the basic, translational, and public health research communities with predictive insights that may help study and battle this novel 2019-nCoV.
erozilox
erozilox
2020
5
Isolation of potent SARS-CoV-2 neutralizing antibodies and protection from disease in a small animal model
Countermeasures to prevent and treat COVID-19 are a global health priority. We enrolled a cohort of SARS-CoV-2-recovered participants, developed neutralization assays to interrogate antibody responses, adapted our high-throughput antibody generation pipeline to rapidly screen over 1800 antibodies, and established an animal model to test protection. We isolated potent neutralizing antibodies (nAbs) to two epitopes on the receptor binding domain (RBD) and to distinct non-RBD epitopes on the spike (S) protein. We showed that passive transfer of a nAb provides protection against disease in high-dose SARS-CoV-2 challenge in Syrian hamsters, as revealed by maintained weight and low lung viral titers in treated animals. The study suggests a role for nAbs in prophylaxis, and potentially therapy, of COVID-19. The nAbs define protective epitopes to guide vaccine design.
es806qhz
es806qhz
2020-06-15
10.1126/science.abc7520
5
Design and synthesis of new tripeptide-type SARS-CoV 3CL protease inhibitors containing an electrophilic arylketone moiety
Abstract We describe here the design, synthesis and biological evaluation of a series of molecules toward the development of novel peptidomimetic inhibitors of SARS-CoV 3CLpro. A docking study involving binding between the initial lead compound 1 and the SARS-CoV 3CLpro motivated the replacement of a thiazole with a benzothiazole unit as a warhead moiety at the P1′ site. This modification led to the identification of more potent derivatives, including 2i, 2k, 2m, 2o, and 2p, with IC50 or K i values in the submicromolar to nanomolar range. In particular, compounds 2i and 2p exhibited the most potent inhibitory activities, with K i values of 4.1 and 3.1nM, respectively. The peptidomimetic compounds identified through this process are attractive leads for the development of potential therapeutic agents against SARS. The structural requirements of the peptidomimetics with potent inhibitory activities against SARS-CoV 3CLpro may be summarized as follows: (i) the presence of a benzothiazole warhead at the S1′-position; (ii) hydrogen bonding capabilities at the cyclic lactam of the S1-site; (iii) appropriate stereochemistry and hydrophobic moiety size at the S2-site and (iv) a unique folding conformation assumed by the phenoxyacetyl moiety at the S4-site.
esogd26s
esogd26s
2013-01-15
10.1016/j.bmc.2012.11.017
3
ACP risk grade: a simple mortality index for patients with confirmed or suspected severe acute respiratory syndrome coronavirus 2 disease (COVID-19) during the early stage of outbreak in Wuhan, China
Background: Since the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) disease (COVID-19) outbreaks in Wuhan, China, healthcare systems capacities in highly endemic areas have been overwhelmed. Approaches to efficient management are urgently needed and key to a quicker control of the outbreaks and casualties. We aimed to characterize the clinical features of hospitalized patients with confirmed or suspected COVID-19, and develop a mortality risk index for COVID-19 patients. Methods: In this retrospective one-centre cohort study, we included all the confirmed or suspected COVID-19 patients hospitalized in a COVID-19-designated hospital from January 21 to February 5, 2020. Demographic, clinical, laboratory, radiological and clinical outcome data were collected from the hospital information system, nursing records and laboratory reports. Results: Of 577 patients with at least one post-admission evaluation, the median age was 55 years (interquartile range [IQR], 39 - 66); 254 (44.0%) were men; 22.8% (100/438) were severe pneumonia on admission, and 37.7% (75/199) patients were SARS-CoV-2 positive. The clinical, laboratory and radiological data were comparable between positive and negative SARS-CoV-2 patients. During a median follow-up of 8.4 days (IQR, 5.8 - 12.0), 39 patients died with a 12-day cumulative mortality of 8.7% (95% CI, 5.9% to 11.5%). A simple mortality risk index (called ACP index), composed of Age and C-reactive Protein, was developed. By applying the ACP index, patients were categorized into three grades. The 12-day cumulative mortality in grade three (age ≥ 60 years and CRP ≥ 34 mg/L) was 33.2% (95% CI, 19.8% to 44.3%), which was significantly higher than those of grade two (age ≥ 60 years and CRP < 34 mg/L; age < 60 years and CRP ≥ 34 mg/L; 5.6% [95% CI, 0 to 11.3%]) and grade one (age < 60 years and CRP < 34 mg/L, 0%) (P <0.001), respectively. Conclusion: The ACP index can predict COVID-19 related short-term mortality, which may be a useful and convenient tool for quickly establishing a COVID-19 hierarchical management system that can greatly reduce the medical burden and therefore mortality in highly endemic areas.
eu3rry7p
eu3rry7p
2020-02-23
10.1101/2020.02.20.20025510
1.5
Virus against virus: a potential treatment for 2019-nCov (SARS-CoV-2) and other RNA viruses
eucpd2ky
eucpd2ky
2020-02-18
10.1038/s41422-020-0290-0
3
Advances in disease diagnosis, vaccine development and other emerging methods to control pathogens in aquaculture
Disease is still regarded as a major constraint to aquaculture production globally. Rapid disease diagnosis and vaccination play a huge part in the control of bacterial diseases, and there has been significant progress in both of these areas. This chapter considers the limitations of existing methods and reviews recent advances made in pathogen detection technologies and vaccine development methodologies. Future directions are discussed, including nanotechnology and reversed vaccinology.
evc37gi0
evc37gi0
2014-03-27
10.1533/9781845696474.2.197
3
COvid MEdicaTion (COMET) study: protocol for a cohort study
Various theories about drugs such as ACE inhibitors or angiotensin II receptor blockers (ARBs) in relation to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and clinical outcomes of COVID-19 are circulating in both mainstream media and medical literature. These are based on the fact that ACE2 facilitates SARS-CoV-2 cell invasion via binding of a viral spike protein to ACE2. However, the effect of ACE inhibitors, ARBs and other drugs on ACE2 is unclear and all theories are based on conflicting evidence mainly from animal studies. Therefore, clinical evidence is urgently needed. The aim of this study is to investigate the relationship between use of these drugs on clinical outcome of patients with COVID-19. Patients will be included from several hospitals in Europe. Data will be collected in a user-friendly database (Digitalis) on an external server. Analyses will be adjusted for sex, age and presence of cardiovascular disease, hypertension and diabetes. These results will enable more rational choices for randomised controlled trials for preventive and therapeutic strategies in COVID-19.
evodle3x
evodle3x
2020
5
An enzyme-based immunodetection assay to quantify SARS-CoV-2 infection
SARS-CoV-2 is a novel pandemic coronavirus that caused a global health and economic crisis. The development of efficient drugs and vaccines against COVID-19 requires detailed knowledge about SARS-CoV-2 biology. Several techniques to detect SARS-CoV-2 infection have been established, mainly based on counting infected cells by staining plaques or foci, or by quantifying the viral genome by PCR. These methods are laborious, time-consuming and expensive and therefore not suitable for a high sample throughput or rapid diagnostics. We here report a novel enzyme-based immunodetection assay that directly quantifies the amount of de novo synthesized viral spike protein within fixed and permeabilized cells. This in-cell ELISA enables a rapid and quantitative detection of SARS-CoV-2 infection in microtiter format, regardless of the virus isolate or target cell culture. It follows the established method of performing ELISA assays and does not require expensive instrumentation. Utilization of the in-cell ELISA allows to e.g. determine TCID50 of virus stocks, antiviral efficiencies (IC50 values) of drugs or neutralizing activity of sera. Thus, the in-cell spike ELISA represents a promising alternative to study SARS-CoV-2 infection and inhibition and may facilitate future research. Highlights Determination of SARS-CoV-2 infection by enzymatically quantifying the expression of viral spike protein in bulk cell cultures Targeting a highly conserved region in the S2 subunit of the S protein allows broad detection of several SARS-CoV-2 isolates in different cell lines Screening of antivirals in microtiter format and determining the antiviral activity as inhibitory concentrations 50 (IC50)
ew78trl9
ew78trl9
2020-06-15
10.1101/2020.06.14.150862
5
The Cytokine storm in COVID-19: An overview of the involvement of the chemokine/chemokine-receptor system
In 2019-2020 a new coronavirus named SARS-CoV-2 was identified as the causative agent of a several acute respiratory infection named COVID-19, which is causing a worldwide pandemic. There are still many unresolved questions regarding the pathogenesis of this disease and especially the reasons underlying the extremely different clinical course, ranging from asymptomatic forms to severe manifestations, including the Acute Respiratory Distress Syndrome (ARDS). SARS-CoV-2 showed phylogenetic similarities to both SARS-CoV and MERS-CoV viruses, and some of the clinical features are shared between COVID-19 and previously identified beta-coronavirus infections. Available evidence indicate that the so called “cytokine storm” an uncontrolled over-production of soluble markers of inflammation which, in turn, sustain an aberrant systemic inflammatory response, is a major responsible for the occurrence of ARDS. Chemokines are low molecular weight proteins with powerful chemoattractant activity which play a role in the immune cell recruitment during inflammation. This review will be aimed at providing an overview of the current knowledge on the involvement of the chemokine/chemokine-receptor system in the cytokine storm related to SARS-CoV-2 infection. Basic and clinical evidences obtained from previous SARS and MERS epidemics and available data from COVID-19 will be taken into account.
ex9nh1yi
ex9nh1yi
2020-05-11
10.1016/j.cytogfr.2020.05.003
3
Discovering drugs to treat coronavirus disease 2019 (COVID-19)
The SARS-CoV-2 virus emerged in December 2019 and then spread rapidly worldwide, particularly to China, Japan, and South Korea. Scientists are endeavoring to find antivirals specific to the virus. Several drugs such as chloroquine, arbidol, remdesivir, and favipiravir are currently undergoing clinical studies to test their efficacy and safety in the treatment of coronavirus disease 2019 (COVID-19) in China; some promising results have been achieved thus far. This article summarizes agents with potential efficacy against SARS-CoV-2.
ey939w17
ey939w17
2020
4.5
Inhibition of infection caused by severe acute respiratory syndrome-associated coronavirus by equine neutralizing antibody in aged mice
Abstract The high susceptibility of elderly to severe acute respiratory syndrome-associated coronavirus (SARS-CoV) indicates how crucial it is to protect the elderly by various strategies. Aged BALB/c mice displayed a high susceptibility to SARS-CoV and have been a valuable platform for evaluation of strategies against SARS-CoV infection. In this study, we confirmed the validity of this model using various methods, and verified that equine anti-SARS-CoV F(ab')2 can prevent aged animals from SARS-CoV infection. In a therapeutic setting, treatment with anti-SARS-CoV F(ab')2 decreased viral load more than several thousand folds in the lungs. Thus, this antibody should be a potential candidate for treatment of elderly patients suffering from SARS.
eyh65q6a
eyh65q6a
2007-03-31
10.1016/j.intimp.2006.10.009
0.5
COVID-19 and therapeutic drugs repurposing in hand: the need for collaborative efforts
Abstract The novel pandemic severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is responsible to cause coronavirus disease-2019 (COVID-19). It is a global pandemic disease and has reached a new dimension with a higher death ratio. On 2 June 2020, World Health Organization (WHO) data showed more than 6,194,500 confirmed and 376,300 deaths globally due to the COVID-19. There are currently no approved medications or vaccines which have been claimed to be effective in COVID-19 prevention or treatment. Drug repurposing of available drugs and research studies for the search of new therapeutic agents are underway in various countries to try different combinations to treat their patients. It is too early to be sure of them as safe treatments because some reports seem to suggest some alarming side effects. However, a lot of work needs to be done to achieve a successful treatment result and the full safety and efficacy of the trial drugs will take some time to be developed. In this narrative perspective review, we addressed evidence-based literature on various possible antiviral medications, plant-derived antivirals drugs, and other valuable treatment options for COVID-19 management.
ez4cljlc
ez4cljlc
2020-06-13
10.1016/j.phclin.2020.06.003
4
Broad and differential animal ACE2 receptor usage by SARS-CoV-2
The COVID-19 pandemic has caused an unprecedented global public health and economy crisis. The origin and emergence of its causal agent, SARS-CoV-2, in the human population remains mysterious, although bat and pangolin were proposed to be the natural reservoirs. Strikingly, comparing to the SARS-CoV-2-like CoVs identified in bats and pangolins, SARS-CoV-2 harbors a polybasic furin cleavage site in its spike (S) glycoprotein. SARS-CoV-2 uses human ACE2 as its receptor to infect cells. Receptor recognition by the S protein is the major determinant of host range, tissue tropism, and pathogenesis of coronaviruses. In an effort to search for the potential intermediate or amplifying animal hosts of SARS-CoV-2, we examined receptor activity of ACE2 from 14 mammal species and found that ACE2 from multiple species can support the infectious entry of lentiviral particles pseudotyped with the wild-type or furin cleavage site deficient S protein of SARS-CoV-2. ACE2 of human/rhesus monkey and rat/mouse exhibited the highest and lowest receptor activity, respectively. Among the remaining species, ACE2 from rabbit and pangolin strongly bound to the S1 subunit of SARS-CoV-2 S protein and efficiently supported the pseudotyped virus infection. These findings have important implications for understanding potential natural reservoirs, zoonotic transmission, human-to-animal transmission, and use of animal models.
f03san07
f03san07
2020-04-20
10.1101/2020.04.19.048710
2
Deducing the N- and O- glycosylation profile of the spike protein of novel coronavirus SARS-CoV-2
The current emergence of the novel coronavirus pandemic caused by SARS-CoV-2 demands the development of new therapeutic strategies to prevent rapid progress of mortalities. The coronavirus spike (S) protein, which facilitates viral attachment, entry and membrane fusion is heavily glycosylated and plays a critical role in the elicitation of the host immune response. The spike protein is comprised of two protein subunits (S1 and S2), which together possess 22 potential N-glycosylation sites. Herein, we report the glycosylation mapping on spike protein subunits S1 and S2 expressed on human cells through high resolution mass spectrometry. We have characterized the quantitative N-glycosylation profile on spike protein and interestingly, observed unexpected O-glycosylation modifications on the receptor binding domain (RBD) of spike protein subunit S1. Even though O-glycosylation has been predicted on the spike protein of SARS-CoV-2, this is the first report of experimental data for both the site of O-glycosylation and identity of the O-glycans attached on the subunit S1. Our data on the N- and O-glycosylation is strengthened by extensive manual interpretation of each glycopeptide spectra in addition to using bioinformatics tools to confirm the complexity of glycosylation in the spike protein. The elucidation of the glycan repertoire on the spike protein provides insights into the viral binding studies and more importantly, propels research towards the development of a suitable vaccine candidate.
f0xsisdg
f0xsisdg
2020-04-06
10.1101/2020.04.01.020966
3
World Pneumonia Day 2011-2016: Twitter contents and retweets.
Background Twitter is used for World Pneumonia Day (WPD; November 12) communication. We evaluate if themes of #pneumonia tweets were associated with retweet frequency. Methods A total of 28 181 original #pneumonia tweets were retrieved (21 November 2016), from which six subcorpora, 1 mo before and 1 mo after WPD 2011-2016, were extracted (n=6721). Underlying topics were identified via latent Dirichlet allocation and were manually coded into themes. The association of themes with retweet count was assessed via multivariable hurdle regression. Results Compared with personal experience tweets, tweets that both raised awareness and promoted intervention were 2.62 times as likely to be retweeted (adjusted odds ratio [aOR] 2.62 [95% 1.79 to 3.85]) and if retweeted had 37% more retweets (adjusted prevalence ratio [aPR] 1.37 [95% CI 1.06 to 1.78]). Tweets that raised concerns about vaccine price were twice as likely to be retweeted (aOR 2.29 [95% CI 1.36 to 3.84]) and if retweeted, had double the retweet count (aPR 2.05 [95% CI 1.27 to 3.29]) of tweets sharing personal experience. Conclusions The #pneumonia tweets that both raised awareness and promoted interventions and those discussing vaccine price were more likely to engage users than tweets about personal experience. These results help health professionals craft WPD messages that will engage the audience.
f1op9r9x
f1op9r9x
2018
10.1093/inthealth/ihy087
3.5
Severe Acute Respiratory Syndrome (SARS) and the GDP. Part II: Implications for GDPs
The transmission modes of SARS-coronavirus appear to be through droplet spread, close contact and fomites although air borne transmission has not been ruled out. This clearly places dental personnel at risks as they work in close proximity to their patients employing droplet and aerosol generating procedures. Although the principle of universal precautions is widely advocated and followed throughout the dental community, additional precautionary measures — termed standard precaution may be necessary to help control the spread of this highly contagious disease. Patient assessment should include questions on recent travel to SARS infected areas and, contacts of patients, fever and symptoms of respiratory infections. Special management protocols and modified measures that regulate droplet and aerosol contamination in a dental setting have to be introduced and may include the reduction or avoidance of droplet/aerosol generation, the disinfection of the treatment field, application of rubber dam, pre-procedural antiseptic mouthrinse and the dilution and efficient removal of contaminated ambient air. The gag, cough or vomiting reflexes that lead to the generation of aerosols should also be prevented.
f1ulk9ce
f1ulk9ce
2004-08-14
10.1038/sj.bdj.4811522
1
Repositioning of 8565 existing drugs for COVID-19
The coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has infected near 5 million people and led to over 0.3 million deaths. Currently, there is no specific anti-SARS-CoV-2 medication. New drug discovery typically takes more than ten years. Drug repositioning becomes one of the most feasible approaches for combating COVID-19. This work curates the largest available experimental dataset for SARS-CoV-2 or SARS-CoV main protease inhibitors. Based on this dataset, we develop validated machine learning models with relatively low root mean square error to screen 1553 FDA-approved drugs as well as other 7012 investigational or off-market drugs in DrugBank. We found that many existing drugs might be potentially potent to SARS-CoV-2. The druggability of many potent SARS-CoV-2 main protease inhibitors is analyzed. This work offers a foundation for further experimental studies of COVID-19 drug repositioning.
f2e4d3bz
f2e4d3bz
2020-05-20
4
Estimating the reproduction number of COVID-19 in Iran using epidemic modeling
Background: As reported by Iranian governments, the first cases of coronavirus (COVID-19) infections confirmed in Qom, Iran on February 19, 2020 (30 Bahman 1398). The number of identified cases afterward increased rapidly and the novel coronavirus spread to all provinces of the country. This study aimed to fit an epidemic model to the reported cases data to estimate the basic reproduction number (R_0) of COVID-19 in Iran. Methods: We used data from February 21, 2020, to April 21, 2020, on the number of cases reported by Iranian governments and we employed the SIR (Susceptible-Infectious-Removed) epidemic spreading model to fit the transmission model to the reported cases data by tuning the parameters in order to estimate the basic reproduction number of COVID-19 in Iran. Results: The value of reproduction number was estimated 4.86 in the first week and 4.5 in the second week. it decreased from 4.29 to 2.37 in the next four weeks. At the seventh week of the outbreak the reproduction number was reduced below 1. Conclusions: The results indicate that the basic reproduction number of COVID-19 was significantly larger than one in the early stages of the outbreak. However, implementing social distancing and preventing travelling on Nowruz (Persian New Year) effectively reduced the reproduction number. Although the results indicate that reproduction number is below one, it is necessary to continue social distancing and control travelling to prevent causing a second wave of outbreak.
f3ikyl9d
f3ikyl9d
2020-03-23
10.1101/2020.03.20.20038422
1
Intestinal lymphatic transport for drug delivery
Abstract Intestinal lymphatic transport has been shown to be an absorptive pathway following oral administration of lipids and an increasing number of lipophilic drugs, which once absorbed, diffuse across the intestinal enterocyte and while in transit associate with secretable enterocyte lipoproteins. The chylomicron-associated drug is then secreted from the enterocyte into the lymphatic circulation, rather than the portal circulation, thus avoiding the metabolically-active liver, but still ultimately returning to the systemic circulation. Because of this parallel and potentially alternative absorptive pathway, first-pass metabolism can be reduced while increasing lymphatic drug exposure, which opens the potential for novel therapeutic modalities and allows the implementation of lipid-based drug delivery systems. This review discusses the physiological features of the lymphatics, enterocyte uptake and metabolism, links between drug transport and lipid digestion/re-acylation, experimental model (in vivo, in vitro, and in silico) of lymphatic transport, and the design of lipid- or prodrug-based drug delivery systems for enhancing lymphatic drug transport.
f65l6tws
f65l6tws
2011-09-10
10.1016/j.addr.2011.05.019
1.5
Prediction of the SARS-CoV-2 (2019-nCoV) 3C-like protease (3CL (pro)) structure: virtual screening reveals velpatasvir, ledipasvir, and other drug repurposing candidates
We prepared the three-dimensional model of the SARS-CoV-2 (aka 2019-nCoV) 3C-like protease (3CL (pro)) using the crystal structure of the highly similar (96% identity) ortholog from the SARS-CoV. All residues involved in the catalysis, substrate binding and dimerisation are 100% conserved. Comparison of the polyprotein PP1AB sequences showed 86% identity. The 3C-like cleavage sites on the coronaviral polyproteins are highly conserved. Based on the near-identical substrate specificities and high sequence identities, we are of the opinion that some of the previous progress of specific inhibitors development for the SARS-CoV enzyme can be conferred on its SARS-CoV-2 counterpart. With the 3CL (pro) molecular model, we performed virtual screening for purchasable drugs and proposed 16 candidates for consideration. Among these, the antivirals ledipasvir or velpatasvir are particularly attractive as therapeutics to combat the new coronavirus with minimal side effects, commonly fatigue and headache. The drugs Epclusa (velpatasvir/sofosbuvir) and Harvoni (ledipasvir/sofosbuvir) could be very effective owing to their dual inhibitory actions on two viral enzymes.
f6muhf3d
f6muhf3d
2020-02-21
10.12688/f1000research.22457.1
1.5
The SARS-CoV-2 main protease as drug target
The unprecedented pandemic of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is threatening global health. The virus emerged in late 2019 and can cause a severe disease associated with significant mortality. Several vaccine development and drug discovery campaigns are underway. The SARS-CoV-2 main protease is considered a promising drug target, as it is dissimilar to human proteases. Sequence and structure of the main protease are closely related to those from other betacoronaviruses, facilitating drug discovery attempts based on previous lead compounds. Covalently binding peptidomimetics and small molecules are investigated. Various compounds show antiviral activity in infected human cells.
f8aolprb
f8aolprb
2020-09-01
10.1016/j.bmcl.2020.127377
5
Charts and Tables
f8la32zl
f8la32zl
2011-10-06
10.1016/b978-1-4377-0798-4.00006-2
3
Structural and molecular modelling studies reveal a new mechanism of action of chloroquine and hydroxychloroquine against SARS-CoV-2 infection
ABSTRACT The recent emergence of the novel pathogenic SARS-coronavirus 2 (SARS-CoV-2) is responsible for a worldwide pandemic. Given the global health emergency, drug repositioning is the most reliable option to design an efficient therapy for infected patients without delay. The first step of the viral replication cycle [i.e. attachment to the surface of respiratory cells, mediated by the spike (S) viral protein] offers several potential therapeutic targets. The S protein uses the angiotension-converting enzyme-2 (ACE-2) receptor for entry, but also sialic acids linked to host cell surface gangliosides. Using a combination of structural and molecular modelling approaches, this study showed that chloroquine (CLQ), one of the drugs currently under investigation for SARS-CoV-2 treatment, binds sialic acids and gangliosides with high affinity. A new type of ganglioside-binding domain at the tip of the N-terminal domain of the SARS-CoV-2 S protein was identified. This domain (111–158), which is fully conserved among clinical isolates worldwide, may improve attachment of the virus to lipid rafts and facilitate contact with the ACE-2 receptor. This study showed that, in the presence of CLQ [or its more active derivative, hydroxychloroquine (CLQ-OH)], the viral S protein is no longer able to bind gangliosides. The identification of this new mechanism of action of CLQ and CLQ-OH supports the use of these repositioned drugs to cure patients infected with SARS-CoV-2. The in-silico approaches used in this study might also be used to assess the efficiency of a broad range of repositioned and/or innovative drug candidates before clinical evaluation.
f99nd3dx
f99nd3dx
2020-04-03
10.1016/j.ijantimicag.2020.105960
1
Computational Design of ACE2-Based Peptide Inhibitors of SARS-CoV-2
[Image: see text] Peptide inhibitors against the SARS-CoV-2 coronavirus, currently causing a worldwide pandemic, are designed and simulated. The inhibitors are mostly formed by two sequential self-supporting α-helices (bundle) extracted from the protease domain (PD) of angiotensin-converting enzyme 2 (ACE2), which bind to the SARS-CoV-2 receptor binding domains. Molecular dynamics simulations revealed that the α-helical peptides maintain their secondary structure and provide a highly specific and stable binding (blocking) to SARS-CoV-2. To provide a multivalent binding to the SARS-CoV-2 receptors, many such peptides could be attached to the surfaces of nanoparticle carriers. The proposed peptide inhibitors could provide simple and efficient therapeutics against the COVID-19 disease.
f9qcabcx
f9qcabcx
2020-04-14
10.1021/acsnano.0c02857
3.5
State-of-the-art tools to identify druggable protein ligand of SARS-CoV-2
INTRODUCTION: The SARS-CoV-2 (previously 2019-nCoV) outbreak in Wuhan, China and other parts of the world affects people and spreads coronavirus disease 2019 (COVID-19) through human-to-human contact, with a mortality rate of > 2%. There are no approved drugs or vaccines yet available against SARS-CoV-2. MATERIAL AND METHODS: State-of-the-art tools based on in-silico methods are a cost-effective initial approach for identifying appropriate ligands against SARS-CoV-2. The present study developed the 3D structure of the envelope and nucleocapsid phosphoprotein of SARS-CoV-2, and molecular docking analysis was done against various ligands. RESULTS: The highest log octanol/water partition coefficient, high number of hydrogen bond donors and acceptors, lowest non-bonded interaction energy between the receptor and the ligand, and high binding affinity were considered for the best ligand for the envelope (mycophenolic acid: log P = 3.00; DG = –10.2567 kcal/mol; pKi = 7.713 µM) and nucleocapsid phosphoprotein (1-[(2,4-dichlorophenyl)methyl]pyrazole-3,5-dicarboxylic acid: log P = 2.901; DG = –12.2112 kcal/mol; pKi = 7.885 µM) of SARS-CoV-2. CONCLUSIONS: The study identifies the most potent compounds against the SARS-CoV-2 envelope and nucleocapsid phosphoprotein through state-of-the-art tools based on an in-silico approach. A combination of these two ligands could be the best option to consider for further detailed studies to develop a drug for treating patients infected with SARS-CoV-2, COVID-19.
f9s46an9
f9s46an9
2020-03-27
10.5114/aoms.2020.94046
3
COvid MEdicaTion (COMET) study: protocol for a cohort study
Various theories about drugs such as ACE inhibitors or angiotensin II receptor blockers (ARBs) in relation to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and clinical outcomes of COVID-19 are circulating in both mainstream media and medical literature. These are based on the fact that ACE2 facilitates SARS-CoV-2 cell invasion via binding of a viral spike protein to ACE2. However, the effect of ACE inhibitors, ARBs and other drugs on ACE2 is unclear and all theories are based on conflicting evidence mainly from animal studies. Therefore, clinical evidence is urgently needed. The aim of this study is to investigate the relationship between use of these drugs on clinical outcome of patients with COVID-19. Patients will be included from several hospitals in Europe. Data will be collected in a user-friendly database (Digitalis) on an external server. Analyses will be adjusted for sex, age and presence of cardiovascular disease, hypertension and diabetes. These results will enable more rational choices for randomised controlled trials for preventive and therapeutic strategies in COVID-19.
fb1zgn7e
fb1zgn7e
2020
5
Chloroquine and hydroxychloroquine for the treatment of COVID-19: A living systematic review protocol
OBJECTIVE: To determine the relative impact of the use of chloroquine and hydroxychloroquine on outcomes important to patients with COVID 19. DESIGN: This is the protocol of a living systematic review. DATA SOURCES: We will conduct searches in PubMed/Medline, Embase, Cochrane Central Register of Controlled Trials (CENTRAL), trial registries, grey literature and in a centralised repository in L-OVE (Living OVerview of Evidence). L-OVE is a platform that maps PICO questions to evidence from Epistemonikos database. In response to the COVID-19 emergency, L-OVE was adapted to expand the range of evidence it covers and customised to group all COVID-19 evidence in one place. The search will cover the period until the day before submission to a journal. ELIGIBILITY CRITERIA FOR SELECTING STUDIES AND METHODS: We will follow a common protocol for multiple parallel systematic reviews, already published and submitted to PROSPERO (awaiting ID allocation). We will include randomised controlled trials evaluating the effect of chloroquine and hydroxychloroquine - as monotherapy or in combination with other drugs - versus placebo or no treatment in patients with COVID-19. Randomised trials evaluating chloroquine and hydroxychloroquine in infections caused by other coronaviruses, such as MERS-CoV and SARS-CoV, and non-randomised studies in COVID-19 will be searched in case no direct evidence from randomised trials is found, or if the direct evidence provides low- or very low-certainty for critical outcomes. Two reviewers will independently screen each study for eligibility, extract data, and assess the risk of bias. We will perform random-effects meta-analyses and use GRADE to assess the certainty of the evidence for each outcome. A living, web-based version of this review will be openly available during the COVID-19 pandemic. We will resubmit it if the conclusions change or there are substantial updates. ETHICS AND DISSEMINATION: No ethics approval is considered necessary. The results of this review will be widely disseminated via peer-reviewed publications, social networks and traditional media.
fckn8ld4
fckn8ld4
2020-04-08
10.1101/2020.04.03.20052530
2.5
COVID-19: The Need for Immunoprevention at Industrial Scale
Novel Coronavirus Disease (COVID-19): The Need for Immunoprevention at Industrial Scale.
fcrunf38
fcrunf38
2020-04-08
10.4269/ajtmh.20-0239
4.5
COVID-19 early warning score: a multi-parameter screening tool to identify highly suspected patients
BACKGROUND Corona Virus Disease 2019 (COVID-19) is spreading worldwide. Effective screening for patients is important to limit the epidemic. However, some defects make the currently applied diagnosis methods are still not very ideal for early warning of patients. We aimed to develop a diagnostic model that allows for the quick screening of highly suspected patients using easy-to-get variables. METHODS A total of 1,311 patients receiving severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) nucleicacid detection were included, whom with a positive result were classified into COVID-19 group. Multivariate logistic regression analyses were performed to construct the diagnostic model. Receiver operating characteristic (ROC) curve analysis were used for model validation. RESULTS After analysis, signs of pneumonia on CT, history of close contact, fever, neutrophil-to-lymphocyte ratio (NLR), Tmax and sex were included in the diagnostic model. Age and meaningful respiratory symptoms were enrolled into COVID-19 early warning score (COVID-19 EWS). The areas under the ROC curve (AUROC) indicated that both of the diagnostic model (training dataset 0.956 [95%CI 0.935-0.977, P < 0.001]; validation dataset 0.960 [95%CI 0.919-1.0, P < 0.001] ) and COVID-19 EWS (training dataset 0.956 [95%CI 0.934-0.978, P < 0.001] ; validate dataset 0.966 [95%CI 0.929-1, P < 0.001]) had good discrimination capacity. In addition, we also obtained the cut-off values of disease severity predictors, such as CT score, CD8+ T cell count, CD4+ T cell count, and so on. CONCLUSIONS The new developed COVID-19 EWS was a considerable tool for early and relatively accurately warning of SARS-CoV-2 infected patients.
fcvstps9
fcvstps9
2020-03-08
10.1101/2020.03.05.20031906
1.5
Antiviral activities of mycophenolic acid and IMD-0354 against SARS-CoV-2
In this study, anti-SARS-CoV-2 activity of mycophenolic acid (MPA) and IMD-0354 was analyzed, these compounds were chosen based on their antiviral activities against other coronaviruses. Since they also inhibit Dengue virus (DENV) infection, other anti-DENV compounds/drugs were also assessed. Using SARS-CoV-2-infected VeroE6/TMPRSS2 cells, MPA and IMD-0354, but not other anti-DENV compounds/drugs, showed significant anti-SARS-CoV-2 activity. Although MPA reduced the viral RNA level by only ~100-fold, its EC50 was as low as 0.87µM, which is easily achievable at therapeutic doses of mycophenolate mofetil. MPA targets coronaviral papain-like protease and its study would be useful in the development of novel anti-SARS-CoV-2 drugs. This article is protected by copyright. All rights reserved.
fcxjt7qf
fcxjt7qf
2020
5
Discovery of the FDA-approved drugs bexarotene, cetilistat, diiodohydroxyquinoline, and abiraterone as potential COVID-19 treatments with a robust two-tier screening system
Coronavirus Disease 2019 (COVID-19) caused by the emerging severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is associated with a crude case fatality rate of about 0.5-10% depending on locality. A few clinically approved drugs, such as remdesivir, chloroquine, hydroxychloroquine, nafamostat, camostat, and ivermectin, exhibited anti-SARS-CoV-2 activity in vitro and/or in a small number of patients. However, their clinical use may be limited by anti-SARS-CoV-2 50% maximal effective concentrations (EC(50)) that exceeded their achievable peak serum concentrations (Cmax), side effects, and/or availability. To find more immediately available COVID-19 antivirals, we established a two-tier drug screening system that combines SARS-CoV-2 enzyme-linked immunosorbent assay and cell viability assay, and applied it to screen a library consisting 1528 FDA-approved drugs. Cetilistat (anti-pancreatic lipase), diiodohydroxyquinoline (anti-parasitic), abiraterone acetate (synthetic androstane steroid), and bexarotene (antineoplastic retinoid) exhibited potent in vitro anti-SARS-CoV-2 activity (EC(50) 1.13-2.01µM). Bexarotene demonstrated the highest Cmax:EC(50) ratio (1.69) which was higher than those of chloroquine, hydroxychloroquine, and ivermectin. These results demonstrated the efficacy of the two-tier screening system and identified potential COVID-19 treatments which can achieve effective levels if given by inhalation or systemically depending on their pharmacokinetics.
fd5rr87z
fd5rr87z
2020-05-28
10.1016/j.phrs.2020.104960
4.5
COVID-19 and diabetes mellitus: An unholy interaction of two pandemics
Abstract Background and aims Diabetes mellitus is associated with poor prognosis in patients with COVID-19. On the other hand, COVID-19 contributes to worsening of dysglycemia in people with diabetes mellitus over and above that contributed by stress hyperglycemia. Herein, we have reviewed the two-way interactions between COVID-19 and diabetes mellitus. Methods We have performed an extensive literature search for articles in PubMed, EMBASE and Google Scholar databases till April 25, 2020, with the following keywords: “COVID-19”, “SARS-CoV-2”, “diabetes”, “diabetes mellitus”, “SARS”, “infection” and “management of diabetes mellitus” with interposition of the Boolean operator “AND”. Results Compromised innate immunity, pro-inflammatory cytokine milieu, reduced expression of ACE2 and use of renin-angiotensin-aldosterone system antagonists in people with DM contribute to poor prognosis in COVID-19. On the contrary, direct β-cell damage, cytokine-induced insulin resistance, hypokalemia and drugs used in the treatment of COVID-19 (like corticosteroids, lopinavir/ritonavir) can contribute to worsening of glucose control in people with diabetes mellitus. Conclusions The two-way interaction between COVID-19 and diabetes mellitus sets up a vicious cycle wherein COVID-19 leads to worsening of dysglycemia and diabetes mellitus, in turn, exacerbates the severity of COVID-19. Thus, it is imperative that people with DM take all necessary precautions and ensure good glycemic control amid the ongoing pandemic.
fe8f7tk1
fe8f7tk1
2020-05-06
10.1016/j.dsx.2020.04.049
4.5
Animal Health Policy
The EU remains under threat of communicable diseases of livestock that may have a severe economic impact or that are of public health significance or both. Such diseases may be introduced and spread by the trading of animals and their products. Measures in line with international agreements are required to prevent the introduction of disease, to control its spread and to protect animal and human health, and to provide safe, wholesome food for European consumers. The EU’s Animal Health Strategy 2013–2017, the Common Financial Framework and the Animal Health Law contributed to the recent update of the EU’s animal health policy. Although the EU’s animal health policy is evaluated to be clearly effective, its cost-effectiveness (efficiency) is difficult to determine.
ff5rggio
ff5rggio
2019-09-28
10.1007/978-3-030-28634-7_11
5
Active or latent tuberculosis increases susceptibility to COVID-19 and disease severity
Importance: Risk factors associated with COVID-19, the viral pneumonia originating in Wuhan, China, in Dec 2019, require clarification so that medical resources can be prioritized for those at highest risk of severe COVID-19 complications. Infection with M. tuberculosis (MTB), the pathogen that causes TB and latently infects ~25% of the global population, may be a risk factor for SARS-CoV-2 infection and severe COVID-19 pneumonia. Objective: To determine if latent or active TB increase susceptibility to SARS-COV-19 infection and disease severity, and lead to more rapid development of COVID-19 pneumonia. Design: An observational case-control study of 36 confirmed COVID-19 cases from Shenyang, China, conducted in Feb 2020. Final date of follow-up: Feb 29, 2020. Cases were grouped according to COVID-19 pneumonia severity (mild/moderate, severe/critical), and MTB infection status compared. Comparisons were made with MTB infection data from another case-control study on bacterial/viral pneumonia at Shenyang Chest Hospital. Setting: Multi-center study involving three primary care hospitals in Shenyang, China. Participants: 86 suspected COVID-19 cases from participating primary-care hospitals in Shenyang. All 36 SARS-CoV-2 +ve cases (based on RT-PCR assay) were included. Disease severity was assessed using the Diagnostic and Treatment Guidelines of the National Health Commission of China (v6). Mean age, 47 years (range: 25-79), gender ratio, 1:1. Exposures: Confirmed COVID-19 pneumonia. Interferon-gamma Release Assays (IGRA) were performed using peripheral blood to determine MTB infection. Main Outcome and Measures: Epidemiological, demographic, clinical, radiological, and laboratory data were collected. Comparison of MTB infection status between patients with mild/moderate and severe/critical COVID-19 pneumonia. Results: Mean age of 36 COVID-19 patients: 47 (range: 25-79); M/F: 18/18; Wuhan/Hubei connection: 42%. Mild/moderate cases: 27 (75%); severe/critical: 9 (25%). MTB infection (IGRA+ve): 13 cases (36.11%), including 7 of 9 severe/critical cases. MTB infection rate: higher in COVID-19 (36.11%) than bacterial pneumonia (20%; p=0.0047) and viral pneumonia patients (16.13%; p=0.024). MTB infection more common than other co-morbidities (36.11% vs diabetes: 25%; hypertension: 22.2%; coronary heart disease: 8.33%; COPD: 5.56%). MTB co-infection linked with disease severity (severe/critical 78% vs mild/moderate cases 22%; p=0.0049), and rate of disease progression: infection to development of symptoms (MTB+SARS-CoV-2: 6.5+/-4.2 days vs SARS-COV-2: 8.9+/-5.2 days; p=0.073); from symptom development to diagnosed as severe (MTB+SARS-CoV-2: 3.4+/-2.0 days vs SARS-COV-2: 7.5+/-0.5 days; p=0.075). Conclusions and Relevance: MTB infection likely increases susceptibility to SARS-CoV-2, and increases COVID-19 severity, but this requires validation in a larger study. MTB infection status of COVID-19 patients should be checked routinely at hospital admission.
ffm5fww3
ffm5fww3
2020-03-16
10.1101/2020.03.10.20033795
1
COVID-19, ECMO, and lymphopenia: a word of caution
fh6f3dkn
fh6f3dkn
2020-03-13
10.1016/s2213-2600(20)30119-3
2
Artificial intelligence approach fighting COVID-19 with repurposing drugs
BACKGROUND: The ongoing COVID-19 pandemic has caused more than 193,825 deaths during the past few months. A quick-to-be-identified cure for the disease will be a therapeutic medicine that has prior use experiences in patients in order to resolve the current pandemic situation before it could become worsening. Artificial intelligence (AI) technology is hereby applied to identify the marketed drugs with potential for treating COVID-19. MATERIAL AND METHODS: An AI platform was established to identify potential old drugs with anti-coronavirus activities by using two different learning databases; one consisted of the compounds reported or proven active against SARS-CoV, SARS-CoV-2, human immunodeficiency virus, influenza virus, and the other one containing the known 3C-like protease inhibitors. All AI predicted drugs were then tested for activities against a feline coronavirus in in vitro cell-based assay. These assay results were feedbacks to the AI system for relearning and thus to generate a modified AI model to search for old drugs again. RESULTS: After a few runs of AI learning and prediction processes, the AI system identified 80 marketed drugs with potential. Among them, 8 drugs (bedaquiline, brequinar, celecoxib, clofazimine, conivaptan, gemcitabine, tolcapone, and vismodegib) showed in vitro activities against the proliferation of a feline infectious peritonitis (FIP) virus in Fcwf-4 cells. In addition, 5 other drugs (boceprevir, chloroquine, homoharringtonine, tilorone, and salinomycin) were also found active during the exercises of AI approaches. CONCLUSION: Having taken advantages of AI, we identified old drugs with activities against FIP coronavirus. Further studies are underway to demonstrate their activities against SARS-CoV-2 in vitro and in vivo at clinically achievable concentrations and doses. With prior use experiences in patients, these old drugs if proven active against SARS-CoV-2 can readily be applied for fighting COVID-19 pandemic.
fhmr1og4
fhmr1og4
2020-05-15
10.1016/j.bj.2020.05.001
3
SARS-CoV-2 RNA dependent RNA polymerase (RdRp) targeting: an in silico perspective
New treatment against SARS-CoV-2 now is a must. Nowadays, the world encounters a huge health crisis by the COVID-19 viral infection. Nucleotide inhibitors gave a lot of promising results in terms of its efficacy against different viral infections. In this work, molecular modeling, docking, and dynamics simulations are used to build a model for the viral protein RNA-dependent RNA polymerase (RdRp) and test its binding affinity to some clinically approved drugs and drug candidates. Molecular dynamics is used to equilibrate the system upon binding calculations to ensure the successful reproduction of previous results, to include the dynamics of the RdRp, and to understand how it affects the binding. The results show the effectiveness of Sofosbuvir, Ribavirin, Galidesivir, Remdesivir, Favipiravir, Cefuroxime, Tenofovir, and Hydroxychloroquine, in binding to SARS-CoV-2 RdRp. Additionally, Setrobuvir, YAK, and IDX-184, show better results, while four novel IDX-184 derivatives show promising results in attaching to the SARS-CoV-2 RdRp. There is an urgent need to specify drugs that can selectively bind and subsequently inhibit SARS-CoV-2 proteins. The availability of a punch of FDA-approved anti-viral drugs can help us in this mission, aiming to reduce the danger of COVID-19. The compounds 2 and 3 may tightly bind to the SARS-CoV-2 RdRp and so may be successful in the treatment of COVID-19.
fhy1goud
fhy1goud
2020-05-06
10.1080/07391102.2020.1761882
3
Combined prophylactic and therapeutic use maximizes hydroxychloroquine anti-SARS-CoV-2 effects in vitro
While the SARS-CoV-2 pandemic is hardly hitting the world, it is of extreme importance that significant in vitro observations guide the quick set up of clinical trials. In this study, we evidence that the anti-SARS-CoV2 activity of a clinically achievable hydroxychloroquine concentration is maximized only when administered before and after the infection of Vero E6 cells. This strongly suggests that only a combined prophylactic and therapeutic use of hydroxychloroquine may be effective in limiting viral replication in patients.
fhy2z49t
fhy2z49t
2020-03-31
10.1101/2020.03.29.014407
1.5
SARS-CoV-2 will continue to circulate in the human population: an opinion from the point of view of the virus-host relationship
At the population level, the virus-host relationship is not set up to end with the complete elimination of either or both. Pathogen-resistant individuals will always remain in the host population. In turn, the virus can never completely eliminate the host population, because evolutionarily such an event is a dead end for the virus as an obligate intracellular parasite. A certain existential balance exists in the virus-host relationship. Against this backdrop, viral epidemics and pandemics only become manifest and egregious to human beings when tens and hundreds of thousands of people die and the question emerges what caused the high mortality peaks on the death chart. The answer seems clear; the emerging strain of the virus is new to the host population, and new mutations of the virus and natural selection will lead to a survival of only genetically resistant individuals in a host population. The dangers inherent to a novel virus are due to new features generally inthe molecular structure of proteins, which enable the virus to infect the cells of the host organism more intensively, dramatically challenging host immunity, and thus be transmitted more readily in the host population. In this article, we will concentrate on the facts currently available about severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which has caused COVID-19 (coronavirus disease 2019) pandemic and try to predict its development and consequences based on the virus-host relationship. In fact, only two scenarios will occur simultaneously in the very near future: people who are genetically resistant to the virus will get sick, recover, and develop immunity, while people who are sensitive to the virus will need drugs and vaccines, which will have to be researched and developed if they are to recover. If the pandemic does not stop, in a few decades it is anticipated that SARS-CoV-2 will become as safe as the four non-severe acute respiratory syndrome human coronaviruses (HCoV-NL63, HCoV-HKU1, HCoV-OC43, and HCoV-229E) currently circulating but causing low mortality in the human population.
fiievwy7
fiievwy7
2020-04-30
10.1007/s00011-020-01352-y
3.5
MERS-CoV: Ein aktueller Überblick
The following article gives a current overview of the newly emerging Middle East Respiratory Syndrome Coronavirus (MERS-CoV). Since first time in summer 2012 in some countries in the Arabian Peninsula there were a number of severe infections of the respiratory tract caused by the new coronavirus. The majority of cases of illness were reported from Saudi Arabia, in Germany several imported cases of the disease have been reported. After beginning with flu-like-symptoms usually follows a pneumonia with a transition to an acute respiratory distress syndrome. The mortality rate is estimated at 55%. In the travel medical advice it should be elucidated about the disease and for that reason it is of great importance also for occupational medicine.
fjcj6htg
fjcj6htg
2014-04-13
10.1007/bf03350872
1.5
In Vitro and Animal Models for SARS-CoV-2 research
Basic research on SARS-CoV-2 is essential to understand its detailed pathophysiology and identify best drug targets. Models that can faithfully reproduce the viral life cycle and reproduce the pathology of COVID-19 are required. Here, we briefly review the cell lines, organoids, and animal models that are currently being used in COVID-19 research.
fkqd6nvt
fkqd6nvt
2020
5
Current development of COVID-19 diagnostics, vaccines and therapeutics
Abstract A novel coronavirus, designated as SARS-CoV-2, first emerged in Wuhan City, Hubei Province, China, in late December 2019. The rapidly increasing number of cases has caused worldwide panic. In this review, we describe some currently applied diagnostic approaches, as well as therapeutics and vaccines, to prevent, treat and control further outbreaks of SARS-CoV-2 infection.
fleibepf
fleibepf
2020-05-06
10.1016/j.micinf.2020.05.001
3
Knowledge‐based structural models of SARS‐CoV‐2 proteins and their complexes with potential drugs
The World Health Organization (WHO) has declared the coronavirus disease 2019 (COVID‐19) caused by the novel coronavirus SARS‐CoV‐2 a pandemic. There is, however, no confirmed anti‐COVID‐19 therapeutic currently. In order to assist structure‐based discovery efforts for repurposing drugs against this disease, we constructed knowledge‐based models of SARS‐CoV‐2 proteins and compared the ligand molecules in the template structures with approved/experimental drugs and components of natural medicines. Our theoretical models suggest several drugs, such as carfilzomib, sinefungin, tecadenoson, and trabodenoson, that could be further investigated for their potential for treating COVID‐19.
flkjekyo
flkjekyo
2020-05-25
10.1002/1873-3468.13806
3.5
Potential Neutralizing Antibodies Discovered for Novel Corona Virus Using Machine Learning
The fast and untraceable virus mutations take lives of thousands of people before the immune system can produce the inhibitory antibody. Recent outbreak of novel coronavirus infected and killed thousands of people in the world. Rapid methods in finding peptides or antibody sequences that can inhibit the viral epitopes of COVID-19 will save the life of thousands. In this paper, we devised a machine learning (ML) model to predict the possible inhibitory synthetic antibodies for Corona virus. We collected 1933 virus-antibody sequences and their clinical patient neutralization response and trained an ML model to predict the antibody response. Using graph featurization with variety of ML methods, we screened thousands of hypothetical antibody sequences and found 8 stable antibodies that potentially inhibit COVID-19. We combined bioinformatics, structural biology, and Molecular Dynamics (MD) simulations to verify the stability of the candidate antibodies that can inhibit the Corona virus.
fn7l93wh
fn7l93wh
2020-03-20
10.1101/2020.03.14.992156
1.5
Repurposing old drugs as antiviral agents for coronaviruses
BACKGROUND: New therapeutic options to address the ongoing COVID-19 pandemic are urgently needed. One possible strategy is the repurposing of existing drugs approved for other indications as antiviral agents for SARS-CoV-2. Due to the commercial unavailability of SARS-CoV-2 drugs for treating COVID-19, we screened approximately 250 existing drugs or pharmacologically active compounds for their inhibitory activities against feline infectious peritonitis coronavirus (FIPV) and human coronavirus OC43 (HCoV-OC43), a human coronavirus in the same genus (Betacoronavirus) as SARS-CoV-2. METHODS: FIPV was proliferated in feline Fcwf-4 cells and HCoV-OC43 in human HCT-8 cells. Viral proliferation was assayed by visualization of cytopathic effects on the infected Fcwf-4 cells and immunofluorescent assay for detection of the nucleocapsid proteins of HCoV-OC43 in the HCT-8 cells. The concentrations (EC(50)) of each drug necessary to diminish viral activity to 50% of that for the untreated controls were determined. The viabilities of Fcwf-4 and HCT-8 cells were measured by crystal violet staining and MTS/PMS assay, respectively. RESULTS: Fifteen out of the 252 drugs or pharmacologically active compounds screened were found to be active against both FIPV and HCoV-OC43, with EC(50) values ranging from 11 nM to 75 μM. They are all old drugs as follows, anisomycin, antimycin A, atovaquone, chloroquine, conivaptan, emetine, gemcitabine, homoharringtonine, niclosamide, nitazoxanide, oligomycin, salinomycin, tilorone, valinomycin, vismodegib. CONCLUSION: All of the old drugs identified as having activity against FIPV and HCoV-OC43 have seen clinical use in their respective indications and are associated with known dosing schedules and adverse effect or toxicity profiles in humans. Those, when later confirmed to have an anti-viral effect on SARS-CoV-2, should be considered for immediate uses in COVID-19 patients.
fo07nxvi
fo07nxvi
2020-05-23
10.1016/j.bj.2020.05.003
4.5
Doomsday preppers and the architecture of dread
Abstract Prepping is a practice of anticipating and adaptating to impending conditions of calamity, ranging from low-level crises to extinction-level events. The 2020 COVID-19 pandemic, which preppers consider a 'mid-level' event, and which many of them were well-prepared for, makes clear that scholarly attention to prepper's motivations and methods is both timely and valuable. Drawing from a three-year ethnographic research project with preppers, this paper traces the activity of a single bunker builder who has constructed a technically sophisticated private underground community. Supplemented by additional fieldwork, the paper argues that the boltholes preppers are building in closed communities built to survive the collapse of society, order, and even the environment itself, refract the seemingly irresolvable problems we are failing to address as a species. In the prepper ideology, faith in adaptation has supplanted hope of mitigation, making contemporary bunkers more speculative than reactionary and more temporal than spatial. The bunkers preppers build are an ark to cross through a likely (but often unspecified) catastrophe; they are a chrysalis from which to be reborn - potentially even into an improved milieu.
fphab5ql
fphab5ql
2020-04-10
10.1016/j.geoforum.2020.03.014
2
A Potently Neutralizing Antibody Protects Mice against SARS-CoV-2 Infection
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is responsible for millions of infections and hundreds of thousands of deaths globally. There are no widely available licensed therapeutics against SARS-CoV-2, highlighting an urgent need for effective interventions. The virus enters host cells through binding of a receptor-binding domain within its trimeric spike glycoprotein to human angiotensin-converting enzyme 2. In this article, we describe the generation and characterization of a panel of murine mAbs directed against the receptor-binding domain. One mAb, 2B04, neutralized wild-type SARS-CoV-2 in vitro with remarkable potency (half-maximal inhibitory concentration of <2 ng/ml). In a murine model of SARS-CoV-2 infection, 2B04 protected challenged animals from weight loss, reduced lung viral load, and blocked systemic dissemination. Thus, 2B04 is a promising candidate for an effective antiviral that can be used to prevent SARS-CoV-2 infection.
frmc8bi5
frmc8bi5
2020
5
High-throughput assay using a GFP-expressing replicon for SARS-CoV drug discovery
Abstract The causative agent of severe acute respiratory syndrome (SARS) has been identified as a novel coronavirus, SARS-CoV. The development of rapid screening assays is essential for antiviral drug discovery. By using a cell line expressing a SARS-CoV subgenomic replicon, we developed a high-throughput assay and used it to screen small molecule compounds for inhibitors of SARS-CoV replication in the absence of live virus. The assay system involves minimal manipulation after assay set-up, facilitates automated read-out and minimizes risks associated with hazardous viruses. Based on this assay system, we screened 7035 small molecule compounds from which we identified 7 compounds with anti-SARS-CoV activity. We demonstrate that the compounds inhibited SARS-CoV replication-dependent GFP expression in the replicon cells and reduced SARS-CoV viral protein accumulation and viral RNA copy number in the replicon cells. In a SARS-CoV plaque reduction assay, these compounds were confirmed to have antiviral activity. The target of one of the hit compounds, C12344, was validated by the generation of resistant replicon cells and the identification of the mutations conferring the resistant phenotype. These compounds should be valuable for developing anti-SARS therapeutic drugs as well as research tools to study the mechanism of SARS-CoV replication.
frmgl65z
frmgl65z
2008-11-30
10.1016/j.antiviral.2008.05.005
0.5
Characteristic and quantifiable COVID-19-like abnormalities in CT- and PET/CT-imaged lungs of SARS-CoV-2-infected crab-eating macaques (Macaca fascicularis)
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is causing an exponentially increasing number of coronavirus disease 19 (COVID-19) cases globally. Prioritization of medical countermeasures for evaluation in randomized clinical trials is critically hindered by the lack of COVID-19 animal models that enable accurate, quantifiable, and reproducible measurement of COVID-19 pulmonary disease free from observer bias. We first used serial computed tomography (CT) to demonstrate that bilateral intrabronchial instillation of SARS-CoV-2 into crab-eating macaques (Macaca fascicularis) results in mild-to-moderate lung abnormalities qualitatively characteristic of subclinical or mild-to-moderate COVID-19 (e.g., ground-glass opacities with or without reticulation, paving, or alveolar consolidation, peri-bronchial thickening, linear opacities) at typical locations (peripheral>central, posterior and dependent, bilateral, multi-lobar). We then used positron emission tomography (PET) analysis to demonstrate increased FDG uptake in the CT-defined lung abnormalities and regional lymph nodes. PET/CT imaging findings appeared in all macaques as early as 2 days post-exposure, variably progressed, and subsequently resolved by 6–12 days post-exposure. Finally, we applied operator-independent, semi-automatic quantification of the volume and radiodensity of CT abnormalities as a possible primary endpoint for immediate and objective efficacy testing of candidate medical countermeasures.
fruzsn26
fruzsn26
2020-05-14
10.1101/2020.05.14.096727
5
Glycosaminoglycan binding motif at S1/S2 proteolytic cleavage site on spike glycoprotein may facilitate novel coronavirus (SARS-CoV-2) host cell entry
Severe acute respiratory syndrome-related coronavirus 2 (SARS-CoV-2) has resulted in a pandemic and continues to spread around the globe at an unprecedented rate. To date, no effective therapeutic is available to fight its associated disease, COVID-19. Our discovery of a novel insertion of glycosaminoglycan (GAG)-binding motif at S1/S2 proteolytic cleavage site (681-686 (PRRARS)) and two other GAG-binding-like motifs within SARS-CoV-2 spike glycoprotein (SGP) led us to hypothesize that host cell surface GAGs might be involved in host cell entry of SARS-CoV-2. Using a surface plasmon resonance direct binding assay, we found that both monomeric and trimeric SARS-CoV-2 spike more tightly bind to immobilized heparin (KD = 40 pM and 73 pM, respectively) than the SARS-CoV and MERS-CoV SGPs (500 nM and 1 nM, respectively). In competitive binding studies, the IC50 of heparin, tri-sulfated non-anticoagulant heparan sulfate, and non-anticoagulant low molecular weight heparin against SARS-CoV-2 SGP binding to immobilized heparin were 0.056 μM, 0.12 μM, and 26.4 μM, respectively. Finally, unbiased computational ligand docking indicates that heparan sulfate interacts with the GAG-binding motif at the S1/S2 site on each monomer interface in the trimeric SARS-CoV-2 SGP, and at another site (453-459 (YRLFRKS)) when the receptor-binding domain is in an open conformation. Our study augments our knowledge in SARS-CoV-2 pathogenesis and advances carbohydrate-based COVID-19 therapeutic development.
fs8dn7ir
fs8dn7ir
2020-04-15
10.1101/2020.04.14.041459
3
Knowledge-based repositioning of the anti-HCV direct antiviral agent Sofosbuvir as SARS-CoV-2 treatment
The new human coronavirus named SARS-CoV-2 is a positive-sense RNA virus for which no specific drugs are currently available. A knowledge-based analysis strongly suggests a possible repositioning of the anti-HCV direct antiviral agent (DAA) Sofosbuvir as treatment for SARS-CoV-2. Indeed, the RNA-dependent RNA-polymerases (RdRp) of the two viruses show high sequence and structural homology, supporting the likelihood of binding the Sofosbuvir molecule with similar efficiency. Such a repositioning would allow the containment of the SARS-CoV-2 pandemic and limit the progression of disease to potentially deadly COVID19.
fspxett8
fspxett8
2020-05-12
10.1186/s13027-020-00302-x
3
Expression of SARS-CoV-2 Entry Molecules ACE2 and TMPRSS2 in the Gut of Patients With IBD
BACKGROUND: Patients with inflammatory bowel disease (IBD) have intestinal inflammation and are treated with immune-modulating medications. In the face of the coronavirus disease-19 pandemic, we do not know whether patients with IBD will be more susceptible to infection or disease. We hypothesized that the viral entry molecules angiotensin I converting enzyme 2 (ACE2) and transmembrane serine protease 2 (TMPRSS2) are expressed in the intestine. We further hypothesized that their expression could be affected by inflammation or medication usage. METHODS: We examined the expression of Ace2 and Tmprss2 by quantitative polymerase chain reacion in animal models of IBD. Publicly available data from organoids and mucosal biopsies from patients with IBD were examined for expression of ACE2 and TMPRSS2. We conducted RNA sequencing for CD11b-enriched cells and peripheral and lamina propria T-cells from well-annotated patient samples. RESULTS: The molecules ACE2 and TMPRSS2 were abundantly expressed in the ileum and colon and had high expression in intestinal epithelial cells. In animal models, inflammation led to downregulation of epithelial Ace2. Expression of ACE2 and TMPRSS2 was not increased in samples from patients with compared with those of control patients. In CD11b-enriched cells but not T-cells, the level of expression of ACE2 and TMPRSS2 in the mucosa was comparable to other functional mucosal genes and was not affected by inflammation. Anti-tumor necrosis factor drugs, vedolizumab, ustekinumab, and steroids were linked to significantly lower expression of ACE2 in CD11b-enriched cells. CONCLUSIONS: The viral entry molecules ACE2 and TMPRSS2 are expressed in the ileum and colon. Patients with IBD do not have higher expression during inflammation; medical therapy is associated with lower levels of ACE2. These data provide reassurance for patients with IBD.
fsyn4wwx
fsyn4wwx
2020-04-25
10.1093/ibd/izaa085
4.5
Syndromic Surveillance
ftp67lkq
ftp67lkq
2004-07-16
10.3201/eid1007.031035
4
Predictions for the binding domain and potential new drug targets of 2019-nCoV
An outbreak of new SARS-like viral in Wuhan, China has been named 2019-nCoV. The current state of the epidemic is increasingly serious, and there has been the urgent necessity to develop an effective new drug. In previous studies, it was found that the conformation change in CTD1 was the region where SARS-CoV bound to human ACE2. Although there are mutations of the 2019-nCoV, the binding energy of ACE2 remains high. The surface glycoprotein of 2019-nCoV was coincident with the CTD1 region of the S-protein by comparing the I-TASSER prediction model with the actual SARS model, which suggests that 2019-nCoV may bind to the ACE2 receptor through conformational changes. Furthermore, site prediction on the surface glycoprotein of 2019-nCoV suggests some core amino acid area may be a novel drug target against 2019-nCoV.
fvig79k3
fvig79k3
2020-03-02
10.1101/2020.02.26.961938
4.5
Powerful Sequence Similarity Search Methods and In-Depth Manual Analyses Can Identify Remote Homologs in Many Apparently “Orphan” Viral Proteins
The genome sequences of new viruses often contain many “orphan” or “taxon-specific” proteins apparently lacking homologs. However, because viral proteins evolve very fast, commonly used sequence similarity detection methods such as BLAST may overlook homologs. We analyzed a data set of proteins from RNA viruses characterized as “genus specific” by BLAST. More powerful methods developed recently, such as HHblits or HHpred (available through web-based, user-friendly interfaces), could detect distant homologs of a quarter of these proteins, suggesting that these methods should be used to annotate viral genomes. In-depth manual analyses of a subset of the remaining sequences, guided by contextual information such as taxonomy, gene order, or domain cooccurrence, identified distant homologs of another third. Thus, a combination of powerful automated methods and manual analyses can uncover distant homologs of many proteins thought to be orphans. We expect these methodological results to be also applicable to cellular organisms, since they generally evolve much more slowly than RNA viruses. As an application, we reanalyzed the genome of a bee pathogen, Chronic bee paralysis virus (CBPV). We could identify homologs of most of its proteins thought to be orphans; in each case, identifying homologs provided functional clues. We discovered that CBPV encodes a domain homologous to the Alphavirus methyltransferase-guanylyltransferase; a putative membrane protein, SP24, with homologs in unrelated insect viruses and insect-transmitted plant viruses having different morphologies (cileviruses, higreviruses, blunerviruses, negeviruses); and a putative virion glycoprotein, ORF2, also found in negeviruses. SP24 and ORF2 are probably major structural components of the virions.
fvj3cpie
fvj3cpie
2014-01-16
10.1128/jvi.02595-13
1
Robust neutralization assay based on SARS-CoV-2 S-bearing vesicular stomatitis virus (VSV) pseudovirus and ACE2-overexpressed BHK21 cells
The global pandemic of Coronavirus disease 2019 (COVID-19) is a disaster for human society. A convenient and reliable in vitro neutralization assay is very important for the development of neutralizing antibodies, vaccines and other inhibitors. In this study, G protein-deficient vesicular stomatitis virus (VSVdG) bearing full-length and truncated spike (S) protein of SARS-CoV-2 were evaluated. The virus packaging efficiency of VSV-SARS-CoV-2-Sdel18 (S with C-terminal 18 amino acid truncation) is much higher than VSV-SARS-CoV-2-S. A neutralization assay for antibody screening and serum neutralizing titer quantification was established based on VSV-SARS-CoV-2-Sdel18 pseudovirus and human angiotensin-converting enzyme 2 (ACE2) overexpressed BHK21 cell (BHK21-hACE2). The experimental results can be obtained by automatically counting EGFP positive cell number at 12 hours after infection, making the assay convenient and high-throughput. The serum neutralizing titer of COVID-19 convalescent patients measured by VSV-SARS-CoV-2-Sdel18 pseudovirus assay has a good correlation with live SARS-CoV-2 assay. Seven neutralizing monoclonal antibodies targeting receptor binding domain (RBD) of SARS-CoV-2-S were obtained. This efficient and reliable pseudovirus assay model could facilitate the development of new drugs and vaccines.
fvjh3g7v
fvjh3g7v
2020-04-13
10.1101/2020.04.08.026948
2.5
3CLpro inhibitors as a potential therapeutic option for COVID-19: Available evidence and ongoing clinical trials
fxcv5feh
fxcv5feh
2020-06-30
10.1016/j.phrs.2020.104779
2
Long Term Culture of Human Kidney Proximal Tubule Epithelial Cells Maintains Lineage Functions and Serves as an Ex vivo Model for Coronavirus Associated Kidney Injury
The mechanism of how SARS-CoV-2 causes severe multi-organ failure is largely unknown. Acute kidney injury (AKI) is one of the frequent organ damage in severe COVID-19 patients. Previous studies have shown that human renal tubule cells could be the potential host cells targeted by SARS-CoV-2. Traditional cancer cell lines or immortalized cell lines are genetically and phenotypically different from host cells. Animal models are widely used, but often fail to reflect a physiological and pathogenic status because of species tropisms. There is an unmet need for normal human epithelial cells for disease modeling. In this study, we successfully established long term cultures of normal human kidney proximal tubule epithelial cells (KPTECs) in 2D and 3D culture systems using conditional reprogramming (CR) and organoids techniques. These cells had the ability to differentiate and repair DNA damage, and showed no transforming property. Importantly, the CR KPTECs maintained lineage function with expression of specific transporters (SLC34A3 and cubilin). They also expressed angiotensin-converting enzyme 2 (ACE2), a receptor for SARS-CoV and SARS-CoV-2. In contrast, cancer cell line did not express endogenous SLC34A3, cubilin and ACE2. Very interestingly, ACE2 expression was around twofold higher in 3D organoids culture compared to that in 2D CR culture condition. Pseudovirion assays demonstrated that SARS-CoV spike (S) protein was able to enter CR cells with luciferase reporter. This integrated 2D CR and 3D organoid cultures provide a physiological ex vivo model to study kidney functions, innate immune response of kidney cells to viruses, and a novel platform for drug discovery and safety evaluation.
fxuk7x12
fxuk7x12
2020
5
The spike protein of severe acute respiratory syndrome (SARS) is cleaved in virus infected Vero-E6 cells
Spike protein is one of the major structural proteins of severe acute respiratory syndrome-coronavirus. It is essential for the interaction of the virons with host cell receptors and subsequent fusion of the viral envelop with host cell membrane to allow infection. Some spike proteins of coronavirus, such as MHV, HCoV-OC43, AIBV and BcoV, are proteolytically cleaved into two subunits, S1 and S2. In contrast, TGV, FIPV and HCoV-229E are not. Many studies have shown that the cleavage of spike protein seriously affects its function. In order to investigate the maturation and proteolytic processing of the S protein of SARS CoV, we generated S1 and S2 subunit specific antibodies (Abs) as well as N, E and 3CL protein-specific Abs. Our results showed that the antibodies could efficiently and specifically bind to their corresponding proteins from E.coli expressed or lysate of SARS-CoV infected Vero-E6 cells by Western blot analysis. Furthermore, the anti-S1 and S2 Abs were proved to be capable of binding to SARS CoV under electron microscope observation. When S2 Ab was used to perform immune precipitation with lysate of SARS-CoV infected cells, a cleaved S2 fragment was detected with S2-specific mAb by Western blot analysis. The data demonstrated that the cleavage of S protein was observed in the lysate, indicating that proteolytic processing of S protein is present in host cells.
fy1lqk00
fy1lqk00
2004-10-16
10.1038/sj.cr.7290240
1
Pathogenic human coronavirus infections: causes and consequences of cytokine storm and immunopathology
Human coronaviruses (hCoVs) can be divided into low pathogenic and highly pathogenic coronaviruses. The low pathogenic CoVs infect the upper respiratory tract and cause mild, cold-like respiratory illness. In contrast, highly pathogenic hCoVs such as severe acute respiratory syndrome CoV (SARS-CoV) and Middle East respiratory syndrome CoV (MERS-CoV) predominantly infect lower airways and cause fatal pneumonia. Severe pneumonia caused by pathogenic hCoVs is often associated with rapid virus replication, massive inflammatory cell infiltration and elevated pro-inflammatory cytokine/chemokine responses resulting in acute lung injury (ALI), and acute respiratory distress syndrome (ARDS). Recent studies in experimentally infected animal strongly suggest a crucial role for virus-induced immunopathological events in causing fatal pneumonia after hCoV infections. Here we review the current understanding of how a dysregulated immune response may cause lung immunopathology leading to deleterious clinical manifestations after pathogenic hCoV infections.
fymfqvp3
fymfqvp3
2017-05-02
10.1007/s00281-017-0629-x
2
Initial success in the identification and management of the coronavirus disease 2019 (COVID-19) indicates human-to-human transmission in Wuhan, China
Coronavirus (CoV) has been one of the major pandemic threats to human health in the last two decades. The human coronavirus was first identified in 1960s. CoVs 229E, NL63, OC43, HKU1, SARS-CoV, and MERS-CoV have caused numerous disasters or human deaths worldwide. Recently, an outbreak of the previously unknown deadly CoV disease 2019 (COVID-19) caused by Severe Acute Respiratory Syndrome CoV 2 (SARS-CoV-2, early named 2019-nCoV) occurred in Wuhan, China, and it had caused 81238 cases of confirmed infection, including 3250 deaths until March 19, 2020. Its risks and pandemic potential have brought global consideration. We summarized epidemiology, virological characteristics, clinical symptoms, diagnostic methods, clinical treatments, and prevention methods for COVID-19 to present a reference for the future wave of probable CoV outbreaks.
fzd4o4xd
fzd4o4xd
2020-04-06
10.7150/ijbs.45018
3
Cryo-EM structure of the SARS coronavirus spike glycoprotein in complex with its host cell receptor ACE2
The trimeric SARS coronavirus (SARS-CoV) surface spike (S) glycoprotein consisting of three S1-S2 heterodimers binds the cellular receptor angiotensin-converting enzyme 2 (ACE2) and mediates fusion of the viral and cellular membranes through a pre- to postfusion conformation transition. Here, we report the structure of the SARS-CoV S glycoprotein in complex with its host cell receptor ACE2 revealed by cryo-electron microscopy (cryo-EM). The complex structure shows that only one receptor-binding domain of the trimeric S glycoprotein binds ACE2 and adopts a protruding “up” conformation. In addition, we studied the structures of the SARS-CoV S glycoprotein and its complexes with ACE2 in different in vitro conditions, which may mimic different conformational states of the S glycoprotein during virus entry. Disassociation of the S1-ACE2 complex from some of the prefusion spikes was observed and characterized. We also characterized the rosette-like structures of the clustered SARS-CoV S2 trimers in the postfusion state observed on electron micrographs. Structural comparisons suggested that the SARS-CoV S glycoprotein retains a prefusion architecture after trypsin cleavage into the S1 and S2 subunits and acidic pH treatment. However, binding to the receptor opens up the receptor-binding domain of S1, which could promote the release of the S1-ACE2 complex and S1 monomers from the prefusion spike and trigger the pre- to postfusion conformational transition.
g28eq99t
g28eq99t
2018-08-13
10.1371/journal.ppat.1007236
2
An overview of COVID-19
Pneumonia caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection emerged in Wuhan City, Hubei Province, China in December 2019. By Feb. 11, 2020, the World Health Organization (WHO) officially named the disease resulting from infection with SARS-CoV-2 as coronavirus disease 2019 (COVID-19). COVID-19 represents a spectrum of clinical manifestations that typically include fever, dry cough, and fatigue, often with pulmonary involvement. SARS-CoV-2 is highly contagious and most individuals within the population at large are susceptible to infection. Wild animal hosts and infected patients are currently the main sources of disease which is transmitted via respiratory droplets and direct contact. Since the outbreak, the Chinese government and scientific community have acted rapidly to identify the causative agent and promptly shared the viral gene sequence, and have carried out measures to contain the epidemic. Meanwhile, recent research has revealed critical aspects of SARS-CoV-2 biology and disease pathogenesis; other studies have focused on epidemiology, clinical features, diagnosis, management, as well as drug and vaccine development. This review aims to summarize the latest research findings and to provide expert consensus. We will also share ongoing efforts and experience in China, which may provide insight on how to contain the epidemic and improve our understanding of this emerging infectious disease, together with updated guidance for prevention, control, and critical management of this pandemic.
g42gfovg
g42gfovg
2020-05-08
10.1631/jzus.b2000083
3
Natural Products as Potential Leads Against Coronaviruses: Could They be Encouraging Structural Models Against SARS-CoV-2?
New coronavirus referred to SARS-CoV-2 has caused a worldwide pandemic (COVID-19) declared by WHO. Coronavirus disease 2019 (COVID-19) is an infectious disease with severe acute respiratory syndrome caused by coronavirus-2 (SARS-CoV-2). SARS-CoV-2 is akin to SARS-CoV, which was the causative agent of severe acute respiratory syndrome (SARS) in 2002 as well as to that of Middle East respiratory syndrome (MERS) in 2012. SARS-CoV-2 has been revealed to belong to Coronaviridiae family as a member of β-coronaviruses. It has a positive-sense single-stranded RNA with the largest RNA genome. Since its genomic sequence has a notable similarity to that of SARS-CoV, antiviral drugs used to treat SARS and MERS are now being also applied for COVID-19 treatment. In order to combat SARS-CoV-2, many drug and vaccine development studies at experimental and clinical levels are currently conducted worldwide. In this sense, medicinal plants and the pure natural molecules isolated from plants have been reported to exhibit significant inhibitory antiviral activity against SARS-CoV and other types of coronaviruses. In the present review, plant extracts and natural molecules with the mentioned activity are discussed in order to give inspiration to researchers to take these molecules into consideration against SARS-CoV-2.
g4bsu8jf
g4bsu8jf
2020-06-11
10.1007/s13659-020-00250-4
4
Binding of SARS-CoV-2 and angiotensin-converting enzyme 2: clinical implications
g4ff9x57
g4ff9x57
2020-04-17
10.1093/cvr/cvaa096
3
Nidovirus RNA polymerases: Complex enzymes handling exceptional RNA genomes
Abstract Coronaviruses and arteriviruses are distantly related human and animal pathogens that belong to the order Nidovirales. Nidoviruses are characterized by their polycistronic plus-stranded RNA genome, the production of subgenomic mRNAs and the conservation of a specific array of replicase domains, including key RNA-synthesizing enzymes. Coronaviruses (26–34 kilobases) have the largest known RNA genomes and their replication presumably requires a processive RNA-dependent RNA polymerase (RdRp) and enzymatic functions that suppress the consequences of the typically high error rate of viral RdRps. The arteriviruses have significantly smaller genomes and form an intriguing package with the coronaviruses to analyse viral RdRp evolution and function. The RdRp domain of nidoviruses resides in a cleavage product of the replicase polyprotein named non-structural protein (nsp) 12 in coronaviruses and nsp9 in arteriviruses. In all nidoviruses, the C-terminal RdRp domain is linked to a conserved N-terminal domain, which has been coined NiRAN (nidovirus RdRp-associated nucleotidyl transferase). Although no structural information is available, the functional characterization of the nidovirus RdRp and the larger enzyme complex of which it is part, has progressed significantly over the past decade. In coronaviruses several smaller, non-enzymatic nsps were characterized that direct RdRp function, while a 3′-to-5′ exoribonuclease activity in nsp14 was implicated in fidelity. In arteriviruses, the nsp1 subunit was found to maintain the balance between genome replication and subgenomic mRNA production. Understanding RdRp behaviour and interactions during RNA synthesis and subsequent processing will be key to rationalising the evolutionary success of nidoviruses and the development of antiviral strategies.
g4sg2nex
g4sg2nex
2017-04-15
10.1016/j.virusres.2017.01.023
0.5
Potentially highly potent drugs for 2019-nCoV
The World Health Organization (WHO) has declared the 2019 novel coronavirus (2019-nCoV) infection outbreak a global health emergency. Currently, there is no effective anti-2019-nCoV medication. The sequence identity of the 3CL proteases of 2019-nCoV and SARS is 96%, which provides a sound foundation for structural-based drug repositioning (SBDR). Based on a SARS 3CL protease X-ray crystal structure, we construct a 3D homology structure of 2019-nCoV 3CL protease. Based on this structure and existing experimental datasets for SARS 3CL protease inhibitors, we develop an SBDR model based on machine learning and mathematics to screen 1465 drugs in the DrugBank that have been approved by the U.S. Food and Drug Administration (FDA). We found that many FDA approved drugs are potentially highly potent to 2019-nCoV.
g5wpa2ee
g5wpa2ee
2020-02-13
10.1101/2020.02.05.936013
1.5
[Comment] Treatment strategies to fight the new coronavirus SARS-CoV-2: A challenge for a Rubik's Cube solver
SARS-coronavirus-2 (SARS-CoV-2), the etiologic agent of the new lung disease COVID-19 is closely related to SARS-CoV, and together with MERS-CoV are three new human coronaviruses that emerged in the last 20 years. The COVID-19 outbreak is a rapidly evolving situation with higher transmissibility and infectivity compared with SARS and MERS. Clinical presentations range from asymptomatic or mild symptoms to severe illness. The prevalent cause of mortality is pneumonia that progresses to ARDS. The ongoing pandemic has already resulted in more than 135,000 deaths and an unprecedented burden on national health systems worldwide. Pending the availability of a vaccine, there is a critical need to identify effective treatments and a number of clinical trials have been implemented worldwide. Trials are based on repurposed drugs that are already approved for other infections, have acceptable safety profiles or have performed well in animal studies against the other two deadly coronaviruses. Supportive care remains the mainstay of therapy at present, as it is still unclear how well these data can be extrapolated to SARS-CoV-2. Most of those emerging re-introduced drugs are administered to patients in the context of clinical trials. In this review, we summarize the strategies currently employed in the treatment of COVID-19.
g8bu2ene
g8bu2ene
2020-04-28
10.3892/etm.2020.8692
4
Care of patients with liver disease during the COVID-19 pandemic: EASL-ESCMID position paper
The coronavirus disease 2019 (COVID-19) pandemic poses an enormous challenge to healthcare systems in affected communities. Older patients and those with pre-existing medical conditions have been identified as populations at risk of a severe disease course. It remains unclear at this point to what extent chronic liver diseases should be considered as risk factors, due to a shortage of appropriate studies. However, patients with advanced liver disease and those after liver transplantation represent vulnerable patient cohorts with an increased risk of infection and/or a severe course of COVID-19. In addition, the current pandemic requires unusual allocation of healthcare resources which may negatively impact the care of patients with chronic liver disease that continue to require medical attention. Thus, the challenge hepatologists are facing is to promote telemedicine in the outpatient setting, prioritise outpatient contacts, avoid nosocomial dissemination of the virus to patients and healthcare providers, and at the same time maintain standard care for patients who require immediate medical attention.
g8saag2o
g8saag2o
2020-04-02
10.1016/j.jhepr.2020.100113
1.5
The pathogenicity of SARS-CoV-2 in hACE2 transgenic mice.
Severe acute respiratory syndrome CoV-2 (SARS-CoV-2) caused the corona virus disease 2019 (COVID-19) cases in China and has become a public health emergency of international concern1. Because angiotensin-converting enzyme 2 (ACE2) is the cell entry receptor of SARS-CoV5, we used transgenic mice bearing human ACE2 and infected with SARS-CoV-2 to study the pathogenicity of the virus. Weight loss and virus replication in lung were observed in hACE2 mice infected with SARS-CoV-2. The typical histopathology was interstitial pneumonia with infiltration of significant macrophages and lymphocytes into the alveolar interstitium, and accumulation of macrophages in alveolar cavities. Viral antigens were observed in the bronchial epithelial cells, macrophages and alveolar epithelia. The phenomenon was not found in wild-type mice with SARS-CoV-2 infection. Notably, we have confirmed the pathogenicity of SARS-CoV-2 in hACE2 mice. The mouse model with SARS-CoV-2 infection will be valuable for evaluating antiviral therapeutics and vaccines as well as understanding the pathogenesis of COVID-19.
gb03fb5t
gb03fb5t
2020-05-07
10.1038/s41586-020-2312-y
4.5
Isolation of potent SARS-CoV-2 neutralizing antibodies and protection from disease in a small animal model
Countermeasures to prevent and treat COVID-19 are a global health priority. We enrolled a cohort of SARS-CoV-2-recovered participants, developed neutralization assays to interrogate antibody responses, adapted our high-throughput antibody generation pipeline to rapidly screen over 1800 antibodies, and established an animal model to test protection. We isolated potent neutralizing antibodies (nAbs) to two epitopes on the receptor binding domain (RBD) and to distinct non-RBD epitopes on the spike (S) protein. We showed that passive transfer of a nAb provides protection against disease in high-dose SARS-CoV-2 challenge in Syrian hamsters, as revealed by maintained weight and low lung viral titers in treated animals. The study suggests a role for nAbs in prophylaxis, and potentially therapy, of COVID-19. The nAbs define protective epitopes to guide vaccine design.
gbffkame
gbffkame
2020
5
Infection and Rapid Transmission of SARS-CoV-2 in Ferrets
The outbreak of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged in China and rapidly spread worldwide. To prevent SARS-CoV-2 dissemination, understanding the in vivo characteristics of SARS-CoV-2 is a high priority. We report a ferret model of SARS-CoV-2 infection and transmission that recapitulates aspects of human disease. SARS-CoV-2-infected ferrets exhibit elevated body temperatures and virus replication. Although fatalities were not observed, SARS-CoV-2-infected ferrets shed virus in nasal washes, saliva, urine, and feces up to 8 days post-infection. At 2 days post-contact, SARS-CoV-2 was detected in all naive direct contact ferrets. Furthermore, a few naive indirect contact ferrets were positive for viral RNA, suggesting airborne transmission. Viral antigens were detected in nasal turbinate, trachea, lungs, and intestine with acute bronchiolitis present in infected lungs. Thus, ferrets represent an infection and transmission animal model of COVID-19 that may facilitate development of SARS-CoV-2 therapeutics and vaccines.
gbkgzvc8
gbkgzvc8
2020-04-06
10.1016/j.chom.2020.03.023
1
Barriers of hepatitis C virus interspecies transmission
Abstract Hepatitis C virus (HCV) is a major causative agent of severe liver disease including fibrosis, cirrhosis and liver cancer. Therapy has improved over the years, but continues to be associated with adverse side effects and variable success rates. Furthermore, a vaccine protecting against HCV infection remains elusive. Development of more effective intervention measures has been delayed by the lack of a suitable animal model. Naturally, HCV infects only humans and chimpanzees. The determinants of this limited host range are poorly understood in part due to difficulties of studying HCV in cell culture. Some progress has been made elucidating the barriers for the HCV lifecycle in non-permissive species which will help in the future to construct animal models for HCV infection, immunity and pathogenesis.
gd53s4dv
gd53s4dv
2013-01-05
10.1016/j.virol.2012.09.044
3.5
Molecular detection of SARS-CoV-2 in formalin-fixed, paraffin-embedded specimens
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the cause of human coronavirus disease 2019 (COVID-19), emerged in Wuhan, China, in December 2019. The virus rapidly spread globally, resulting in a public health crisis including almost 5 million cases and 323,256 deaths as of May 21, 2020. Here, we describe the identification and evaluation of commercially available reagents and assays for the molecular detection of SARS-CoV-2 in infected FFPE cell pellets. We identified a suitable rabbit polyclonal anti-SARS-CoV spike protein antibody and a mouse monoclonal anti-SARS-CoV nucleocapsid protein (NP) antibody for cross-detection of the respective SARS-CoV-2 proteins by IHC and immunofluorescence assay (IFA). Next, we established RNAscope in situ hybridization (ISH) to detect SARS-CoV-2 RNA. Furthermore, we established a multiplex FISH (mFISH) to detect positive-sense SARS-CoV-2 RNA and negative-sense SARS-CoV-2 RNA (a replicative intermediate indicating viral replication). Finally, we developed a dual staining assay using IHC and ISH to detect SARS-CoV-2 antigen and RNA in the same FFPE section. It is hoped that these reagents and assays will accelerate COVID-19 pathogenesis studies in humans and in COVID-19 animal models.
gdmhvs2j
gdmhvs2j
2020
3
The IMPDH inhibitor merimepodib suppresses SARS-CoV-2 replication in vitro
The ongoing COVID-19 pandemic continues to pose a major public health burden around the world. The novel coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has infected over one million people worldwide as of April, 2020, and has led to the deaths of nearly 300,000 people. No approved vaccines or treatments in the USA currently exist for COVID-19, so there is an urgent need to develop effective countermeasures. The IMPDH inhibitor merimepodib (MMPD) is an investigational antiviral drug that acts as a noncompetitive inhibitor of IMPDH. It has been demonstrated to suppress replication of a variety of emerging RNA viruses. We report here that MMPD suppresses SARS-CoV-2 replication in vitro. After overnight pretreatment of Vero cells with 10 μM of MMPD, viral titers were reduced by 4 logs of magnitude, while pretreatment for 4 hours resulted in a 3-log drop. The effect is dose-dependent, and concentrations as low as 3.3 μM significantly reduced viral titers when the cells were pretreated prior to infection. The results of this study provide evidence that MMPD may be a viable treatment option for COVID-19.
geb4esu5
geb4esu5
2020-04-09
10.1101/2020.04.07.028589
2.5
Truncated human angiotensin converting enzyme 2; a potential inhibitor of SARS-CoV-2 spike glycoprotein and potent COVID-19 therapeutic agent
The current pandemic of Covid-19 caused by SARS-CoV-2 is continued to spread globally and no potential drug or vaccine against it is available. Spike (S) glycoprotein is the structural protein of SARS-CoV-2 located on the envelope surface, involve in interaction with angiotensin converting enzyme 2 (ACE2), a cell surface receptor, followed by entry into the host cell. Thereby, blocking the S glycoprotein through potential inhibitor may interfere its interaction with ACE2 and impede its entry into the host cell. Here, we present a truncated version of human ACE2 (tACE2), comprising the N terminus region of the intact ACE2 from amino acid position 21-119, involved in binding with receptor binding domain (RBD) of SARS-CoV-2. We analyzed the in-silico potential of tACE2 to compete with intact ACE2 for binding with RBD. The protein-protein docking and molecular dynamic simulation showed that tACE2 has higher binding affinity for RBD and form more stabilized complex with RBD than the intact ACE2. Furthermore, prediction of tACE2 soluble expression in E. coli makes it a suitable candidate to be targeted for Covid-19 therapeutics. This is the first MD simulation based findings to provide a high affinity protein inhibitor for SARS-CoV-2 S glycoprotein, an important target for drug designing against this unprecedented challenge.Communicated by Ramaswamy H. Sarma.
gf4o3n3z
gf4o3n3z
2020
4.5
Rapid adaptation of SARS-CoV-2 in BALB/c mice: Novel mouse model for vaccine efficacy
Coronavirus disease 2019 (COVID-19) threatens global public health and economy. In order to develop safe and effective vaccines, suitable animal models must be established. Here we report the rapid adaption of SARS-CoV-2 in BALB/c mice, based on which a convenient, economical and effective animal model was developed. Specifically, we found that mouse-adapted SARS-CoV-2 at passage 6 (MACSp6) efficiently infected both aged and young wild-type BALB/c mice, resulting in moderate pneumonia as well as inflammatory responses. The elevated infectivity of MACSp6 in mice could be attributed to the substitution of a key residue (N501Y) in the receptorbinding domain (RBD). Using this novel animal model, we further evaluated the in vivo protective efficacy of an RBD-based SARS-CoV-2 subunit vaccine, which elicited highly potent neutralizing antibodies and conferred full protection against SARS-CoV-2 MACSp6 challenge. This novel mouse model is convenient and effective in evaluating the in vivo protective efficacy of SARS-CoV-2 vaccine. Summary This study describes a unique mouse model for SARS-CoV-2 infection and confirms protective efficacy of a SARS-CoV-2 RBD subunit vaccine.
gg0p6ct8
gg0p6ct8
2020-05-02
10.1101/2020.05.02.073411
3
Immunopathogenesis of coronavirus infections: implications for SARS
At the end of 2002, the first cases of severe acute respiratory syndrome (SARS) were reported, and in the following year, SARS resulted in considerable mortality and morbidity worldwide. SARS is caused by a novel species of coronavirus (SARS-CoV) and is the most severe coronavirus-mediated human disease that has been described so far. On the basis of similarities with other coronavirus infections, SARS might, in part, be immune mediated. As discussed in this Review, studies of animals that are infected with other coronaviruses indicate that excessive and sometimes dysregulated responses by macrophages and other pro-inflammatory cells might be particularly important in the pathogenesis of disease that is caused by infection with these viruses. It is hoped that lessons from such studies will help us to understand more about the pathogenesis of SARS in humans and to prevent or control outbreaks of SARS in the future.
ggmm8w2t
ggmm8w2t
2005
10.1038/nri1732
1
Does SARS-Cov-2 invade the brain? Translational lessons from animal models
The current coronavirus disease (COVID-19) outbreak, caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has raised the possibility of potential neurotropic properties of this virus. Indeed, neurological sequelae of SARS-CoV-2 infection have already been reported and highlight the relevance of considering the neurological impact of coronavirus (CoV) from a translational perspective. Animal models of SARS and Middle East respiratory syndrome, caused by structurally similar CoVs during the 2002 and 2012 epidemics, have provided valuable data on nervous system involvement by CoVs and the potential for central nervous system spread of SARS-CoV-2. One key finding that may unify these pathogens is that all require angiotensin-converting enzyme 2 as a cell entry receptor. The CoV spike glycoprotein, by which SARS-CoV-2 binds to cell membranes, binds angiotensin-converting enzyme 2 with a higher affinity compared with SARS-CoV. The expression of this receptor in neurons and endothelial cells hints that SARS-CoV-2 may have higher neuroinvasive potential compared with previous CoVs. However, it remains to be determined how such invasiveness might contribute to respiratory failure or cause direct neurological damage. Both direct and indirect mechanisms may be of relevance. Clinical heterogeneity potentially driven by differential host immune-mediated responses will require extensive investigation. Development of disease models to anticipate emerging neurological complications and to explore mechanisms of direct or immune-mediated pathogenicity in the short and medium term is therefore of great importance. In this brief review, we describe the current knowledge from models of previous CoV infections and discuss their potential relevance to COVID-19.
ggofvijc
ggofvijc
2020
3
Radiological findings from 81 patients with COVID-19 pneumonia in Wuhan, China: a descriptive study
Summary Background A cluster of patients with coronavirus disease 2019 (COVID-19) pneumonia caused by infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) were successively reported in Wuhan, China. We aimed to describe the CT findings across different timepoints throughout the disease course. Methods Patients with COVID-19 pneumonia (confirmed by next-generation sequencing or RT-PCR) who were admitted to one of two hospitals in Wuhan and who underwent serial chest CT scans were retrospectively enrolled. Patients were grouped on the basis of the interval between symptom onset and the first CT scan: group 1 (subclinical patients; scans done before symptom onset), group 2 (scans done ≤1 week after symptom onset), group 3 (>1 week to 2 weeks), and group 4 (>2 weeks to 3 weeks). Imaging features and their distribution were analysed and compared across the four groups. Findings 81 patients admitted to hospital between Dec 20, 2019, and Jan 23, 2020, were retrospectively enrolled. The cohort included 42 (52%) men and 39 (48%) women, and the mean age was 49·5 years (SD 11·0). The mean number of involved lung segments was 10·5 (SD 6·4) overall, 2·8 (3·3) in group 1, 11·1 (5·4) in group 2, 13·0 (5·7) in group 3, and 12·1 (5·9) in group 4. The predominant pattern of abnormality observed was bilateral (64 [79%] patients), peripheral (44 [54%]), ill-defined (66 [81%]), and ground-glass opacification (53 [65%]), mainly involving the right lower lobes (225 [27%] of 849 affected segments). In group 1 (n=15), the predominant pattern was unilateral (nine [60%]) and multifocal (eight [53%]) ground-glass opacities (14 [93%]). Lesions quickly evolved to bilateral (19 [90%]), diffuse (11 [52%]) ground-glass opacity predominance (17 [81%]) in group 2 (n=21). Thereafter, the prevalence of ground-glass opacities continued to decrease (17 [57%] of 30 patients in group 3, and five [33%] of 15 in group 4), and consolidation and mixed patterns became more frequent (12 [40%] in group 3, eight [53%] in group 4). Interpretation COVID-19 pneumonia manifests with chest CT imaging abnormalities, even in asymptomatic patients, with rapid evolution from focal unilateral to diffuse bilateral ground-glass opacities that progressed to or co-existed with consolidations within 1–3 weeks. Combining assessment of imaging features with clinical and laboratory findings could facilitate early diagnosis of COVID-19 pneumonia. Funding None.
ghi0ekm5
ghi0ekm5
2020-02-24
10.1016/s1473-3099(20)30086-4
2.5
List of compounds chromatographed
ghktrnsu
ghktrnsu
1987-07-17
10.1016/0378-4347(87)80017-8
1.5
Remdesivir potently inhibits SARS-CoV-2 in human lung cells and chimeric SARS-CoV expressing the SARS-CoV-2 RNA polymerase in mice
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged in 2019 as the causative agent of the novel pandemic viral disease COVID-19. With no approved therapies, this pandemic illustrates the urgent need for safe, broad-spectrum antiviral countermeasures against SARS-CoV-2 and future emerging CoVs. We report that remdesivir (RDV), a monophosphoramidate prodrug of an adenosine analog, potently inhibits SARS-CoV-2 replication in human lung cells and primary human airway epithelial cultures (EC50 = 0.01 μM). Weaker activity was observed in Vero E6 cells (EC50 = 1.65 μM) due to their low capacity to metabolize RDV. To rapidly evaluate in vivo efficacy, we engineered a chimeric SARS-CoV encoding the viral target of RDV, the RNA-dependent RNA polymerase, of SARS-CoV-2. In mice infected with chimeric virus, therapeutic RDV administration diminished lung viral load and improved pulmonary function as compared to vehicle treated animals. These data provide evidence that RDV is potently active against SARS-CoV-2 in vitro and in vivo, supporting its further clinical testing for treatment of COVID-19.
ghrlj6b2
ghrlj6b2
2020-04-27
10.1101/2020.04.27.064279
2
Coronaviruses and SARS-COV-2
Coronaviruses (CoVs) cause a broad spectrum of diseases in domestic and wild animals, poultry, and rodents, ranging from mild to severe enteric, respiratory, and systemic disease, and also cause the common cold or pneumonia in humans. Seven coronavirus species are known to cause human infection, 4 of which, HCoV 229E, HCoV NL63, HCoV HKU1 and HCoV OC43, typically cause cold symptoms in immunocompetent individuals. The others namely SARS-CoV (severe acute respiratory syndrome coronavirus), MERS-CoV (Middle East respiratory syndrome coronavirus) were zoonotic in origin and cause severe respiratory illness and fatalities. On 31 December 2019, the existence of patients with pneumonia of an unknown aetiology was reported to WHO by the national authorities in China. This virus was officially identified by the coronavirus study group as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and the present outbreak of a coronavirus-associated acute respiratory disease was labelled coronavirus disease 19 (COVID-19). COVID-19’s first cases were seen in Turkey on March 10, 2020 and was number 47,029 cases and 1006 deaths after 1 month. Infections with SARS-CoV-2 are now widespread, and as of 10 April 2020, 1,727,602 cases have been confirmed in more than 210 countries, with 105,728 deaths.
gjdlp10q
gjdlp10q
2020-04-21
10.3906/sag-2004-127
4
Analysis of psychological state and clinical psychological intervention model of patients with COVID-19
Background:Patients with the 2019 coronavirus disease (COVID-19) have different degrees of psychological pain, such as anxiety and depression, which may related to their prognosis. Psychological intervention can be conducted in different ways to improve psychological pain and improve the treatment effect. Objective:The present study aimed to investigate and analyze the psychological status of patients with COVID-19 during the course of illness, and to evaluate the effect and influencing factors of psychological crisis intervention, so as to explore the effective mode of clinical psychological intervention in acute patients under isolation environment. Methods:A total of 143 persons participated in the study, including 26 patients diagnosed with COVID-19 in the isolation ward (COVID-19 group), 87 patients with general pneumonia in the observation ward (General Pneumonia group) and 30 healthy volunteers (Normal group). All the patients in the ward received comprehensive psychological intervention, including telephone psychological counseling (active and passive), self-adjustment of written materials and one-to-one psychological crisis intervention. Hamilton depression scale (HAMD) and Hamilton anxiety scale (HAMA) were used to evaluate the mental health status of all patients on the day of admission and 1 week after treatment. Results:The scores of HAMA and HAMD of all patients (including isolation ward and observation ward) were significantly higher than the healthy volunteers at the time of admission. The total score of HAMA and HAMD in CVOID-19 group were both higher than that General Pneumonia group. After 1 week`s hospitalization with comprehensive psychological intervention, the scores of HAMA and HAMD in CVOID-19 group were significantly decreased. Conclusion:Patients those who diagnosed with COVID-19 in the isolation ward and/or general pneumonia in observation ward have different degrees of anxiety, depression and sleep problems. While receiving antiviral treatment, patients also need psychological intervention. Comprehensive psychological intervention model has been proved to be effective.
gjfd1jhb
gjfd1jhb
2020-03-24
10.1101/2020.03.22.20040899
1.5
Identification of Antiviral Drug Candidates against SARS-CoV-2 from FDA-Approved Drugs
Drug repositioning is the only feasible option to immediately address the COVID-19 global challenge. We screened a panel of 48 FDA-approved drugs against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) which were preselected by an assay of SARS-CoV. We identified 24 potential antiviral drug candidates against SARS-CoV-2 infection. Some drug candidates showed very low 50% inhibitory concentrations (IC(50)s), and in particular, two FDA-approved drugs—niclosamide and ciclesonide—were notable in some respects.
gka6f34c
gka6f34c
2020-06-23
10.1128/aac.00819-20
3
A review on Promising vaccine development progress for COVID-19 disease
Abstract The emergence of the strain of coronavirus SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) that causes corona virus disease 2019 (COVID-19) and its impact on in the world have made imperative progress to develop an effective and safe vaccine. Despite several measures undertaken, the spread of this virus is ongoing. So far, more than 1,560,000 cases and 1000,000 deaths occurred in the world. Efforts have been made to develop vaccines against human coronavirus (CoV) infections such as MERS and SARS. However, currently, no approved vaccine exists for these coronavirus strains. Such Previous research efforts to develop a coronavirus vaccine in the years following the 2003 pandemic have opened the door for the scientist to design a new vaccine for the COVID-19. Both SARS-CoV and SARS-CoV-2 has a high degree of genetic similarity and bind to the same host cell ACE2 receptor. By using different vaccine development platforms including whole virus vaccines, recombinant protein subunit vaccines, and nucleic acid vaccines several candidates displayed efficacy in vitro studies but few progressed to clinical trials. This review provides a brief introduction of the general features of SARS-CoV-2 and discusses the current progress of ongoing advances in designing vaccine development efforts to counter COVID-19.
gkcan78j
gkcan78j
2020-06-13
10.1016/j.vacun.2020.05.002
4
Early dynamics of transmission and control of COVID-19: a mathematical modelling study
Background: An outbreak of the novel coronavirus SARS-CoV-2 has led to 46,997 confirmed cases as of 13th February 2020. Understanding the early transmission dynamics of the infection and evaluating the effectiveness of control measures is crucial for assessing the potential for sustained transmission to occur in new areas. Methods: We combined a stochastic transmission model with data on cases of novel coronavirus disease (COVID-19) in Wuhan and international cases that originated in Wuhan to estimate how transmission had varied over time during January and February 2020. Based on these estimates, we then calculated the probability that newly introduced cases might generate outbreaks in other areas. Findings: We estimated that the median daily reproduction number, Rt , declined from 2.35 (95% CI: 1.15-4.77) one week before travel restrictions were introduced on 23rd January to 1.05 (95% CI: 0.413-2.39) one week after. Based on our estimates of Rt,we calculated that in locations with similar transmission potential as Wuhan in early January, once there are at least four independently introduced cases, there is a more than 50% chance the infection will establish within that population. Interpretation: Our results show that COVID-19 transmission likely declined in Wuhan during late January 2020, coinciding with the introduction of control measures. As more cases arrive in international locations with similar transmission potential to Wuhan pre-control, it is likely many chains of transmission will fail to establish initially, but may still cause new outbreaks eventually.
gmi1ewc2
gmi1ewc2
2020-02-02
10.1101/2020.01.31.20019901
1
COVID-19 in Iran: A Deeper Look Into The Future
The novel corona-virus (COVID-19) has led to a pandemic, affecting almost all countries and regions in a few weeks, and therefore a global plan is needed to overcome this battle. Iran has been among the first few countries that has been affected severely, after China, which forced the government to put some restriction and enforce social distancing in majority of the country. In less than 2 months, Iran has more than 80,000 confirmed cases, and more than 5,000 death. Based on the official statistics from Iran's government, the number of daily cases has started to go down recently, but many people believe if the lockdown is lifted without proper social distancing enforcement, there is a possibility for a second wave of COVID-19 cases. In this work, we analyze at the data for the number cases in Iran in the past few weeks, and train a predictive model to estimate the possible future trends for the number of cases in Iran, depending on the government policy in the coming weeks and months. Our analysis may help political leaders and health officials to take proper action toward handling COVID-19 in the coming months.
gns5omyb
gns5omyb
2020-04-27
10.1101/2020.04.24.20078477
2.5
Infection of dogs with SARS-CoV-2.
SARS-CoV-2 emerged in Wuhan in December 2019 and caused the pandemic respiratory disease, COVID-191,2. In 2003, the closely related SARS-CoV had been detected in domestic cats and a dog3. However, little is known about the susceptibility of domestic pet mammals to SARS-CoV-2. Two out of fifteen dogs from households with confirmed human cases of COVID-19 in Hong Kong SAR were found to be infected using quantitative RT-PCR, serology, sequencing the viral genome, and in one dog, virus isolation. SARS-CoV-2 RNA was detected in a 17-year-old neutered male Pomeranian from five nasal swabs collected over a 13-day period. A 2.5-year-old male German Shepherd dog had SARS CoV-2 RNA on two occasions and virus was isolated from nasal and oral swabs. Both dogs had antibody responses detected using plaque reduction neutralization assays. Viral genetic sequences of viruses from the two dogs were identical to the virus detected in the respective human cases. The animals remained asymptomatic during quarantine. The evidence suggests that these are instances of human-to-animal transmission of SARS-CoV-2. It is unclear whether infected dogs can transmit the virus to other animals or back to humans.
go0tueah
go0tueah
2020-05-14
10.1038/s41586-020-2334-5
3
A Note on COVID-19 Diagnosis Number Prediction Model in China
Importance: To predict the diagnosed COVID-19 patients and the trend of the epidemic in China. It may give the public some scientific information to ease the fear of the epidemic. Objective: In December 2019, pneumonia infected with the novel coronavirus burst in Wuhan, China. We aimed to use a mathematical model to predict number of diagnosed patients in future to ease anxiety on the emergent situation. Design: According to all diagnosis number from WHO website and combining with the transmission mode of infectious diseases, the mathematical model was fitted to predict future trend of outbreak. Setting: Our model was based on the epidemic situation in China, which could provide referential significance for disease prediction in other countries, and provide clues for prevention and intervention of relevant health authorities. Participants: In this retrospective, all diagnosis number from Jan 21 to Feb 10, 2020 reported from China was included and downloaded from WHO website. Main Outcome(s) and Measure(s): We develop a simple but accurate formula to predict the next day diagnosis number:N_i/N_(i-1) =[(N_(i-1)/N_(i-2) )]^α，where Ni is the total diagnosed patient till the ith day, and α was estimated as 0.904 at Feb 10. Results: Based on this model, it is predicted that the rate of disease infection will decrease exponentially. The total number of infected people is limited; thus, the disease will have limited impact. However, new diagnosis will last to March. Conclusions and Relevance: Through the establishment of our model, we can better predict the trend of the epidemic in China.
goqgv2cc
goqgv2cc
2020-02-23
10.1101/2020.02.19.20025262
1
Pharmacokinetic bases of the hydroxychloroquine response in COVID-19: implications for therapy and prevention
Chloroquine/hydroxychloroquine has recently been the subject of intense debate in regard to its potential antiviral activity against SARS-Cov-2, the etiological agent of COVID-19. Some report possible curative effects, others do not. In order to shed some light on this rather controversial topic, we used mathematical modelling to simulate possible scenarios of response to hydroxychloroquine in COVID-19 patients. Our computer-aided simulations show that hydroxychloroquine may have an impact on the amplitude of the viral load peak but that viral clearance is not significantly accelerated if the drug is not administered early enough (i.e. when viral loads range from 1 to 1,000 copies/mL). Although some authors had used the trough plasma concentrations or the theoretical drug distribution in the lung to model the effect of chloroquine/hydroxychloroquine on COVID-19, the theoretical drug response based on the trough whole blood concentrations of the drug agreed well with the results of the clinical trials so far reported. Moreover, the effects of chloroquine/hydroxychloroquine could be fully explained when taking into account also the capacity of this drug to raise cell-mediated responses against the productively SARS-Cov-2-infected cells. On the whole, the present study suggests that chloroquine/hydroxychloroquine has a narrow therapeutic window, which overlaps with the highest tolerated doses. These considerations may have implications for development of anti-COVID-19 combination therapies and prevention strategies.
gpofwyux
gpofwyux
2020-04-28
10.1101/2020.04.23.20076471
2
SARS-CoV-2 and SARS-CoV differ in their cell tropism and drug sensitivity profiles
SARS-CoV-2 is a novel coronavirus currently causing a pandemic. We show that the majority of amino acid positions, which differ between SARS-CoV-2 and the closely related SARS-CoV, are differentially conserved suggesting differences in biological behaviour. In agreement, novel cell culture models revealed differences between the tropism of SARS-CoV-2 and SARS-CoV. Moreover, cellular ACE2 (SARS-CoV-2 receptor) and TMPRSS2 (enables virus entry via S protein cleavage) levels did not reliably indicate cell susceptibility to SARS-CoV-2. SARS-CoV-2 and SARS-CoV further differed in their drug sensitivity profiles. Thus, only drug testing using SARS-CoV-2 reliably identifies therapy candidates. Therapeutic concentrations of the approved protease inhibitor aprotinin displayed anti-SARS-CoV-2 activity. The efficacy of aprotinin and of remdesivir (currently under clinical investigation against SARS-CoV-2) were further enhanced by therapeutic concentrations of the proton pump inhibitor omeprazole (aprotinin 2.7-fold, remdesivir 10-fold). Hence, our study has also identified anti-SARS-CoV-2 therapy candidates that can be readily tested in patients.
gpr86lxe
gpr86lxe
2020-04-05
10.1101/2020.04.03.024257
1
Effects of Toll-like receptor stimulation on eosinophilic infiltration in lungs of BALB/c mice immunized with UV-inactivated severe acute respiratory syndrome-related coronavirus vaccine.
UNLABELLED Severe acute respiratory syndrome-related coronavirus (SARS-CoV) is an emerging pathogen that causes severe respiratory illness. Whole UV-inactivated SARS-CoV (UV-V), bearing multiple epitopes and proteins, is a candidate vaccine against this virus. However, whole inactivated SARS vaccine that includes nucleocapsid protein is reported to induce eosinophilic infiltration in mouse lungs after challenge with live SARS-CoV. In this study, an ability of Toll-like receptor (TLR) agonists to reduce the side effects of UV-V vaccination in a 6-month-old adult BALB/c mouse model was investigated, using the mouse-passaged Frankfurt 1 isolate of SARS-CoV. Immunization of adult mice with UV-V, with or without alum, resulted in partial protection from lethal doses of SARS-CoV challenge, but extensive eosinophil infiltration in the lungs was observed. In contrast, TLR agonists added to UV-V vaccine, including lipopolysaccharide, poly(U), and poly(I·C) (UV-V+TLR), strikingly reduced excess eosinophilic infiltration in the lungs and induced lower levels of interleukin-4 and -13 and eotaxin in the lungs than UV-V-immunization alone. Additionally, microarray analysis showed that genes associated with chemotaxis, eosinophil migration, eosinophilia, and cell movement and the polarization of Th2 cells were upregulated in UV-V-immunized but not in UV-V+TLR-immunized mice. In particular, CD11b(+) cells in the lungs of UV-V-immunized mice showed the upregulation of genes associated with the induction of eosinophils after challenge. These findings suggest that vaccine-induced eosinophil immunopathology in the lungs upon SARS-CoV infection could be avoided by the TLR agonist adjuvants. IMPORTANCE Inactivated whole severe acute respiratory syndrome-related coronavirus (SARS-CoV) vaccines induce neutralizing antibodies in mouse models; however, they also cause increased eosinophilic immunopathology in the lungs upon SARS-CoV challenge. In this study, the ability of adjuvant Toll-like receptor (TLR) agonists to reduce the side effects of UV-inactivated SARS-CoV vaccination in a BALB/c mouse model was tested, using the mouse-passaged Frankfurt 1 isolate of SARS-CoV. We found that TLR stimulation reduced the high level of eosinophilic infiltration that occurred in the lungs of mice immunized with UV-inactivated SARS-CoV. Microarray analysis revealed that genes associated with chemotaxis, eosinophil migration, eosinophilia, and cell movement and the polarization of Th2 cells were upregulated in UV-inactivated SARS-CoV-immunized mice. This study may be helpful for elucidating the pathogenesis underlying eosinophilic infiltration resulting from immunization with inactivated vaccine.
gq9age1b
gq9age1b
2014
10.1128/jvi.00983-14
4
Perspectives for the use of therapeutic Botulinum toxin as a multifaceted candidate drug to attenuate COVID-19
Abstract The recent outbreak of coronavirus disease (COVID-19) resulting from a distinctive severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) continues to evolve in many countries and pose life-threatening clinical issues to global public health. While the lungs are the primary target for the SARS-CoV-2-mediated pathological consequence, SARS-CoV-2 appear to invade the brain and cause neurological deficits. In the later stage, COVID-19 can progress to pneumonia, acute respiratory failure, neurological deficits and multi-organ dysfunctions leading to death. Though a significant portion of SARS-CoV-2 infected individuals has been recovering from pathological symptoms, the impact of the COVID-19 on the structural and functional properties of the lungs, heart, brain and other organs at the post-recovery state remains unknown. Presently, there is an urgent need for a remedial measure to combat this devastating COVID-19. Botulinum toxins (BoNTs) are potent neurotoxins that can induce paralysis of muscle and acute respiratory arrest in human. However, a mild dose of the purified form of BoNT has been known to attenuate chronic cough, dyspnoea, pneumonia, acute respiratory failure, abnormal circulation, cardiac defects and various neurological deficits that have been recognised as the prominent clinical symptoms of COVID-19. Considering the fact, this review article provides 1) an overview on the SARS-CoV-2 mediated pathological impact on the lungs, heart and brain, 2) signifies the therapeutic uses of BoNTs against pulmonary failure, cardiac arrest and neurological deficits, and 3) emphasize the rationality for the possible use of BoNT to prevent SARS-CoV-2 infection and manage COVID-19.
gs3r6en8
gs3r6en8
2020-04-29
10.1016/j.medidd.2020.100042
2.5
Emergence of Novel Coronavirus 2019-nCoV: Need for Rapid Vaccine and Biologics Development
Novel Coronavirus (2019-nCoV) is an emerging pathogen that was first identified in Wuhan, China in late December 2019. This virus is responsible for the ongoing outbreak that causes severe respiratory illness and pneumonia-like infection in humans. Due to the increasing number of cases in China and outside China, the WHO declared coronavirus as a global health emergency. Nearly 35,000 cases were reported and at least 24 other countries or territories have reported coronavirus cases as early on as February. Inter-human transmission was reported in a few countries, including the United States. Neither an effective anti-viral nor a vaccine is currently available to treat this infection. As the virus is a newly emerging pathogen, many questions remain unanswered regarding the virus’s reservoirs, pathogenesis, transmissibility, and much more is unknown. The collaborative efforts of researchers are needed to fill the knowledge gaps about this new virus, to develop the proper diagnostic tools, and effective treatment to combat this infection. Recent advancements in plant biotechnology proved that plants have the ability to produce vaccines or biopharmaceuticals rapidly in a short time. In this review, the outbreak of 2019-nCoV in China, the need for rapid vaccine development, and the potential of a plant system for biopharmaceutical development are discussed.
gu2mt6zp
gu2mt6zp
2020-02-22
10.3390/pathogens9020148
1.5
Strategies to trace back the origin of COVID-19
gv1k7u7j
gv1k7u7j
2020-04-08
10.1016/j.jinf.2020.03.032
4
Clinical and microbiologic efficacy of the piperazine-based drug lead MMV665917 in the dairy calf cryptosporidiosis model
Cryptosporidiosis causes life-threatening diarrhea in infants, but the best available treatment is only modestly efficacious. Rodents infected with relevant Cryptosporidium species do not develop diarrhea, which complicates drug development. Cryptosporidium parvum infection of dairy calves, however, causes an illness like that seen in infants. Here, the clinical and microbiologic anti-Cryptosporidium efficacy of the piperazine-based compound MMV665917 was demonstrated in neonatal calves. Oral administration of MMV665917 (22 mg/kg once daily) was begun two days after the onset of severe diarrhea and continued for seven days. Treatment resulted in prompt resolution of diarrhea, and reduced total fecal oocyst shedding by ~94%. MMV665917 was useful for treatment, rather than just prophylaxis, since it was safe and effective when administered well after the onset of diarrhea. Furthermore, even though all animals received intensive supportive care, there was a strong trend towards improved secondary health outcomes, including general health, appetite, and dehydration measures amongst treated animals. These data establish MMV665917 as an outstanding lead compound for Cryptosporidium drug development.
gvfbyeyt
gvfbyeyt
2018-01-08
10.1371/journal.pntd.0006183
2.5
The nucleoside analog GS-441524 strongly inhibits feline infectious peritonitis (FIP) virus in tissue culture and experimental cat infection studies
Abstract Feline infectious peritonitis (FIP) is a common and highly lethal coronavirus disease of domestic cats. Recent studies of diseases caused by several RNA viruses in people and other species indicate that antiviral therapy may be effective against FIP in cats. The small molecule nucleoside analog GS-441524 is a molecular precursor to a pharmacologically active nucleoside triphosphate molecule. These analogs act as an alternative substrate and RNA-chain terminator of viral RNA dependent RNA polymerase. We determined that GS-441524 was non-toxic in feline cells at concentrations as high as 100 uM and effectively inhibited FIPV replication in cultured CRFK cells and in naturally infected feline peritoneal macrophages at concentrations as low as 1 uM. We determined the pharmacokinetics of GS-441524 in cats in vivo and established a dosage that would sustain effective blood levels for 24 h. In an experimental FIPV infection of cats, GS-441524 treatment caused a rapid reversal of disease signs and return to normality with as little as two weeks of treatment in 10/10 cats and with no apparent toxicity.
gw1pr7fw
gw1pr7fw
2018-06-30
10.1016/j.vetmic.2018.04.026
5
Docking study of Chloroquine and Hydroxychloroquine interaction with SARS-CoV-2 spike glycoprotein-An in silico insight into the comparative efficacy of repurposing antiviral drugs.
Recent outbreak of novel Coronavirus disease (Covid-19) pandemic around the world is associated with severe acute respiratory syndrome. The death toll associated with the pandemic is increasing day by day. SARS-CoV-2 is an enveloped virus and there are ample evidences that its Spike protein (S-protein) is mainly associated with pathogenesis as it is surface-exposed and mediates entry into host cells by binding to angiotensin-converting enzyme-2 (ACE-2) receptor. Therefore, it is the main target of neutralizing antibodies upon infection and there is always a quest to inhibit the S-protein which in turn may help in controlling diseases caused by SARS-CoV-2 in humans. The role of Chloroquine and Hydroxychloroquine as potential treatments for Covid-19 is still under debate globally because of some side effects associated with it. This study involves the In silico interactions of Chloroquine and Hydroxychloroquine with the S-protein of SARS-CoV-2. With the help of various computational methods, we have re-explored the potential role of both of these antiviral drugs for the treatment of Covid-19 patients by comparing the efficacy of both of the drugs to bind to S-protein at its host receptor region. In our research Hydroxychloroquine exhibited potential inhibitory effectsof S-protein with binding energy -7.28 kcal/mol than Chloroquine (-6.30 kcal/mol) at SARS-CoV-2 receptor recognition of susceptible cells. The outcomes of this research strongly appeal for in vivo trials of Hydroxychloroquine for the patients infected with Covid-19. Furthermore, the recommended doses of Hydroxychloroquine may reduce the chances of catching Covid-19 to the healthcare workers and staff who are in contact with or delivering direct care to coronavirus patients as long as they have not been diagnosed with Covid-19. We further hypothesize that the comparative S-protein-drug docking interactions may help to understand the comparative efficacy of other candidate repurposing drugs until discovery of a proper vaccine.
gwm36n75
gwm36n75
2020-05-29
10.1080/07391102.2020.1775703
4
Griffithsin, a Highly Potent Broad-Spectrum Antiviral Lectin from Red Algae: From Discovery to Clinical Application
Virus entry into a susceptible host cell is the first step in the formation of all viral diseases. Controlling viral infections by disrupting viral entry is advantageous for antibody-mediated neutralization by the host’s immune system and as a preventive and therapeutic antiviral strategy. Recently, several plant-derived carbohydrate-binding proteins (lectins) have emerged as a new class of antiviral biologics by taking advantage of a unique glycosylation pattern only found on the surface of viruses. In particular, a red algae-derived griffithsin (GRFT) protein has demonstrated superior in vitro and in vivo antiviral activity with minimum host toxicity against a variety of clinically relevant, enveloped viruses. This review examines the structural characteristics of GRFT, focusing on its carbohydrate-binding capability. Its in vitro antiviral profiles against human immunodeficiency virus (HIV) are also discussed followed by a description of the results from a combination study using anti-HIV drugs. The results of several studies regarding its novel antiviral mechanism of action are provided in conjunction with an explanation of viral resistance profiles to GRFT. In addition, its in vitro and in vivo host toxicity profiles are summarized with its pharmacokinetic behavior using in vivo efficacy study results. Also, a large-scale production and formulation strategy, as well as a drug delivery strategy, for GRFT as a new class of broad-spectrum microbicides is discussed. Finally, results from two ongoing clinical studies examining GRFT’s effects on viruses are presented.
gxbrgy6g
gxbrgy6g
2019-10-06
10.3390/md17100567
3.5
In silico screening of Chinese herbal medicines with the potential to directly inhibit 2019 novel coronavirus
Abstract Objective In this study we execute a rational screen to identify Chinese medical herbs that are commonly used in treating viral respiratory infections and also contain compounds that might directly inhibit 2019 novel coronavirus (2019-nCoV), an ongoing novel coronavirus that causes pneumonia. Methods There were two main steps in the screening process. In the first step we conducted a literature search for natural compounds that had been biologically confirmed as against sever acute respiratory syndrome coronavirus or Middle East respiratory syndrome coronavirus. Resulting compounds were cross-checked for listing in the Traditional Chinese Medicine Systems Pharmacology Database. Compounds meeting both requirements were subjected to absorption, distribution, metabolism and excretion (ADME) evaluation to verify that oral administration would be effective. Next, a docking analysis was used to test whether the compound had the potential for direct 2019-nCoV protein interaction. In the second step we searched Chinese herbal databases to identify plants containing the selected compounds. Plants containing 2 or more of the compounds identified in our screen were then checked against the catalogue for classic herbal usage. Finally, network pharmacology analysis was used to predict the general in vivo effects of each selected herb. Results Of the natural compounds screened, 13 that exist in traditional Chinese medicines were also found to have potential anti-2019-nCoV activity. Further, 125 Chinese herbs were found to contain 2 or more of these 13 compounds. Of these 125 herbs, 26 are classically catalogued as treating viral respiratory infections. Network pharmacology analysis predicted that the general in vivo roles of these 26 herbal plants were related to regulating viral infection, immune/inflammation reactions and hypoxia response. Conclusion Chinese herbal treatments classically used for treating viral respiratory infection might contain direct anti-2019-nCoV compounds.
gy35gsl2
gy35gsl2
2020-03-31
10.1016/j.joim.2020.02.005
2
In silico prediction of potential inhibitors for the Main protease of SARS-CoV-2 using molecular docking and dynamics simulation based drug-repurposing
BACKGROUND: The rapidly enlarging COVID-19 pandemic caused by the novel SARS-corona virus-2 is a global public health emergency of an unprecedented level. Unfortunately no treatment therapy or vaccine is yet available to counter the SARS-CoV-2 infection, which substantiates the need to expand research efforts in this direction. The indispensable function of the main protease in virus replication makes this enzyme a promising target for inhibitors screening and drug discovery to treat novel coronavirus infection. The recently concluded &#945;-ketoamide ligand-bound X-ray crystal structure of SARS-CoV-2 Mpro (PDB ID: 6Y2F) from Zhang et al. has revealed the potential inhibitor binding mechanism and the molecular determinants responsible for substrate binding. METHODS: For the study, we have targeted the SARS-CoV-2 Mpro for the screening of FDA approved antiviral drugs and carried out molecular docking based virtual screening. Further molecular dynamic simulation studies of the top three selected drugs carried out to investigated for their binding affinity and stability in the SARS-CoV-2 Mpro active site. The phylogenetic analysis was also performed to know the relatedness between the SARS-CoV-2 genomes isolated from different countries. RESULTS: The phylogenetic analysis of the SARS-CoV-2 genome reveals that the virus is closely related to the Bat-SL-CoV and does not exhibit any divergence at the genomic level. Molecular docking studies revealed that among the 77 drugs, screened top ten drugs shows good binding affinities, whereas the top three drugs: Lopinavir-Ritonavir, Tipranavir, and Raltegravir were undergone for molecular dynamics simulation studies for their conformational stability in the active site of the SARS-CoV-2 Mpro protein. CONCLUSIONS: In the present study among the library of FDA approved antiviral drugs, the top three inhibitors Lopinavir-Ritonavir, Tipranavir, and Raltegravir show the best molecular interaction with the main protease of SARS-CoV-2. However, the in-vitro efficacy of the drug molecules screened in this study further needs to be corroborated by carrying out a biochemical and structural investigation.
gykudnxf
gykudnxf
2020
5
How Change of Public Transportation Usage Reveals Fear of the SARS Virus in a City
The outbreaks of the severe acute respiratory syndrome (SARS) epidemic in 2003 resulted in unprecedented impacts on people's daily life. One of the most significant impacts to people is the fear of contacting the SARS virus while engaging daily routine activity. Here we use data from daily underground ridership in Taipei City and daily reported new SARS cases in Taiwan to model the dynamics of the public fear of the SARS virus during the wax and wane of the SARS period. We found that for each reported new SARS case there is an immediate loss of about 1200 underground ridership (the fresh fear). These daily loss rates dissipate to the following days with an e-folding time of about 28 days, reflecting the public perception on the risk of contacting SARS virus when traveling with the underground system (the residual fear). About 50% of daily ridership was lost during the peak of the 2003 SARS period, compared with the loss of 80% daily ridership during the closure of the underground system after Typhoon Nari, the loss of 50–70% ridership due to the closure of the governmental offices and schools during typhoon periods, and the loss of 60% daily ridership during Chinese New Year holidays.
gymjr9i1
gymjr9i1
2014-03-19
10.1371/journal.pone.0089405
1
Targeting the SARS-CoV-2 spike glycoprotein prefusion conformation: virtual screening and molecular dynamics simulations applied to the identification of potential fusion inhibitors
The emergence of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has led to a renewed interest in studying the role of the spike S glycoprotein in regulating coronavirus infections in the natural host. Taking advantage of the cryo-electron microscopy structure of SARS-CoV-2 S trimer in the prefusion conformation, we performed a virtual screening simulation with the aim to identify novel molecules that could be used as fusion inhibitors. The spike glycoprotein structure has been completed using modeling techniques and its inner cavity, needful for the postfusion transition of the trimer, has been scanned for the identification of strongly interacting available drugs. Finally, the stability of the protein-drug top complexes has been tested using classical molecular dynamics simulations. The free energy of interaction of the molecules to the spike protein has been evaluated through the MM/GBSA method and per-residue decomposition analysis. Results have been critically discussed considering previous scientific knowledge concerning the selected compounds and sequence alignments have been carried out to evaluate the spike glycoprotein similarity among the betacoronavirus family members. Finally, a cocktail of drugs that may be used as SARS-CoV-2 fusion inhibitors has been suggested.
gyxwwcmg
gyxwwcmg
2020-06-18
10.1016/j.virusres.2020.198068
5
Anti-TNF-α therapy does not ameliorate disease in a model of acute virus-endotoxin mediated respiratory disease in pigs
Tumour necrosis factor-α (TNF-α) has been shown to play a role in many inflammatory conditions. Currently anti-TNF-α drugs (e.g. etanercept) are used in humans for treatment of autoimmune diseases. In this study we aimed to elucidate the role of TNF-α in the development of virus-endotoxin-induced respiratory disease. Twenty-two caesarean derived colostrum deprived pigs were used. Initially, the availability in the lungs and circulation, and possible clinical and inflammatory effects of etanercept alone were assessed in 4 pigs after intratracheal and intraperitoneal administration of 0.5 mg/per route/per pig. High anti-TNF-α activity was detected in bronchoalveolar lavage (BAL) fluids, peritoneal lavage fluids and serum of all animals for at least 8 hours post inoculation (HPI). No clinical symptoms, lung lesions, lung cell infiltration or induction of IFN-α, IL-1, IL-6, IL-12 and TNF-α in BAL were detected. Subsequently, the ability of etanercept to block porcine TNF-α and its effect on the above mentioned parameters and on lung virus titres were assessed in 8 pigs. They were inoculated intratracheally with porcine respiratory coronavirus (PRCV) followed by lipopolysaccharide (LPS) 24 hours later. Etanercept was administered at the time of LPS inoculation via the same routes and dose as in the initial experiment. The parameters were compared with a control group (n=8), receiving only PRCV-LPS. Half of the animals from each group were euthanized at 4 and the rest at 8 hours after LPS inoculation. TNF-α was completely neutralized in 3 of the 4 animals euthanized at 4 HPI and significantly lower than in the PRCV-LPS group at all times. No significant differences in disease severity, lung lesions, virus replication, lung cell infiltration or levels of IFN-α, IL-1, IL-6 and IL-12/IL-23 were observed between the two groups. Blocking of TNF-α alone was not sufficient to ameliorate disease in the PRCV-LPS model of respiratory disease, possibly due to the redundancy in the proinflammatory cytokine cascade, or the involvement of other unidentified disease mediators.
gzvfz8tw
gzvfz8tw
2010-09-01
10.1016/j.vetimm.2010.04.003
1
Simultaneous treatment of human bronchial epithelial cells with serine and cysteine protease inhibitors prevents severe acute respiratory syndrome coronavirus entry.
The type II transmembrane protease TMPRSS2 activates the spike (S) protein of severe acute respiratory syndrome coronavirus (SARS-CoV) on the cell surface following receptor binding during viral entry into cells. In the absence of TMPRSS2, SARS-CoV achieves cell entry via an endosomal pathway in which cathepsin L may play an important role, i.e., the activation of spike protein fusogenicity. This study shows that a commercial serine protease inhibitor (camostat) partially blocked infection by SARS-CoV and human coronavirus NL63 (HCoV-NL63) in HeLa cells expressing the receptor angiotensin-converting enzyme 2 (ACE2) and TMPRSS2. Simultaneous treatment of the cells with camostat and EST [(23,25)trans-epoxysuccinyl-L-leucylamindo-3-methylbutane ethyl ester], a cathepsin inhibitor, efficiently prevented both cell entry and the multistep growth of SARS-CoV in human Calu-3 airway epithelial cells. This efficient inhibition could be attributed to the dual blockade of entry from the cell surface and through the endosomal pathway. These observations suggest camostat as a candidate antiviral drug to prevent or depress TMPRSS2-dependent infection by SARS-CoV.
h06zxykb
h06zxykb
2012
10.1128/jvi.00094-12
4
Commentary on two reports on animal models of COVID‐19
h0fh9lem
h0fh9lem
2020-06-24
10.1002/ame2.12127
5
Assessing the potential impact of COVID-19 in Brazil: Mobility, Morbidity and the burden on the Health Care System
The two largest Brazilian cities, Rio de Janeiro and Sao Paulo, have declared community transmission of COVID-19 on mid March, 2020. In this study we estimated the most vulnerable areas in Brazil for COVID-19, both in terms of risk of introduction and risk of mortality associated with social vulnerability. We explore the most likely routes of spread through the country, from the already exposed cities, according to human mobility statistics. The resulting maps should help authorities in their efforts to prioritize actions and if resource allocation to mitigate the effects of the pandemic.
h1b0s2wy
h1b0s2wy
2020-03-23
10.1101/2020.03.19.20039131
1.5
Long Term Culture of Human Kidney Proximal Tubule Epithelial Cells Maintains Lineage Functions and Serves as an Ex vivo Model for Coronavirus Associated Kidney Injury
The mechanism of how SARS-CoV-2 causes severe multi-organ failure is largely unknown. Acute kidney injury (AKI) is one of the frequent organ damage in severe COVID-19 patients. Previous studies have shown that human renal tubule cells could be the potential host cells targeted by SARS-CoV-2. Traditional cancer cell lines or immortalized cell lines are genetically and phenotypically different from host cells. Animal models are widely used, but often fail to reflect a physiological and pathogenic status because of species tropisms. There is an unmet need for normal human epithelial cells for disease modeling. In this study, we successfully established long term cultures of normal human kidney proximal tubule epithelial cells (KPTECs) in 2D and 3D culture systems using conditional reprogramming (CR) and organoids techniques. These cells had the ability to differentiate and repair DNA damage, and showed no transforming property. Importantly, the CR KPTECs maintained lineage function with expression of specific transporters (SLC34A3 and cubilin). They also expressed angiotensin-converting enzyme 2 (ACE2), a receptor for SARS-CoV and SARS-CoV-2. In contrast, cancer cell line did not express endogenous SLC34A3, cubilin and ACE2. Very interestingly, ACE2 expression was around twofold higher in 3D organoids culture compared to that in 2D CR culture condition. Pseudovirion assays demonstrated that SARS-CoV spike (S) protein was able to enter CR cells with luciferase reporter. This integrated 2D CR and 3D organoid cultures provide a physiological ex vivo model to study kidney functions, innate immune response of kidney cells to viruses, and a novel platform for drug discovery and safety evaluation. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s12250-020-00253-y) contains supplementary material, which is available to authorized users.
h286m32c
h286m32c
2020-06-29
10.1007/s12250-020-00253-y
5
Animal models for the risk assessment of viral pandemic potential
Pandemics affect human lives severely and globally. Experience predicts that there will be a pandemic for sure although the time is unknown. When a viral epidemic breaks out, assessing its pandemic risk is an important part of the process that characterizes genomic property, viral pathogenicity, transmission in animal model, and so forth. In this review, we intend to figure out how a pandemic may occur by looking into the past influenza pandemic events. We discuss interpretations of the experimental evidences resulted from animal model studies and extend implications of viral pandemic potentials and ingredients to emerging viral epidemics. Focusing on the pandemic potential of viral infectious diseases, we suggest what should be assessed to prevent global catastrophes from influenza virus, Middle East respiratory syndrome coronavirus, dengue and Zika viruses.
h3oix9zc
h3oix9zc
2020-04-22
10.1186/s42826-020-00040-6
3.5
The Nonhuman Primate as a Model for Biomedical Research
This chapter provides a brief summary of issues surrounding the utilization of nonhuman primates in biomedical research. Although a relatively small proportion of the total number of animals utilized in biomedical research, nonhuman primates occupy a unique position as the species most closely related to humans, and thus have the potential to provide highly relevant information regarding human health issues. Nonhuman primates are utilized across a wide diversity of research topics and examples are provided including infectious disease, neuroscience, and genomics. Pertinent information relating to ethical issues, species selection, housing, and specific pathogen-free status are provided as an overview of relevant issues associated with selection of nonhuman primate models. Selected references are provided as a reference for more comprehensive information relating to these topics.
h49gsxn9
h49gsxn9
2008
10.1007/978-1-59745-285-4_28
1
Research progress on repositioning drugs and specific therapeutic drugs for SARS-CoV-2
SARS-CoV-2 has been widely spread around the world and COVID-19 was declared a global pandemic by the World Health Organization. Limited clinically effective antiviral drugs are available now. The development of anti-SARS-CoV-2 drugs has become an urgent work worldwide. At present, potential therapeutic targets and drugs for SARS-CoV-2 are continuously reported, and many repositioning drugs are undergoing extensive clinical research, including remdesivir and chloroquine. On the other hand, structures of many important viral target proteins and host target proteins, including that of RdRp and Mpro were constantly reported, which greatly promoted structure-based drug design. This paper summarizes the current research progress and challenges in the development of anti-SARS-CoV-2 drugs, and proposes novel short-term and long-term drug research strategies.
h6dwlmvb
h6dwlmvb
2020-07-08
10.4155/fmc-2020-0158
5
Antiviral activity of carbohydrate-binding agents against Nidovirales in cell culture
Abstract Coronaviruses are important human and animal pathogens, the relevance of which increased due to the emergence of new human coronaviruses like SARS-CoV, HKU1 and NL63. Together with toroviruses, arteriviruses, and roniviruses the coronaviruses belong to the order Nidovirales. So far antivirals are hardly available to combat infections with viruses of this order. Therefore, various antiviral strategies to counter nidoviral infections are under evaluation. Lectins, which bind to N-linked oligosaccharide elements of enveloped viruses, can be considered as a conceptionally new class of virus inhibitors. These agents were recently evaluated for their antiviral activity towards a variety of enveloped viruses and were shown in most cases to inhibit virus infection at low concentrations. However, limited knowledge is available for their efficacy towards nidoviruses. In this article the application of the plant lectins Hippeastrum hybrid agglutinin (HHA), Galanthus nivalis agglutinin (GNA), Cymbidium sp. agglutinin (CA) and Urtica dioica agglutinin (UDA) as well as non-plant derived pradimicin-A (PRM-A) and cyanovirin-N (CV-N) as potential antiviral agents was evaluated. Three antiviral tests were compared based on different evaluation principles: cell viability (MTT-based colorimetric assay), number of infected cells (immunoperoxidase assay) and amount of viral protein expression (luciferase-based assay). The presence of carbohydrate-binding agents strongly inhibited coronaviruses (transmissible gastroenteritis virus, infectious bronchitis virus, feline coronaviruses serotypes I and II, mouse hepatitis virus), arteriviruses (equine arteritis virus and porcine respiratory and reproductive syndrome virus) and torovirus (equine Berne virus). Remarkably, serotype II feline coronaviruses and arteriviruses were not inhibited by PRM-A, in contrast to the other viruses tested.
h8fvrbch
h8fvrbch
2007-10-31
10.1016/j.antiviral.2007.04.003
5
Coronavirus COV-19/SARS-CoV-2 affects women less than men: clinical response to viral infection.
CoV-19/SARS-CoV-2 is a highly pathogenic virus that causes coronavirus-19 disease (COVID-19) an acute respiratory distress syndrome which provokes serious problems for global health. Studies suggest that there are many differences between men and women in the immune response to CoV-19 infection and inflammatory diseases. Women, compared to men, are less susceptible to viral infections based on a different innate immunity, steroid hormones and factors related to sex chromosomes. The presence of two X chromosomes in women emphasize the immune system even if one is inactive. The immune regulatory genes encoded by X chromosome in female gender causes lower viral load levels, and less inflammation than in man, while CD4+ T cells are higher with better immune response. In addition, women generally produce higher levels of antibodies which remain in the circulation longer. The levels of activation of the immune cells are higher in women than in men, and it is correlated with the trigger of TLR7 and the production of IFN. TLR7 is higher in women than in men and its biallelic expression leads to higher immune responses and increases the resistance to viral infections. TLR7 is expressed in innate immune cells which recognizes single strand RNA virus by promoting the production of antibodies against the virus and the generation of pro-inflammatory cytokines including IL-6 and IL-1 family members. Moreover, in women the production of inflammatory IL-6 after viral infection is lower than in males and is often correlated with a better longevity. In addition, on the X chromosome there are loci that code for the genes involved in the regulation of immune cells such as FOXP3, and transcription factor for Treg involved in virus pathogenesis. The X chromosome influences the immune system by acting on many other proteins, including TLR8, CD40L and CXCR3 which can be over-expressed in women, and influence the response to viral infections and vaccinations. However, the biallelic expression of the X-linked genes can promote harmful autoimmune and inflammatory responses. Cardiovascular diseases are more frequent in males and subjects without cardiovascular dysfunctions infected by CoV-19 have a better prognosis. ACE2 is a receptor for CoV-19 and protects lung damage. CoV-19 infection and the virus's Spike protein inhibit the expression of ACE2, abolishing its protective function. Inhibitors of the angiotensin converting enzyme (ACEI) are used to stem the devastating effects of CoV-19, to increase the number of CD3 and CD8 T cells and to reduce the viral load and IL-6 levels that control CoV-19 replication via NF-B, but these effects are still under study. It is hoped that certain drugs, such as CoV-19 receptor blockers, anti-inflammatories (against rheumatic diseases), monoclonal antibodies, anti-IL-1 and anti-IL-6, the remdesevir drug (analogue adenosine, effective against ebola), hydroxychloroquine (for the treatment of malaria) and vaccines, will open up new strategies and new therapeutic ways to combat this terrible virus.
h8vcxudk
h8vcxudk
2020-04-07
10.23812/editorial-conti-3
3.5
Advances in respiratory virus therapeutics – A meeting report from the 6th isirv Antiviral Group conference
Abstract The International Society for Influenza and other Respiratory Virus Diseases held its 6th Antiviral Group (isirv-AVG) conference in Rockville, Maryland, November 13–15, 2018. The three-day program was focused on therapeutics towards seasonal and pandemic influenza, respiratory syncytial virus, coronaviruses including MERS-CoV and SARS-CoV, human rhinovirus, and other respiratory viruses. Updates were presented on several influenza antivirals including baloxavir, CC-42344, VIS410, immunoglobulin, immune plasma, MHAA4549A, pimodivir (JNJ-63623872), umifenovir, and HA minibinders; RSV antivirals including presatovir (GS-5806), ziresovir (AK0529), lumicitabine (ALS-008176), JNJ-53718678, JNJ-64417184, and EDP-938; broad spectrum antivirals such as favipiravir, VH244, remdesivir, and EIDD-1931/EIDD-2801; and host directed strategies including nitazoxanide, eritoran, and diltiazem. Other topics included considerations of novel endpoints such as ordinal scales and patient reported outcomes (PRO), and study design issues, and other regulatory considerations for antiviral drug development. The aim of this report is to provide a summary of the presentations given at this meeting.
h97dui9n
h97dui9n
2019-07-31
10.1016/j.antiviral.2019.04.006
0.5
Immunization with SARS Coronavirus Vaccines Leads to Pulmonary Immunopathology on Challenge with the SARS Virus
BACKGROUND: Severe acute respiratory syndrome (SARS) emerged in China in 2002 and spread to other countries before brought under control. Because of a concern for reemergence or a deliberate release of the SARS coronavirus, vaccine development was initiated. Evaluations of an inactivated whole virus vaccine in ferrets and nonhuman primates and a virus-like-particle vaccine in mice induced protection against infection but challenged animals exhibited an immunopathologic-type lung disease. DESIGN: Four candidate vaccines for humans with or without alum adjuvant were evaluated in a mouse model of SARS, a VLP vaccine, the vaccine given to ferrets and NHP, another whole virus vaccine and an rDNA-produced S protein. Balb/c or C57BL/6 mice were vaccinated IM on day 0 and 28 and sacrificed for serum antibody measurements or challenged with live virus on day 56. On day 58, challenged mice were sacrificed and lungs obtained for virus and histopathology. RESULTS: All vaccines induced serum neutralizing antibody with increasing dosages and/or alum significantly increasing responses. Significant reductions of SARS-CoV two days after challenge was seen for all vaccines and prior live SARS-CoV. All mice exhibited histopathologic changes in lungs two days after challenge including all animals vaccinated (Balb/C and C57BL/6) or given live virus, influenza vaccine, or PBS suggesting infection occurred in all. Histopathology seen in animals given one of the SARS-CoV vaccines was uniformly a Th2-type immunopathology with prominent eosinophil infiltration, confirmed with special eosinophil stains. The pathologic changes seen in all control groups lacked the eosinophil prominence. CONCLUSIONS: These SARS-CoV vaccines all induced antibody and protection against infection with SARS-CoV. However, challenge of mice given any of the vaccines led to occurrence of Th2-type immunopathology suggesting hypersensitivity to SARS-CoV components was induced. Caution in proceeding to application of a SARS-CoV vaccine in humans is indicated.
hb2lieh3
hb2lieh3
2012-04-20
10.1371/journal.pone.0035421
1.5
Computational Models Identify Several FDA Approved or Experimental Drugs as Putative Agents Against SARS-CoV-2.
The outbreak of a novel human coronavirus (SARS-CoV-2) has evolved into global health emergency, infecting hundreds of thousands of people worldwide. We have identified experimental data on the inhibitory activity of compounds tested against closely related (96% sequence identity, 100% active site conservation) protease of SARS-CoV and employed this data to build QSAR models for this dataset. We employed these models for virtual screening of all drugs from DrugBank, including compounds in clinical trials. Molecular docking and similarity search approaches were explored in parallel with QSAR modeling, but molecular docking failed to correctly discriminate between experimentally active and inactive compounds. As a result of our studies, we recommended 41 approved, experimental, or investigational drugs as potential agents against SARS-CoV-2 acting as putative inhibitors of Mpro. Ten compounds with feasible prices were purchased and are awaiting the experimental validation..
hchioraj
hchioraj
2020-04-22
10.26434/chemrxiv.12153594.v1
4.5
Lessons from SARS-CoV-2 Pandemic: Evolution, Disease Dynamics and Future
The COVID-19 pandemic is rising at an unprecedented rate. The surging number of deaths every day, global lockdown and travel restrictions have resulted in huge losses to society. The impact is massive and will leave a historical footprint. The Spanish Flu of 1918, which was the last pandemic that had a similar impact, was shadowed under the consequences of World War I. All the brilliance, strength and economies of countries worldwide are aimed at fighting the COVID-19 pandemic. The knowledge about coronavirus dynamics, its nature and epidemiology are expanding every day. The present review aims to summarize the structure, epidemiology, symptoms, statistical status of the disease status, intervention strategies and deliberates the lessons learnt during the pandemic. The intervention approaches, antiviral drug repurposing and vaccine trials are intensified now. Statistical interpretations of disease dynamics and their projections may help the decision-makers.
hdkmzdq9
hdkmzdq9
2020-06-26
10.3390/biology9060141
5
Is There a Role for Tissue Plasminogen Activator (tPA) as a Novel Treatment for Refractory COVID-19 Associated Acute Respiratory Distress Syndrome (ARDS)?
hdrxwy9t
hdrxwy9t
2020-03-20
10.1097/ta.0000000000002694
2
SEIR and Regression Model based COVID-19 outbreak predictions in India
COVID-19 pandemic has become a major threat to the country. Till date, well tested medication or antidote is not available to cure this disease. According to WHO reports, COVID-19 is a severe acute respiratory syndrome which is transmitted through respiratory droplets and contact routes. Analysis of this disease requires major attention by the Government to take necessary steps in reducing the effect of this global pandemic. In this study, outbreak of this disease has been analysed for India till 30th March 2020 and predictions have been made for the number of cases for the next 2 weeks. SEIR model and Regression model have been used for predictions based on the data collected from John Hopkins University repository in the time period of 30th January 2020 to 30th March 2020. The performance of the models was evaluated using RMSLE and achieved 1.52 for SEIR model and 1.75 for the regression model. The RMSLE error rate between SEIR model and Regression model was found to be 2.01. Also, the value of R0 which is the spread of the disease was calculated to be 2.02. Expected cases may rise between 5000-6000 in the next two weeks of time. This study will help the Government and doctors in preparing their plans for the next two weeks. Based on the predictions for short-term interval, these models can be tuned for forecasting in long-term intervals.
hf0jtfmx
hf0jtfmx
2020-04-03
10.1101/2020.04.01.20049825
2
SARS-CoV-2 and COVID-19: The most important research questions
Coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is an ongoing global health emergency. Here we highlight nine most important research questions concerning virus transmission, asymptomatic and presymptomatic virus shedding, diagnosis, treatment, vaccine development, origin of virus and viral pathogenesis.
hfkzu18p
hfkzu18p
2020-03-16
10.1186/s13578-020-00404-4
1
In silico prediction of potential inhibitors for the Main protease of SARS-CoV-2 using molecular docking and dynamics simulation based drug-repurposing
BACKGROUND: The rapidly enlarging COVID-19 pandemic caused by the novel SARS-corona virus-2 is a global public health emergency of an unprecedented level. Unfortunately no treatment therapy or vaccine is yet available to counter the SARS-CoV-2 infection, which substantiates the need to expand research efforts in this direction. The indispensable function of the main protease in virus replication makes this enzyme a promising target for inhibitors screening and drug discovery to treat novel coronavirus infection. The recently concluded α-ketoamide ligand-bound X-ray crystal structure of SARS-CoV-2 M(pro) (PDB ID: 6Y2F) from Zhang et al. has revealed the potential inhibitor binding mechanism and the molecular determinants responsible for substrate binding. METHODS: For the study, we have targeted the SARS-CoV-2 M(pro) for the screening of FDA approved antiviral drugs and carried out molecular docking based virtual screening. Further molecular dynamic simulation studies of the top three selected drugs carried out to investigated for their binding affinity and stability in the SARS-CoV-2 M(pro) active site. The phylogenetic analysis was also performed to know the relatedness between the SARS-CoV-2 genomes isolated from different countries. RESULTS: The phylogenetic analysis of the SARS-CoV-2 genome reveals that the virus is closely related to the Bat-SL-CoV and does not exhibit any divergence at the genomic level. Molecular docking studies revealed that among the 77 drugs, screened top ten drugs shows good binding affinities, whereas the top three drugs: Lopinavir-Ritonavir, Tipranavir, and Raltegravir were undergone for molecular dynamics simulation studies for their conformational stability in the active site of the SARS-CoV-2 M(pro) protein. CONCLUSIONS: In the present study among the library of FDA approved antiviral drugs, the top three inhibitors Lopinavir-Ritonavir, Tipranavir, and Raltegravir show the best molecular interaction with the main protease of SARS-CoV-2. However, the in-vitro efficacy of the drug molecules screened in this study further needs to be corroborated by carrying out a biochemical and structural investigation.
hgpfib1z
hgpfib1z
2020-06-16
10.1016/j.jiph.2020.06.016
4
Molecular mechanism of evolution and human infection with the novel coronavirus (2019-nCoV)
Since December, 2019, an outbreak of pneumonia caused by the new coronavirus (2019-nCoV) has hit the city of Wuhan in the Hubei Province. With the continuous development of the epidemic, it has become a national public health crisis and calls for urgent antiviral treatments or vaccines. The spike protein on the coronavirus envelope is critical for host cell infection and virus vitality. Previous studies showed that 2019-nCoV is highly homologous to human SARS-CoV and attaches host cells though the binding of the spike receptor binding domain (RBD) domain to the angiotensin-converting enzyme II (ACE2). However, the molecular mechanisms of 2019-nCoV binding to human ACE2 and evolution of 2019-nCoV remain unclear. In this study, we have extensively studied the RBD-ACE2 complex, spike protein, and free RBD systems of 2019-nCoV and SARS-CoV using protein-protein docking and molecular dynamics (MD) simulations. It was shown that the RBD-ACE2 binding free energy for 2019-nCoV is significantly lower than that for SARS-CoV, which is consistent with the fact that 2019-nCoV is much more infectious than SARS-CoV. In addition, the spike protein of 2019-nCoV shows a significantly lower free energy than that of SARS-CoV, suggesting that 2019-nCoV is more stable and able to survive a higher temperature than SARS-CoV. This may also provide insights into the evolution of 2019-nCoV because SARS-like coronaviruses are thought to have originated in bats that are known to have a higher body-temperature than humans. It was also revealed that the RBD of 2019-nCoV is much more flexible especially near the binding site and thus will have a higher entropy penalty upon binding ACE2, compared to the RBD of SARS-CoV. That means that 2019-nCoV will be much more temperature-sensitive in terms of human infection than SARS-CoV. With the rising temperature, 2019-nCoV is expected to decrease its infection ability much faster than SARS-CoV, and get controlled more easily. The present findings are expected to be helpful for the disease prevention and control as well as drug and vaccine development of 2019-nCoV.
hicqy5sj
hicqy5sj
2020-02-21
10.1101/2020.02.17.952903
4.5
Nucleotide Analogues as Inhibitors of SARS-CoV Polymerase
SARS-CoV-2, a member of the coronavirus family, has caused a global public health emergency.1 Based on our analysis of hepatitis C virus and coronavirus replication, and the molecular structures and activities of viral inhibitors, we previously reasoned that the FDA-approved heptatitis C drug EPCLUSA (Sofosbuvir/Velpatasvir) should inhibit coronaviruses, including SARS-CoV-2.2 Here, using model polymerase extension experiments, we demonstrate that the activated triphosphate form of Sofosbuvir is incorporated by low-fidelity polymerases and SARS-CoV RNA-dependent RNA polymerase (RdRp), and blocks further incorporation by these polymerases; the activated triphosphate form of Sofosbuvir is not incorporated by a host-like high-fidelity DNA polymerase. Using the same molecular insight, we selected two other anti-viral agents, Alovudine and AZT (an FDA approved HIV/AIDS drug) for evaluation as inhibitors of SARS-CoV RdRp. We demonstrate the ability of two HIV reverse transcriptase inhibitors, 3’-fluoro-3’-deoxythymidine triphosphate and 3’-azido-3’-deoxythymidine triphosphate (the active triphosphate forms of Alovudine and AZT), to be incorporated by SARS-CoV RdRp where they also terminate further polymerase extension. Given the 98% amino acid similarity of the SARS-CoV and SARS-CoV-2 RdRps, we expect these nucleotide analogues would also inhibit the SARS-CoV-2 polymerase. These results offer guidance to further modify these nucleotide analogues to generate more potent broad-spectrum anti-coronavirus agents.
hj675z1b
hj675z1b
2020-03-14
10.1101/2020.03.12.989186
2
The role of Neutrophil Extracellular Traps in Covid-19: Only an hypothesis or a potential new field of research?
hjgk8cx2
hjgk8cx2
2020-04-27
10.1016/j.thromres.2020.04.031
2.5
Mouse-Passaged Severe Acute Respiratory Syndrome-Associated Coronavirus Leads to Lethal Pulmonary Edema and Diffuse Alveolar Damage in Adult but Not Young Mice
Advanced age is a risk factor of severe acute respiratory syndrome (SARS) in humans. To understand its pathogenesis, we developed an animal model using BALB/c mice and the mouse-passaged Frankfurt 1 isolate of SARS coronavirus (SARS-CoV). We examined the immune responses to SARS-CoV in both young and adult mice. SARS-CoV induced severe respiratory illness in all adult, but not young, mice on day 2 after inoculation with a mortality rate of 30 to 50%. Moribund adult mice showed severe pulmonary edema and diffuse alveolar damage accompanied by virus replication. Adult murine lungs, which had significantly higher interleukin (IL)-4 and lower IL-10 and IL-13 levels before infection than young murine lungs, rapidly produced high levels of proinflammatory chemokines and cytokines known to induce macrophage and neutrophil infiltration and activation (eg, tumor necrosis factor-α). On day 2 after inoculation, young murine lungs produced not only proinflammatory cytokines but also IL-2, interferon-γ, IL-10, and IL-13. Adult mice showed early and acute excessive proinflammatory responses (ie, cytokine storm) in the lungs after SARS-CoV infection, which led to severe pulmonary edema and diffuse alveolar damage. Intravenous injection with anti-tumor necrosis factor-α antibody 3 hours after infection had no effect on SARS-CoV infection. However, intraperitoneal interferon-γ injection protected adult mice from the lethal respiratory illness. The experimental model described here may be useful for elucidating the pathophysiology of SARS and for evaluating therapies to treat SARS-CoV infection.
hkyiy1gm
hkyiy1gm
2008-06-30
10.2353/ajpath.2008.071060
4
Structural Basis for Potent Neutralization of Betacoronaviruses by Single-Domain Camelid Antibodies
Summary Coronaviruses make use of a large envelope protein called spike (S) to engage host cell receptors and catalyze membrane fusion. Because of the vital role that these S proteins play, they represent a vulnerable target for the development of therapeutics. Here, we describe the isolation of single-domain antibodies (VHHs) from a llama immunized with prefusion-stabilized coronavirus spikes. These VHHs neutralize MERS-CoV or SARS-CoV-1 S pseudotyped viruses, respectively. Crystal structures of these VHHs bound to their respective viral targets reveal two distinct epitopes, but both VHHs interfere with receptor binding. We also show cross-reactivity between the SARS-CoV-1 S-directed VHH and SARS-CoV-2 S and demonstrate that this cross-reactive VHH neutralizes SARS-CoV-2 S pseudotyped viruses as a bivalent human IgG Fc-fusion. These data provide a molecular basis for the neutralization of pathogenic betacoronaviruses by VHHs and suggest that these molecules may serve as useful therapeutics during coronavirus outbreaks.
hlktf15o
hlktf15o
2020-05-05
10.1016/j.cell.2020.04.031
3
Study of combining virtual screening and antiviral treatments of the Sars-CoV-2 (Covid-19)
The recent epidemic outbreak of a novel human coronavirus called SARS-CoV-2 and causing the respiratory tract disease COVID-19 has reached worldwide resonance and a global effort is being undertaken to characterize the molecular features and evolutionary origins of this virus. Therefore, rapid and accurate identification of pathogenic viruses plays a vital role in selecting appropriate treatments, saving people's lives and preventing epidemics. Additionally, general treatments, coronavirus-specific treatments, and antiviral treatments useful in fighting COVID-19 are addressed. This review sets out to shed light on the SARS-CoV-2 and host receptor recognition, a crucial factor for successful virus infection and taking immune-informatics approaches to identify B- and T-cell epitopes for surface glycoprotein of SARS-CoV-2. A variety of improved or new approaches also have been developed. It is anticipated that this will assist researchers and clinicians in developing better techniques for timely and effective detection of coronavirus infection. Moreover, the genomic sequence of the virus responsible for COVID-19, as well as the experimentally determined three-dimensional structure of the Main protease (Mpro) is available. The reported structure of the target Mpro was described in this review to identify potential drugs for COVID-19 using virtual high throughput screening.
hlw3t2rb
hlw3t2rb
2020-05-05
10.1016/j.micpath.2020.104241
3
Vaccine Development Against Middle East Respiratory Syndrome
Various types of vaccines are under pre-clinical and clinical development to address the recent appearance of Middle East respiratory syndrome or MERS, an emerging infectious disease that has already caused over 600 deaths and remains a threat to world health. The causative agent for this respiratory disease is a member of the betacoronavirus genus, phylogenetically closely related to the SARS coronavirus that caused an international health emergency in 2002. With lessons learned from the outbreak of severe acute respiratory syndrome, and with undeniable technological advances, vaccine development against MERS was initially fast-paced and has produced several DNA and protein vaccine candidates with promising results during early pre-clinical testing. At least one vaccine candidate has even entered first-in-humans clinical trials now. With the number of MERS cases declining though and other infectious diseases attracting increased attention, the question remains, whether, similar to the situation after the SARS pandemic, vaccine development is halted or remains the priority it rightfully should.
hmeg2t9m
hmeg2t9m
2016-07-11
10.1007/s40475-016-0084-0
1.5
COVID-19 and Liver Dysfunction: Current Insights and Emergent Therapeutic Strategies
The outbreak of coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has attracted increasing worldwide attention. Cases of liver damage or dysfunction (mainly characterized by moderately elevated serum aspartate aminotransferase levels) have been reported among patients with COVID-19. However, it is currently uncertain whether the COVID-19-related liver damage/dysfunction is due mainly to the viral infection per se or other coexisting conditions, such as the use of potentially hepatotoxic drugs and the coexistence of systemic inflammatory response, respiratory distress syndrome-induced hypoxia, and multiple organ dysfunction. Based on the current evidence from case reports and case series, this review article focuses on the demographic and clinical characteristics, potential mechanisms, and treatment options for COVID-19-related liver dysfunction. This review also describes the geographical and demographic distribution of COVID-19-related liver dysfunction, as well as possible underlying mechanisms linking COVID-19 to liver dysfunction, in order to facilitate future drug development, prevention, and control measures for COVID-19.
hmpmm9k8
hmpmm9k8
2020-03-30
10.14218/jcth.2020.00018
3
Old and re-purposed drugs for the treatment of COVID-19
INTRODUCTION: The coronavirus disease 2019 (COVID-19) caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has developed since December 2019. It has caused a global pandemic with more than three hundred thousand case fatalities. However, apart from supportive care by respirators, no standard medical therapy is validated. AREAS COVERED: This paper presents old drugs with potential in vitro efficacy against SARS-CoV-2. The in vitro database, adverse effects, and potential toxicities of these drugs are reviewed regarding their feasibility of clinical prescription for the treatment of patients with COVID-19. To obtain convincing recommendations, we referred to opinions from the US National Institute of Health regarding drugs repurposed for COVID-19 therapy. EXPERT OPINION: Although strong evidence of well-designed randomized controlled studies regarding COVID-19 therapy is presently lacking, remdesivir, teicoplanin, hydroxychloroquine (not in combination with azithromycin), and ivermectin might be effective antiviral drugs and are deemed promising candidates for controlling SARS-CoV-2. In addition, tocilizumab might be considered as the supplementary treatment for COVID-19 patients with cytokine release syndrome. In future, clinical trials regarding a combination of potentially effective drugs against SARS-CoV-2 need to be conducted to establish the optimal regimen for the treatment of patients with moderate-to-severe COVID-19.
hn12194u
hn12194u
2020
4.5
Synthesis and activity of an octapeptide inhibitor designed for SARS coronavirus main proteinase
The outbreak of SARS, a life-threatening disease, has spread over many countries around the world. So far there is no effective drug for the treatment of SARS. Stimulated by the binding mechanism of SARS-CoV M(pro) with the octapeptide AVLQSGFR reported recently as well as the “Chou's distorted key” theory, we synthesized the octapeptide AVLQSGFR for conducting various biochemical experiments to investigate the antiviral potential of the octapeptide against SARS coronavirus (BJ-01). The results demonstrate that, compared with other compounds reported so far, AVLQSGFR is the most active in inhibiting replication of the SARS coronavirus, and that no detectable toxicity is observed on Vero cells under the condition of experimental concentration.
hp6m6qrn
hp6m6qrn
2005-10-19
10.1016/j.peptides.2005.09.006
0.5
Subunit Vaccines Against Emerging Pathogenic Human Coronaviruses
Seven coronaviruses (CoVs) have been isolated from humans so far. Among them, three emerging pathogenic CoVs, including severe acute respiratory syndrome coronavirus (SARS-CoV), Middle East respiratory syndrome coronavirus (MERS-CoV), and a newly identified CoV (2019-nCoV), once caused or continue to cause severe infections in humans, posing significant threats to global public health. SARS-CoV infection in humans (with about 10% case fatality rate) was first reported from China in 2002, while MERS-CoV infection in humans (with about 34.4% case fatality rate) was first reported from Saudi Arabia in June 2012. 2019-nCoV was first reported from China in December 2019, and is currently infecting more than 70000 people (with about 2.7% case fatality rate). Both SARS-CoV and MERS-CoV are zoonotic viruses, using bats as their natural reservoirs, and then transmitting through intermediate hosts, leading to human infections. Nevertheless, the intermediate host for 2019-nCoV is still under investigation and the vaccines against this new CoV have not been available. Although a variety of vaccines have been developed against infections of SARS-CoV and MERS-CoV, none of them has been approved for use in humans. In this review, we have described the structure and function of key proteins of emerging human CoVs, overviewed the current vaccine types to be developed against SARS-CoV and MERS-CoV, and summarized recent advances in subunit vaccines against these two pathogenic human CoVs. These subunit vaccines are introduced on the basis of full-length spike (S) protein, receptor-binding domain (RBD), non-RBD S protein fragments, and non-S structural proteins, and the potential factors affecting these subunit vaccines are also illustrated. Overall, this review will be helpful for rapid design and development of vaccines against the new 2019-nCoV and any future CoVs with pandemic potential. This review was written for the topic of Antivirals for Emerging Viruses: Vaccines and Therapeutics in the Virology section of Frontiers in Microbiology.
hq4jb2wy
hq4jb2wy
2020-02-28
10.3389/fmicb.2020.00298
3
Novel and potent inhibitors targeting DHODH, a rate-limiting enzyme in de novo pyrimidine biosynthesis, are broad-spectrum antiviral against RNA viruses including newly emerged coronavirus SARS-CoV-2
Emerging and re-emerging RNA viruses occasionally cause epidemics and pandemics worldwide, such as the on-going outbreak of coronavirus SARS-CoV-2. Existing direct-acting antiviral (DAA) drugs cannot be applied immediately to new viruses because of virus-specificity, and the development of new DAA drugs from the beginning is not timely for outbreaks. Thus, host-targeting antiviral (HTA) drugs have many advantages to fight against a broad spectrum of viruses, by blocking the viral replication and overcoming the potential viral mutagenesis simultaneously. Herein, we identified two potent inhibitors of DHODH, S312 and S416, with favorable drug-like and pharmacokinetic profiles, which all showed broad-spectrum antiviral effects against various RNA viruses, including influenza A virus (H1N1, H3N2, H9N2), Zika virus, Ebola virus, and particularly against the recent novel coronavirus SARS-CoV-2. Our results are the first to validate that DHODH is an attractive host target through high antiviral efficacy in vivo and low virus replication in DHODH knocking-out cells. We also proposed the drug combination of DAA and HTA was a promising strategy for anti-virus treatment and proved that S312 showed more advantageous than Oseltamivir to treat advanced influenza diseases in severely infected animals. Notably, S416 is reported to be the most potent inhibitor with an EC50 of 17nM and SI value >5882 in SARS-CoV-2-infected cells so far. This work demonstrates that both our self-designed candidates and old drugs (Leflunomide/Teriflunomide) with dual actions of antiviral and immuno-repression may have clinical potentials not only to influenza but also to COVID-19 circulating worldwide, no matter such viruses mutate or not.
hq5um68k
hq5um68k
2020-03-12
10.1101/2020.03.11.983056
0.5
In-silico strategies for probing chloroquine based inhibitors against SARS-CoV-2
The global health emergency of novel COVID-19 is due to severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). Currently there are no approved drugs for the treatment of coronaviral disease (COVID-19), although some of the drugs have been tried. Chloroquine is being widely used in treatment of SARS-CoV-2 infection. Hydroxychloroquine, the derivative of Chloroquine shows better inhibition than Chloroquine and has in vitro activity against SARS-CoV-2 also used to treat COVID-19. To study the interactions of Chloroquine and derivatives of Chloroquine with SARS-CoV-2, series of computational approaches like pharmacophore model, molecular docking, MM_GBSA study and ADME property analysis are explored. The pharmacophore model and molecular docking study are used to explore the structural properties of the compounds and the ligand-receptor (PDB_ID: 6LU7) interactions respectively. MM_GBSA study gives the binding free energy of the protein-ligand complex and ADME property analysis explains the pharmacological property of the compounds. The resultant best molecule (CQD15) further subjected to molecular dynamics (MD) simulation study which explains the protein stability (RMSD), ligand properties as well as protein-ligand contacts. Outcomes of the present study conclude with the molecule CQD15 which shows better interactions for the inhibition of SARS-CoV-2 in comparison to Chloroquine and Hydroxychloroquine.Communicated by Ramaswamy H. Sarma.
hqg5j51t
hqg5j51t
2020
5
Animals as Reservoir for Human Norovirus
Norovirus is the most common cause of non-bacterial gastroenteritis and is a burden worldwide. The increasing norovirus diversity is currently categorized into at least 10 genogroups which are further classified into more than 40 genotypes. In addition to humans, norovirus can infect a broad range of hosts including livestock, pets, and wild animals, e.g., marine mammals and bats. Little is known about norovirus infections in most non-human hosts, but the close genetic relatedness between some animal and human noroviruses coupled with lack of understanding where newly appearing human norovirus genotypes and variants are emerging from has led to the hypothesis that norovirus may not be host restricted and might be able to jump the species barrier. We have systematically reviewed the literature to describe the diversity, prevalence, and geographic distribution of noroviruses found in animals, and the pathology associated with infection. We further discuss the evidence that exists for or against interspecies transmission including surveillance data and data from in vitro and in vivo experiments.
hqo2p060
hqo2p060
2019-05-25
10.3390/v11050478
1
Developing clinical practice guidelines for the integration of Chinese medicine and biomedicine: A new process
Abstract Introduction Despite the integration of Chinese medicine and biomedicine which has emerged in clinical practice worldwide, a comprehensive development process for clinical practice guidelines (CPG) has up to now been missing. A valid method for the rational use of predictions for herb-drug interaction is a biggest challenge in guideline development process. Methods This article summarises the development process by reviewing key literature from CPG developers. It focuseson key methods and challenges specific to CPGs for integration by using text mining and bioinformatics to provide a powerful adjunct to CPG development. Results The guideline development process identified, together with new approaches, incorporates evidence-based methodology and provides better decisions through analysis of uncertain herb-drug interaction. Conclusions This new process used three basic phases (preparation, development, and finalization) and seven steps providing a set of methodological principles for CPG development intergrating Chinese medicine and biomedicine.
hqoluzz2
hqoluzz2
2016-12-31
10.1016/j.eujim.2016.11.013
1.5
Boosting the arsenal against COVID-19 through computational drug repurposing
hrntvohh
hrntvohh
2020-04-15
10.1016/j.drudis.2020.04.005
2
Drug repurposing screens reveal FDA approved drugs active against SARS-Cov-2
There are an urgent need for antivirals to treat the newly emerged SARS-CoV-2. To identify new candidates we screened a repurposing library of ~3,000 drugs. Screening in Vero cells found few antivirals, while screening in human Huh7.5 cells validated 23 diverse antiviral drugs. Extending our studies to lung epithelial cells, we found that there are major differences in drug sensitivity and entry pathways used by SARS-CoV-2 in these cells. Entry in lung epithelial Calu-3 cells is pH-independent and requires TMPRSS2, while entry in Vero and Huh7.5 cells requires low pH and triggering by acid-dependent endosomal proteases. Moreover, we found 9 drugs are antiviral in lung cells, 7 of which have been tested in humans, and 3 are FDA approved including Cyclosporine which we found is targeting Cyclophilin rather than Calcineurin for its antiviral activity. These antivirals reveal essential host targets and have the potential for rapid clinical implementation.
hsc2x36j
hsc2x36j
2020-06-19
10.1101/2020.06.19.161042
5
Inbred Strain Variant Database (ISVdb): A Repository for Probabilistically Informed Sequence Differences Among the Collaborative Cross Strains and Their Founders
The Collaborative Cross (CC) is a panel of recently established multiparental recombinant inbred mouse strains. For the CC, as for any multiparental population (MPP), effective experimental design and analysis benefit from detailed knowledge of the genetic differences between strains. Such differences can be directly determined by sequencing, but until now whole-genome sequencing was not publicly available for individual CC strains. An alternative and complementary approach is to infer genetic differences by combining two pieces of information: probabilistic estimates of the CC haplotype mosaic from a custom genotyping array, and probabilistic variant calls from sequencing of the CC founders. The computation for this inference, especially when performed genome-wide, can be intricate and time-consuming, requiring the researcher to generate nontrivial and potentially error-prone scripts. To provide standardized, easy-to-access CC sequence information, we have developed the Inbred Strain Variant Database (ISVdb). The ISVdb provides, for all the exonic variants from the Sanger Institute mouse sequencing dataset, direct sequence information for CC founders and, critically, the imputed sequence information for CC strains. Notably, the ISVdb also: (1) provides predicted variant consequence metadata; (2) allows rapid simulation of F1 populations; and (3) preserves imputation uncertainty, which will allow imputed data to be refined in the future as additional sequencing and genotyping data are collected. The ISVdb information is housed in an SQL database and is easily accessible through a custom online interface (http://isvdb.unc.edu), reducing the analytic burden on any researcher using the CC.
hstomkk5
hstomkk5
2017-06-05
10.1534/g3.117.041491
1
Lymphocytopaenia is associated with severe SARS-CoV-2 disease: A Systematic Review and Meta-Analysis of Clinical Data
Background: Most patients infected by SARS-CoV-2 have favourable outcomes, however some develop severe disease which may progress to acute respiratory distress syndrome, multi-organ failure, and death. Markers that could predict patients at risk of poor outcomes would be extremely useful clinically. Evidence has emerged that low lymphocyte count is associated with increased disease severity. Methods: We performed a systematic review and meta-analysis to assess the association between lymphocyte count and severity of SARS-CoV-2 associated clinical disease. Results: Seven papers were included in the meta-analysis. These papers included data from 2083 patients, 25% (n=521) with severe SAR-CoV-2 disease and 75% (n=1562) with non-severe SAR-CoV-2 disease. Heterogenicity was seen in the definition of severe disease. Metanalysis produced metamedians of 1x109/L (95% CI 1-1.1) and 0.7x109/L (95% CI 0.63-0.8) lymphocytes for patients with non-severe and severe disease respectively (p-value of p=0.006 Wilcoxon test). Calculation of metamedians from the two papers classifying severe disease according to death alone gave 1.1 1x109/L lymphocytes (95% CI 1.0-1.1) for “survivors” (n=163) and 0.63 1x109/L lymphocytes (95% CI 0.60-0.63) for “non-survivors” (n=253) of SAR-CoV-2 disease. Conclusions: Lower lymphocyte counts are significantly associated with more severe disease in patients with SARS-CoV-2 infection. Lymphocytopenia may therefore be useful laboratory measure to allow prognostication of patients presenting with SARS-CoV-2 infection.
hv7y5apt
hv7y5apt
2020-04-17
10.1101/2020.04.14.20064659
2
Port d’Entrée for Respiratory Infections – Does the Influenza A Virus Pave the Way for Bacteria?
Bacterial and viral co-infections of the respiratory tract are life-threatening and present a global burden to the global community. Staphylococcus aureus, Streptococcus pneumoniae, and Streptococcus pyogenes are frequent colonizers of the upper respiratory tract. Imbalances through acquisition of seasonal viruses, e.g., Influenza A virus, can lead to bacterial dissemination to the lower respiratory tract, which in turn can result in severe pneumonia. In this review, we summarize the current knowledge about bacterial and viral co-infections of the respiratory tract and focus on potential experimental models suitable for mimicking this disease. Transmission of IAV and pneumonia is mainly modeled by mouse infection. Few studies utilizing ferrets, rats, guinea pigs, rabbits, and non-human primates are also available. The knowledge gained from these studies led to important discoveries and advances in understanding these infectious diseases. Nevertheless, mouse and other infection models have limitations, especially in translation of the discoveries to humans. Here, we suggest the use of human engineered lung tissue, human ex vivo lung tissue, and porcine models to study respiratory co-infections, which might contribute to a greater translation of the results to humans and improve both, animal and human health.
hwywzb0a
hwywzb0a
2017-12-21
10.3389/fmicb.2017.02602
1.5
FOCIS abstract supplement
hxj4z228
hxj4z228
2005-04-19
10.1016/j.clim.2005.03.007
1.5
An artificial intelligence system reveals liquiritin inhibits SARS-CoV-2 by mimicking type I interferon
The pandemic COVID-19 has spread to all over the world and greatly threatens safety and health of people. COVID-19 is highly infectious and with high mortality rate. As no effective antiviral treatment is currently available, new drugs are urgently needed. We employed transcriptional analysis to uncover potential antiviral drugs from natural products or FDA approved drugs. We found liquiritin significantly inhibit replication of SARS-CoV-2 in Vero E6 cells with EC50 = 2.39 μM. Mechanistically, we found liquiritin exerts anti-viral function by mimicking type I interferon. Upregulated genes induced by liquiritin are enriched in GO categories including type I interferon signaling pathway, negative regulation of viral genome replication and etc. In toxicity experiment, no death was observed when treated at dose of 300 mg/kg for a week in ICR mice. All the organ indexes but liver and serum biochemical indexes were normal after treatment. Liquiritin is abundant in licorice tablet (~0.2% by mass), a traditional Chinese medicine. Together, we recommend liquiritin as a competitive candidate for treating COVID-19. We also expect liquiritin to have a broad and potent antiviral function to other viral pathogens, like HBV, HIV and etc.
hxq6zazs
hxq6zazs
2020-05-02
10.1101/2020.05.02.074021
5
Middle East Respiratory Syndrome and Severe Acute Respiratory Syndrome: Current Therapeutic Options and Potential Targets for Novel Therapies
No specific antivirals are currently available for two emerging infectious diseases, Middle East respiratory syndrome (MERS) and severe acute respiratory syndrome (SARS). A literature search covering pathogenesis, clinical features and therapeutics, clinically developed drugs for repurposing and novel drug targets was performed. This review presents current knowledge on the epidemiology, pathogenesis and clinical features of the SARS and MERS coronaviruses. The rationale for and outcomes with treatments used for SARS and MERS is discussed. The main focus of the review is on drug development and the potential that drugs approved for other indications provide for repurposing. The drugs we discuss belong to a wide range of different drug classes, such as cancer therapeutics, antipsychotics, and antimalarials. In addition to their activity against MERS and SARS coronaviruses, many of these approved drugs have broad-spectrum potential and have already been in clinical use for treating other viral infections. A wealth of knowledge is available for these drugs. However, the information in this review is not meant to guide clinical decisions, and any therapeutic described here should only be used in context of a clinical trial. Potential targets for novel antivirals and antibodies are discussed as well as lessons learned from treatment development for other RNA viruses. The article concludes with a discussion of the gaps in our knowledge and areas for future research on emerging coronaviruses.
hyihoelf
hyihoelf
2017-12-16
10.1007/s40265-017-0830-1
0.5
Potential inhibitors against 2019-nCoV coronavirus M protease from clinically approved medicines
hylue5wq
hylue5wq
2020-02-20
10.1016/j.jgg.2020.02.001
2.5
Geo temporal distribution of 1,688 Chinese healthcare workers infected with COVID-19 in severe conditions, a secondary data analysis
Introduction The COVID 19 outbreak is posing an unprecedented challenge to healthcare workers. This study analyzes the geo temporal effects on disease severity for the 1,688 Chinese healthcare workers infected with COVID 19. Method Using the descriptive results recently reported by the Chinese CDC, we compare the percentage of infected healthcare workers in severe conditions over time and across three areas in China, and the fatality rate of infected healthcare workers with all the infected individuals in China aged 22 to 59 years. Results Among the infected Chinese healthcare workers whose symptoms onset appeared during the same ten day period, the percentage of those in severe conditions decreased statistical significantly from 19.7% (Jan 11 to 20) to 14.4% (Jan 21 to 31) to 8.7% (Feb 1 to 11). Across the country, there was also a significant difference in the disease severity among patients symptoms onset during the same period, with Wuhan being the most severe (17%), followed by Hubei Province (10.4%), and the rest of China (7.0%). The case fatality rate for the 1,688 infected Chinese healthcare workers was significantly lower than that for the 29,798 infected patients aged 20 to 59 years 0.3% (5/1,688) vs. 0.65% (193/29,798), respectively. Conclusion The disease severity improved considerably over a short period of time in China. The more severe conditions in Wuhan compared to the rest of the country may be attributable to the draconian lockdown. The clinical outcomes of infected Chinese healthcare workers may represent a more accurate estimation of the severity of COVID 19 for those who have access to quality healthcare.
hypyxzk2
hypyxzk2
2020-03-23
10.1101/2020.03.19.20032532
1
Virus discovery: one step beyond
Recent advances in the metagenomics field have had huge effects on the identification and characterization of newly emerging viral pathogens. To allow timely and efficient responses to future viral threats, an integrated multidisciplinary approach utilizing expertises in several areas, including clinical assessment, virus surveillance, virus discovery, pathogenesis, and the molecular basis of the host response to infection, is required. It requires the scientific community involved in virus discovery to go one step beyond.
hzu9cw2m
hzu9cw2m
2013-04-30
10.1016/j.coviro.2013.03.007
2.5
Pathological and Virological Analyses of Severe Acute Respiratory Syndrome–Associated Coronavirus Infections in Experimantal Animals
i02z0hgx
i02z0hgx
2006
10.1007/978-0-387-33012-9_92
1.5
Unravelling lead antiviral phytochemicals for the inhibition of SARS-CoV-2 M(pro) enzyme through in silico approach
A new SARS coronavirus (SARS-CoV-2) belonging to the genus Betacoronavirus has caused a pandemic known as COVID-19. Among coronaviruses, the main protease (M(pro)) is an essential drug target which, along with papain-like proteases catalyzes the processing of polyproteins translated from viral RNA and recognizes specific cleavage sites. There are no human proteases with similar cleavage specificity and therefore, inhibitors are highly likely to be nontoxic. Therefore, targeting the SARS-CoV-2 M(pro) enzyme with small molecules can block viral replication. The present study is aimed at the identification of promising lead molecules for SARS-CoV-2 M(pro) enzyme through virtual screening of antiviral compounds from plants. The binding affinity of selected small drug-like molecules to SARS-CoV-2 M(pro), SARS-CoV M(pro) and MERS-CoV M(pro) were studied using molecular docking. Bonducellpin D was identified as the best lead molecule which shows higher binding affinity (−9.28 kcal/mol) as compared to the control (−8.24 kcal/mol). The molecular binding was stabilized through four hydrogen bonds with Glu166 and Thr190 as well as hydrophobic interactions via eight residues. The SARS-CoV-2 M(pro) shows identities of 96.08% and 50.65% to that of SARS-CoV M(pro) and MERS-CoV M(pro) respectively at the sequence level. At the structural level, the root mean square deviation (RMSD) between SARS-CoV-2 M(pro) and SARS-CoV M(pro) was found to be 0.517 Å and 0.817 Å between SARS-CoV-2 M(pro) and MERS-CoV M(pro). Bonducellpin D exhibited broad-spectrum inhibition potential against SARS-CoV M(pro) and MERS-CoV M(pro) and therefore is a promising drug candidate, which needs further validations through in vitro and in vivo studies.
i0d4lxko
i0d4lxko
2020-05-22
10.1016/j.lfs.2020.117831
4.5
In Silico Discovery of Candidate Drugs against Covid-19
Previous studies reported that Angiotensin converting enzyme 2 (ACE2) is the main cell receptor of SARS-CoV and SARS-CoV-2. It plays a key role in the access of the virus into the cell to produce the final infection. In the present study we investigated in silico the basic mechanism of ACE2 in the lung and provided evidences for new potentially effective drugs for Covid-19. Specifically, we used the gene expression profiles from public datasets including The Cancer Genome Atlas, Gene Expression Omnibus and Genotype-Tissue Expression, Gene Ontology and pathway enrichment analysis to investigate the main functions of ACE2-correlated genes. We constructed a protein-protein interaction network containing the genes co-expressed with ACE2. Finally, we focused on the genes in the network that are already associated with known drugs and evaluated their role for a potential treatment of Covid-19. Our results demonstrate that the genes correlated with ACE2 are mainly enriched in the sterol biosynthetic process, Aryldialkylphosphatase activity, adenosylhomocysteinase activity, trialkylsulfonium hydrolase activity, acetate-CoA and CoA ligase activity. We identified a network of 193 genes, 222 interactions and 36 potential drugs that could have a crucial role. Among possible interesting drugs for Covid-19 treatment, we found Nimesulide, Fluticasone Propionate, Thiabendazole, Photofrin, Didanosine and Flutamide.
i0mti49x
i0mti49x
2020
3
Immunogenicity of a DNA vaccine candidate for COVID-19
The coronavirus family member, SARS-CoV-2 has been identified as the causal agent for the pandemic viral pneumonia disease, COVID-19. At this time, no vaccine is available to control further dissemination of the disease. We have previously engineered a synthetic DNA vaccine targeting the MERS coronavirus Spike (S) protein, the major surface antigen of coronaviruses, which is currently in clinical study. Here we build on this prior experience to generate a synthetic DNA-based vaccine candidate targeting SARS-CoV-2 S protein. The engineered construct, INO-4800, results in robust expression of the S protein in vitro. Following immunization of mice and guinea pigs with INO-4800 we measure antigen-specific T cell responses, functional antibodies which neutralize the SARS-CoV-2 infection and block Spike protein binding to the ACE2 receptor, and biodistribution of SARS-CoV-2 targeting antibodies to the lungs. This preliminary dataset identifies INO-4800 as a potential COVID-19 vaccine candidate, supporting further translational study.
i1hyk962
i1hyk962
2020-05-20
10.1038/s41467-020-16505-0
4
Analysis of therapeutic targets for SARS-CoV-2 and discovery of potential drugs by computational methods
SARS-CoV-2 has caused tens of thousands of infections and more than one thousand deaths. There are currently no registered therapies for treating coronavirus infections. Because of time consuming process of new drug development, drug repositioning may be the only solution to the epidemic of sudden infectious diseases. We systematically analyzed all the proteins encoded by SARS-CoV-2 genes, compared them with proteins from other coronaviruses, predicted their structures, and built 19 structures that could be done by homology modeling. By performing target-based virtual ligand screening, a total of 21 targets (including two human targets) were screened against compound libraries including ZINC drug database and our own database of natural products. Structure and screening results of important targets such as 3-chymotrypsin-like protease (3CLpro), Spike, RNA-dependent RNA polymerase (RdRp), and papain like protease (PLpro) were discussed in detail. In addition, a database of 78 commonly used anti-viral drugs including those currently on the market and undergoing clinical trials for SARS-CoV-2 was constructed. Possible targets of these compounds and potential drugs acting on a certain target were predicted. This study will provide new lead compounds and targets for further in vitro and in vivo studies of SARS-CoV-2, new insights for those drugs currently ongoing clinical studies, and also possible new strategies for drug repositioning to treat SARS-CoV-2 infections.
i1lyno9g
i1lyno9g
2020
4.5
Neutralizing antibody against severe acute respiratory syndrome (SARS)‐coronavirus spike is highly effective for the protection of mice in the murine SARS model
We evaluated the efficacy of three SARS vaccine candidates in a murine SARS model utilizing low‐virulence Pp and SARS‐CoV coinfection. Vaccinated mice were protected from severe respiratory disease in parallel with a low virus titer in the lungs and a high neutralizing antibody titer in the plasma. Importantly, the administration of spike protein‐specific neutralizing monoclonal antibody protected mice from the disease, indicating that the neutralization is sufficient for protection. Moreover, a high level of IL‐6 and MCP‐1 production, but not other 18 cytokines tested, on days 2 and 3 after SARS‐CoV infection was closely linked to the virus replication and disease severity, suggesting the importance of these cytokines in the lung pathogenicity of SARS‐CoV infection.
i21njpno
i21njpno
2008-11-10
10.1111/j.1348-0421.2008.00097.x
4.5
ECB12: 12th European Congess on Biotechnology
i2reanan
i2reanan
2005-07-19
10.1016/j.jbiotec.2005.06.005
2.5
Suramin inhibits SARS-CoV-2 infection in cell culture by interfering with early steps of the replication cycle.
The SARS-CoV-2 pandemic that originated from Wuhan, China, in December 2019 has impacted public health, society and economy and the daily lives of billions of people in an unprecedented manner. There are currently no specific registered antiviral drugs to treat or prevent SARS-CoV-2 infections. Therefore, drug repurposing would be the fastest route to provide at least a temporary solution while better, more specific drugs are being developed. Here we demonstrate that the antiparasitic drug suramin inhibits SARS-CoV-2 replication, protecting Vero E6 cells with an EC50 of ∼20 μM, which is well below the maximum attainable level in human serum. Suramin also decreased the viral load by 2-3 logs when Vero E6 cells or cells of a human lung epithelial cell line (Calu-3) were treated. Time of addition and plaque reduction assays performed on Vero E6 cells showed that suramin acts on early steps of the replication cycle, possibly preventing binding or entry of the virus. In a primary human airway epithelial cell culture model, suramin also inhibited the progression of infection. The results of our preclinical study warrant further investigation and suggest it is worth evaluating whether suramin provides any benefit for COVID-19 patients, which obviously requires safety studies and well-designed, properly controlled randomized clinical trials.
i3674z5x
i3674z5x
2020-06-08
10.1128/aac.00900-20
4
Antiviral Efficacy of Verdinexor In Vivo in Two Animal Models of Influenza A Virus Infection
Influenza A virus (IAV) causes seasonal epidemics of respiratory illness that can cause mild to severe illness and potentially death. Antiviral drugs are an important countermeasure against IAV; however, drug resistance has developed, thus new therapeutic approaches are being sought. Previously, we demonstrated the antiviral activity of a novel nuclear export inhibitor drug, verdinexor, to reduce influenza replication in vitro and pulmonary virus burden in mice. In this study, in vivo efficacy of verdinexor was further evaluated in two animal models or influenza virus infection, mice and ferrets. In mice, verdinexor was efficacious to limit virus shedding, reduce pulmonary pro-inflammatory cytokine expression, and moderate leukocyte infiltration into the bronchoalveolar space. Similarly, verdinexor-treated ferrets had reduced lung pathology, virus burden, and inflammatory cytokine expression in the nasal wash exudate. These findings support the anti-viral efficacy of verdinexor, and warrant its development as a novel antiviral therapeutic for influenza infection.
i3681ul1
i3681ul1
2016-11-28
10.1371/journal.pone.0167221
3
Hospital pharmacists’ pharmaceutical care for hospitalized patients with COVID-19: Recommendations and guidance from clinical experience
Abstract Objective To discuss hospital pharmacists’ role in providing pharmaceutical care for hospitalized patients with COVID-19 to promote patient care and management during the pandemic. Method Based on the method of evidence-based pharmacy, clinical evidence of therapeutical drugs for COVID-19 were retrieved and summarized. Based on clinical experience Chinese hospital pharmacists gained from providing pharmaceutical care services during COVID-19 pandemic, taking COVID-19 hospitalized patients’ needs into consideration, the methods and strategies hospital pharmacists shall use to provide pharmaceutical care were analyzed and summarized. Results Hospital pharmacists shall support pharmaceutical care services by participating in making evidence-based decisions for medication, monitoring and evaluation of medication safety and efficacy, providing strengthened care for special population and patients with combined underlying diseases, monitoring and management of convalescent plasma therapy, providing emotional counselling and psychological support, and providing scientific information about COVID-19 vaccines. Conclusion The need of pharmaceutical care services in COVID-19 hospitalized patients during this pandemic was quite distinguished from the past. Hospital pharmacists shall join the collaborative multidisciplinary team to improve COVID-19 patients’ outcome and reduce mortality, and to facilitate the pandemic control.
i3b647wv
i3b647wv
2020-04-03
10.1016/j.sapharm.2020.03.027
1.5
Animal models: an important tool in mycology
Animal models of fungal infections are, and will remain, a key tool in the advancement of the medical mycology. Many different types of animal models of fungal infection have been developed, with murine models the most frequently used, for studies of pathogenesis, virulence, immunology, diagnosis, and therapy. The ability to control numerous variables in performing the model allows us to mimic human disease states and quantitatively monitor the course of the disease. However, no single model can answer all questions and different animal species or different routes of infection can show somewhat different results. Thus, the choice of which animal model to use must be made carefully, addressing issues of the type of human disease to mimic, the parameters to follow and collection of the appropriate data to answer those questions being asked. This review addresses a variety of uses for animal models in medical mycology. It focuses on the most clinically important diseases affecting humans and cites various examples of the different types of studies that have been performed. Overall, animal models of fungal infection will continue to be valuable tools in addressing questions concerning fungal infections and contribute to our deeper understanding of how these infections occur, progress and can be controlled and eliminated.
i4t84krs
i4t84krs
2007-12-16
10.1080/13693780701644140
1.5
Interactions of coronaviruses with ACE2, angiotensin II, and RAS inhibitors-lessons from available evidence and insights into COVID-19
The rapid spread of a novel coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has led to an ongoing pandemic of coronavirus disease 2019 (COVID-19). Recently, angiotensin-converting enzyme 2 (ACE2) has been shown to be a functional receptor for SARS-CoV-2 to enter host target cells. Given that angiotensin receptor blockers (ARBs) and an ACE inhibitor (ACEI) upregulated ACE2 expression in animal studies, the concern might arise regarding whether ARBs and ACEIs would increase the morbidity and mortality of COVID-19. On the other hand, animal data suggested a potential protective effect of ARBs against COVID-19 pneumonia because an ARB prevented the aggravation of acute lung injury in mice infected with SARS-CoV, which is closely related to SARS-CoV-2. Importantly, however, there is no clinical or experimental evidence supporting that ARBs and ACEIs either augment the susceptibility to SARS-CoV-2 or aggravate the severity and outcomes of COVID-19 at present. Until further data are available, it is recommended that ARB and ACEI medications be continued for the treatment of patients with cardiovascular disease and hypertension, especially those at high risk, according to guideline-directed medical therapy based on the currently available evidence.
i5i2owvv
i5i2owvv
2020
3
COVID-19: Living through Another Pandemic
Novel beta-coronavirus SARS-CoV-2 is the pathogenic agent responsible for coronavirus disease-2019 (COVID-19), a globally pandemic infectious disease. Due to its high virulence and the absence of immunity among the general population, SARS-CoV-2 has quickly spread to all countries. This pandemic highlights the urgent unmet need to expand and focus our research tools on what are considered “neglected infectious diseases” and to prepare for future inevitable pandemics. This global emergency has generated unprecedented momentum and scientific efforts around the globe unifying scientists from academia, government and the pharmaceutical industry to accelerate the discovery of vaccines and treatments. Herein, we shed light on the virus structure and life cycle and the potential therapeutic targets in SARS-CoV-2 and briefly refer to both active and passive immunization modalities, drug repurposing focused on speed to market, and novel agents against specific viral targets as therapeutic interventions for COVID-19.
i5wbndov
i5wbndov
2020-05-10
10.1021/acsinfecdis.0c00224
3
Characterization of the SARS-CoV-2 Spike in an Early Prefusion Conformation
Pandemic coronavirus disease 2019 (COVID-19) is caused by the emerging severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), for which there are no efficacious vaccines or therapeutics that are urgently needed. We expressed three versions of spike (S) proteins—receptor binding domain (RBD), S1 subunit and S ectodomain—in insect cells. RBD appears monomer in solutions, whereas S1 and S associate into homotrimer with substantial glycosylation. The three proteins confer excellent antigenicity with six convalescent COVID-19 patient sera. Cryo-electron microscopy (cryo-EM) analyses indicate that the SARS-CoV-2 S trimer dominate in a unique conformation distinguished from the classic prefusion conformation of coronaviruses by the upper S1 region at lower position ~15 Å proximal to viral membrane. Such conformation is proposed as an early prefusion state for the SARS-CoV-2 spike that may broaden the knowledge of coronavirus and facilitate vaccine development.
i9r77o70
i9r77o70
2020-03-18
10.1101/2020.03.16.994152
1.5
Modeling pathogenesis of emergent and pre-emergent human coronaviruses in mice
The emergence of highly pathogenic human coronaviruses (hCoVs) in the last two decades has illuminated their potential to cause high morbidity and mortality in human populations and disrupt global economies. Global pandemic concerns stem from their high mortality rates, capacity for human-to-human spread by respiratory transmission, and complete lack of approved therapeutic countermeasures. Limiting disease may require the development of virus-directed and host-directed therapeutic strategies due to the acute etiology of hCoV infections. Therefore, understanding how hCoV–host interactions cause pathogenic outcomes relies upon mammalian models that closely recapitulate the pathogenesis of hCoVs in humans. Pragmatism has largely been the driving force underpinning mice as highly effective mammalian models for elucidating hCoV–host interactions that govern pathogenesis. Notably, tractable mouse genetics combined with hCoV reverse genetic systems has afforded the concomitant manipulation of virus and host genetics to evaluate virus–host interaction networks in disease. In addition to assessing etiologies of known hCoVs, mouse models have clinically predictive value as tools to appraise potential disease phenotypes associated with pre-emergent CoVs. Knowledge of CoV pathogenic potential before it crosses the species barrier into the human population provides a highly desirable preclinical platform for addressing global pathogen preparedness, an overarching directive of the World Health Organization. Although we recognize that results obtained in robust mouse models require evaluation in non-human primates, we focus this review on the current state of hCoV mouse models, their use as tractable complex genetic organisms for untangling complex hCoV–host interactions, and as pathogenesis models for preclinical evaluation of novel therapeutic interventions.
i9tzr13z
i9tzr13z
2018-07-24
10.1007/s00335-018-9760-9
1.5
A Potently Neutralizing Antibody Protects Mice against SARS-CoV-2 Infection
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is responsible for millions of infections and hundreds of thousands of deaths globally. There are no widely available licensed therapeutics against SARS-CoV-2, highlighting an urgent need for effective interventions. The virus enters host cells through binding of a receptor-binding domain within its trimeric spike glycoprotein to human angiotensin-converting enzyme 2. In this article, we describe the generation and characterization of a panel of murine mAbs directed against the receptor-binding domain. One mAb, 2B04, neutralized wild-type SARS-CoV-2 in vitro with remarkable potency (half-maximal inhibitory concentration of <2 ng/ml). In a murine model of SARS-CoV-2 infection, 2B04 protected challenged animals from weight loss, reduced lung viral load, and blocked systemic dissemination. Thus, 2B04 is a promising candidate for an effective antiviral that can be used to prevent SARS-CoV-2 infection.
iausfh0f
iausfh0f
2020
5
COvid MEdicaTion (COMET) study: protocol for a cohort study
Various theories about drugs such as ACE inhibitors or angiotensin II receptor blockers (ARBs) in relation to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and clinical outcomes of COVID-19 are circulating in both mainstream media and medical literature. These are based on the fact that ACE2 facilitates SARS-CoV-2 cell invasion via binding of a viral spike protein to ACE2. However, the effect of ACE inhibitors, ARBs and other drugs on ACE2 is unclear and all theories are based on conflicting evidence mainly from animal studies. Therefore, clinical evidence is urgently needed. The aim of this study is to investigate the relationship between use of these drugs on clinical outcome of patients with COVID-19. Patients will be included from several hospitals in Europe. Data will be collected in a user-friendly database (Digitalis) on an external server. Analyses will be adjusted for sex, age and presence of cardiovascular disease, hypertension and diabetes. These results will enable more rational choices for randomised controlled trials for preventive and therapeutic strategies in COVID-19.
icjt8bbw
icjt8bbw
2020-06-25
10.1136/ejhpharm-2020-002329
5
Low serum 25-hydroxyvitamin D levels are associated with increased risk of viral coinfections in wheezing children
icp5iuwb
icp5iuwb
2010-11-02
10.1016/j.jaci.2010.09.004
4.5
The E Protein Is a Multifunctional Membrane Protein of SARS-CoV
The E (envelope) protein is the smallest structural protein in all coronaviruses and is the only viral structural protein in which no variation has been detected. We conducted genome sequencing and phylogenetic analyses of SARS-CoV. Based on genome sequencing, we predicted the E protein is a transmembrane (TM) protein characterized by a TM region with strong hydrophobicity and α-helix conformation. We identified a segment (NH(2)-_L-Cys-A-Y-Cys-Cys-N_-COOH) in the carboxyl-terminal region of the E protein that appears to form three disulfide bonds with another segment of corresponding cysteines in the carboxyl-terminus of the S (spike) protein. These bonds point to a possible structural association between the E and S proteins. Our phylogenetic analyses of the E protein sequences in all published coronaviruses place SARS-CoV in an independent group in Coronaviridae and suggest a non-human animal origin.
ids74oez
ids74oez
2016-11-28
10.1016/s1672-0229(03)01017-9
2.5
SARS-CoV-2 and Coronavirus Disease 2019: What We Know So Far
In December 2019, a cluster of fatal pneumonia cases presented in Wuhan, China. They were caused by a previously unknown coronavirus. All patients had been associated with the Wuhan Wholefood market, where seafood and live animals are sold. The virus spread rapidly and public health authorities in China initiated a containment effort. However, by that time, travelers had carried the virus to many countries, sparking memories of the previous coronavirus epidemics, severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS), and causing widespread media attention and panic. Based on clinical criteria and available serological and molecular information, the new disease was called coronavirus disease of 2019 (COVID-19), and the novel coronavirus was called SARS Coronavirus-2 (SARS-CoV-2), emphasizing its close relationship to the 2002 SARS virus (SARS-CoV). The scientific community raced to uncover the origin of the virus, understand the pathogenesis of the disease, develop treatment options, define the risk factors, and work on vaccine development. Here we present a summary of current knowledge regarding the novel coronavirus and the disease it causes.
ifoe8x28
ifoe8x28
2020-03-20
10.3390/pathogens9030231
3.5
On the evolutionary epidemiology of SARS-CoV-2
There is no doubt that the novel coronavirus SARS-CoV-2 that causes COVID-19 is mutating and thus has the potential to adapt during the current pandemic. Whether this evolution will lead to changes in the transmission, the duration, or the severity of the disease is not clear. This has led to considerable scientific and media debate, from raising alarms about evolutionary change to dismissing it. Here we review what little is currently known about the evolution of SARS-CoV-2 and extend existing evolutionary theory to consider how selection might be acting upon the virus during the COVID-19 pandemic. While there is currently no definitive evidence that SARS-CoV-2 is undergoing further adaptation, continued, evidence-based, analysis of evolutionary change is important so that public health measures can be adjusted in response to substantive changes in the infectivity or severity of COVID-19.
ig0rnbqb
ig0rnbqb
2020-06-11
10.1016/j.cub.2020.06.031
4
ACE2 polymorphisms and individual susceptibility to SARS-CoV-2 infection: insights from an in silico study
The current SARS covid-19 epidemic spread appears to be influenced by ethnical, geographical and sex-related factors that may involve genetic susceptibility to diseases. Similar to SARS-CoV, SARS-CoV-2 exploits angiotensin-converting enzyme 2 (ACE2) as a receptor to invade cells, notably type II alveolar epithelial cells. Importantly, ACE2 gene is highly polymorphic. Here we have used in silico tools to analyze the possible impact of ACE2 single-nucleotide polymorphisms (SNPs) on the interaction with SARS-CoV-2 spike glycoprotein. We found that S19P (common in African people) and K26R (common in European people) were, among the most diffused SNPs worldwide, the only two SNPs that were able to potentially affect the interaction of ACE2 with SARS-CoV-2 spike. FireDock simulations demonstrated that while S19P may decrease, K26R might increase the ACE2 affinity for SARS-CoV-2 Spike. This finding suggests that the S19P may genetically protect, and K26R may predispose to more severe SARS-CoV-2 disease.
iguhy1z8
iguhy1z8
2020-04-24
10.1101/2020.04.23.057042
3
Hypertension prevalence in human coronavirus disease: the role of ACE system in infection spread and severity
The prevalence of hypertension is high in patients affected by coronavirus disease 2019 (COVID-2019) and it appears to be related to an increased risk of mortality, as shown in many epidemiological studies. The angiotensin-converting enzyme (ACE) system is not uniformly expressed in all of the human races, and current differences could explain some of the geographical discrepancies in infection around the world. Furthermore, animal studies have shown that the ACE2 receptor is a potential pathway for host infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of COVID-19. As two-thirds of hypertensive patients take ACE inhibitors/angiotensin receptor blockers, several concerns have been raised about the detrimental role of current antihypertensive drugs in COVID-19. This report summarizes the recent evidence for and against the administration of ACE blockade in the COVID-19 era.
ih8oxr40
ih8oxr40
2020
5
Drug repositioning is an alternative for the treatment of coronavirus COVID-19
Given the extreme importance of the current pandemic caused by COVID-19, and as scientists agree there is no identified pharmacological treatment, where possible, therapeutic alternatives are raised through drug repositioning. This paper presents a selection of studies involving drugs from different pharmaceutical classes with activity against SARS-CoV-2 and SARS-CoV, with the potential for use in the treatment of COVID-19 disease.
ij8wk06v
ij8wk06v
2020
4.5
Crucial Inflammatory Mediators and Efficacy of Drug Interventions in Pneumonia Inflated COVID-19: An Invivo Mathematical Modelling Study
The virus SARS-COV-2 caused disease COVID-19 has been declared a pandemic by WHO. Currently, over 210 countries and territories have been affected. Careful, well-designed drugs and vaccine for the total elimination of this virus seem to be the need of the hour. In this context, the invivo mathematical modelling studies can be extremely helpful in understanding the efficacy of the drug interventions. These studies can also help understand the role of the crucial inflammatory mediators and the behaviour of immune response towards this novel coronavirus. Motivated by these facts, in this paper, we study the invivo dynamics of Covid-19. The results obtained here are inline with some of the clinical findings for Covid-19. This invivo modelling study involving the crucial biomarkers of Covid-19 is the first of its kind and the results obtained from this can be helpful to researchers, epidemiologists, clinicians and doctors who are working in this field.
ijnrx18l
ijnrx18l
2020-05-03
3.5
Nouveau coronavirus (NcOV)
ikz3vwgc
ikz3vwgc
2013-06-13
10.1016/j.lpm.2013.05.001
1.5
Computational Design of Peptides to Block Binding of the SARS-CoV-2 Spike Protein to Human ACE2
The outbreak of COVID-19 has now become a global pandemic and it continues to spread rapidly worldwide, severely threatening lives and economic stability. Making the problem worse, there is no specific antiviral drug that can be used to treat COVID-19 to date. SARS-CoV-2 initiates its entry into human cells by binding to angiotensin-converting enzyme 2 (hACE2) via the receptor binding domain (RBD) of its spike protein. Therefore, molecules that can block SARS-CoV-2 from binding to hACE2 may potentially prevent the virus from entering human cells and serve as an effective antiviral drug. Based on this idea, we designed a series of peptides that can strongly bind to SARS-CoV-2 RBD in computational experiments. Specifically, we first constructed a 31-mer peptidic scaffold by linking two fragments grafted from hACE2 (a.a. 22-44 and 351-357) with a linker glycine, and then redesigned the peptide sequence to enhance its binding affinity to SARS-CoV-2 RBD. Compared with several computational studies that failed to identify that SARS-CoV-2 shows higher binding affinity for hACE2 than SARS-CoV, our protein design scoring function, EvoEF2, makes a correct identification, which is consistent with the recently reported experimental data, implying its high accuracy. The top designed peptide binders exhibited much stronger binding potency to hACE2 than the wild-type (−53.35 vs. −46.46 EvoEF2 energy unit for design and wild-type, respectively). The extensive and detailed computational analyses support the high reasonability of the designed binders, which not only recapitulated the critical native binding interactions but also introduced new favorable interactions to enhance binding. Due to the urgent situation created by COVID-19, we share these computational data to the community, which should be helpful to develop potential antiviral peptide drugs to combat this pandemic.
imkeghfd
imkeghfd
2020-03-31
10.1101/2020.03.28.013607
1
Alisporivir inhibits MERS- and SARS-coronavirus replication in cell culture, but not SARS-coronavirus infection in a mouse model
Abstract Currently, there is no registered treatment for infections with emerging zoonotic coronaviruses like SARS- and MERS-coronavirus. We here report that in cultured cells low-micromolar concentrations of alisporivir, a non-immunosuppressive cyclosporin A-analog, inhibit the replication of four different coronaviruses, including MERS- and SARS-coronavirus. Ribavirin was found to further potentiate the antiviral effect of alisporivir in these cell culture-based infection models, but this combination treatment was unable to improve the outcome of SARS-CoV infection in a mouse model. Nevertheless, our data provide a basis to further explore the potential of Cyp inhibitors as host-directed, broad-spectrum inhibitors of coronavirus replication.
ipoj13va
ipoj13va
2017-01-15
10.1016/j.virusres.2016.11.011
2
Sequential circulation of canine adenoviruses 1 and 2 in captive wild carnivores, France
Abstract Scarce data are currently available about the ecology of canine adenoviruses (CAdVs) in wild carnivores. In this paper, the consecutive circulation of CAdV-1 and CAdV-2 in wild carnivores maintained in a French zoological park is reported. A fatal CAdV-1 infection was observed in a Eurasian wolf (Canis lupus lupus), which displayed gross lesions, histopathological changes and immunohistochemical findings suggestive of CAdV-1 infection. The virus was isolated on cell cultures and its genome was determined through next-generation sequencing, resulting genetically related to a recent Italian CAdV-1 strain detected in an Italian wolf. Subsequently, subclinical circulation of CAdV-2 was demonstrated by molecular methods in wild carnivores maintained in the same zoological park, some of which had been previously vaccinated with a CAdV-2 vaccine. Virus detection at a long distance from vaccination and by unvaccinated animals was suggestive of infection by a CAdV-2 field strain, although no data are available about the extent and duration of shedding of CAdV-2 modified-live virus in wild or domestic carnivores. The present paper provides new insights into the CAdV ecology in wildlife, although future studies are needed to fully understand the pathogenic potential of both CAdVs especially in endangered carnivore species.
ir86s8j0
ir86s8j0
2018-07-31
10.1016/j.vetmic.2018.05.025
3.5
In Vitro Inhibition of SARS-CoV-2 Infection by Bovine Lactoferrin
Since its emergence in late 2019, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been posing a serious threat to public health worldwide as the causative agent of coronavirus disease 2019 (COVID-19). Now distributed in a pandemic pattern, this disease still lacks an effective drug treatment with low toxicity, leading pharmaceutical companies and research labs to work against time to find a candidate molecule to efficiently treat the affected patients. Due to the well-known broad-spectrum antimicrobial activity of the lactoferrin protein, we sought to verify whether its bovine form (bLf) would also be effective in vitro against SARS-CoV-2. Using an antiviral assay based on quantitative reverse transcription-polymerase chain reaction (qRT-PCR), we found that bLf reduced progeny virus yield by up to ∼84,6% in African green monkey kidney epithelial cells (Vero E6) and ∼68,6% in adenocarcinomic human alveolar basal epithelial cells (A549) at 1 mg/mL, a concentration previously shown to have low cytotoxicity. Therefore, our preliminary data suggest that bLf has the potential to constitute a biochemical approach to fight the new coronavirus pandemic.
irqdb024
irqdb024
2020-05-13
10.1101/2020.05.13.093781
4.5
Gold nanoparticle‐adjuvanted S protein induces a strong antigen‐specific IgG response against severe acute respiratory syndrome‐related coronavirus infection, but fails to induce protective antibodies and limit eosinophilic infiltration in lungs
The spike (S) protein of coronavirus, which binds to cellular receptors and mediates membrane fusion for cell entry, is a candidate vaccine target for blocking coronavirus infection. However, some animal studies have suggested that inadequate immunization against severe acute respiratory syndrome coronavirus (SARS‐CoV) induces a lung eosinophilic immunopathology upon infection. The present study evaluated two kinds of vaccine adjuvants for use with recombinant S protein: gold nanoparticles (AuNPs), which are expected to function as both an antigen carrier and an adjuvant in immunization; and Toll‐like receptor (TLR) agonists, which have previously been shown to be an effective adjuvant in an ultraviolet‐inactivated SARS‐CoV vaccine. All the mice immunized with more than 0.5 µg S protein without adjuvant escaped from SARS after infection with mouse‐adapted SARS‐CoV; however, eosinophilic infiltrations were observed in the lungs of almost all the immunized mice. The AuNP‐adjuvanted protein induced a strong IgG response but failed to improve vaccine efficacy or to reduce eosinophilic infiltration because of highly allergic inflammatory responses. Whereas similar virus titers were observed in the control animals and the animals immunized with S protein with or without AuNPs, Type 1 interferon and pro‐inflammatory responses were moderate in the mice treated with S protein with and without AuNPs. On the other hand, the TLR agonist‐adjuvanted vaccine induced highly protective antibodies without eosinophilic infiltrations, as well as Th1/17 cytokine responses. The findings of this study will support the development of vaccines against severe pneumonia‐associated coronaviruses.
itrv27tm
itrv27tm
2019-11-18
10.1111/1348-0421.12754
4.5
Protocol and reagents for pseudotyping lentiviral particles with SARS-CoV-2 Spike protein for neutralization assays
SARS-CoV-2 enters cells using its Spike protein, which is also the main target of neutralizing antibodies. Therefore, assays to measure how antibodies and sera affect Spike-mediated viral infection are important for studying immunity. Because SARS-CoV-2 is a biosafety-level-3 virus, one way to simplify such assays is to pseudotype biosafety-level-2 viral particles with Spike. Such pseudotyping has now been described for single-cycle lentiviral, retroviral and VSV particles, but the reagents and protocols are not widely available. Here we detail how to effectively pseudotype lentiviral particles with SARS-CoV-2 Spike and infect 293T cells engineered to express the SARS-CoV-2 receptor, ACE2. We also make all the key experimental reagents available in the BEI Resources repository of ATCC and the NIH. Furthermore, we demonstrate how these pseudotyped lentiviral particles can be used to measure the neutralizing activity of human sera or plasma against SARS-CoV-2 in convenient luciferase-based assays, thereby providing a valuable complement to ELISA-based methods that measure antibody binding rather than neutralization.
iudsk7ac
iudsk7ac
2020-04-20
10.1101/2020.04.20.051219
3
Reprint of: Coronavirus reverse genetic systems: Infectious clones and replicons
Abstract Coronaviruses (CoVs) infect humans and many animal species, and are associated with respiratory, enteric, hepatic, and central nervous system diseases. The large size of the CoV genome and the instability of some CoV replicase gene sequences during its propagation in bacteria, represent serious obstacles for the development of reverse genetic systems similar to those used for smaller positive sense RNA viruses. To overcome these limitations, several alternatives to more conventional plasmid-based approaches have been established in the last 13 years. In this report, we briefly review and discuss the different reverse genetic systems developed for CoVs, paying special attention to the severe acute respiratory syndrome CoV (SARS-CoV).
iv4lzpev
iv4lzpev
2014-12-19
10.1016/j.virusres.2014.09.006
1.5
Genomics functional analysis and drug screening of SARS-CoV-2
Abstract A novel coronavirus appeared in Wuhan, China has led to major outbreaks. Recently, rapid classification of virus species, analysis of genome and screening for effective drugs are the most important tasks. In the present study, through literature review, sequence alignment, ORF identification, motif recognition, secondary and tertiary structure prediction, the whole genome of SARS-CoV-2 were comprehensively analyzed. To find effective drugs, the parameters of binding sites were calculated by SeeSAR. In addition, potential miRNAs were predicted according to RNA base-pairing. After prediction by using NCBI, WebMGA and GeneMark and comparison, a total of 8 credible ORFs were detected. Even the whole genome have great difference with other CoVs, each ORF has high homology with SARS-CoVs (>90%). Furthermore, domain composition in each ORFs was also similar to SARS. In the DrugBank database, only 7 potential drugs were screened based on the sequence search module. Further predicted binding sites between drug and ORFs revealed that 2-(N-Morpholino)-ethanesulfonic acid could bind 1# ORF in 4 different regions ideally. Meanwhile, both benzyl (2-oxopropyl) carbamate and 4-(dimehylamina) benzoic acid have bene demonstrated to inhibit SARS-CoV infection effectively. Interestingly, 2 miRNAs (miR-1307-3p and miR-3613-5p) were predicted to prevent virus replication via targeting 3′-UTR of the genome or as biomarkers. In conclusion, the novel coronavirus may have consanguinity with SARS. Drugs used to treat SARS may also be effective against the novel virus. In addition, altering miRNA expression may become a potential therapeutic schedule.
ivf3o5yu
ivf3o5yu
2020-04-14
10.1016/j.gendis.2020.04.002
3
Respiratory disease in rhesus macaques inoculated with SARS-CoV-2
An outbreak of coronavirus disease 2019 (COVID-19), which is caused by a novel coronavirus (named SARS-CoV-2) and has a case fatality rate of approximately 2%, started in Wuhan (China) in December 20191,2. Following an unprecedented global spread3, the World Health Organization declared COVID-19 a pandemic on 11 March 2020. Although data on COVID-19 in humans are emerging at a steady pace, some aspects of the pathogenesis of SARS-CoV-2 can be studied in detail only in animal models, in which repeated sampling and tissue collection is possible. Here we show that SARS-CoV-2 causes a respiratory disease in rhesus macaques that lasts between 8 and 16 days. Pulmonary infiltrates, which are a hallmark of COVID-19 in humans, were visible in lung radiographs. We detected high viral loads in swabs from the nose and throat of all of the macaques, as well as in bronchoalveolar lavages; in one macaque, we observed prolonged rectal shedding. Taken together, the rhesus macaque recapitulates the moderate disease that has been observed in the majority of human cases of COVID-19. The establishment of the rhesus macaque as a model of COVID-19 will increase our understanding of the pathogenesis of this disease, and aid in the development and testing of medical countermeasures.
ivvfcw85
ivvfcw85
2020
4.5
The FDA-approved drug ivermectin inhibits the replication of SARS-CoV-2 in vitro
Abstract Although several clinical trials are now underway to test possible therapies, the worldwide response to the COVID-19 outbreak has been largely limited to monitoring/containment. We report here that Ivermectin, an FDA-approved anti-parasitic previously shown to have broad-spectrum anti-viral activity in vitro, is an inhibitor of the causative virus (SARS-CoV-2), with a single addition to Vero-hSLAM cells 2 h post infection with SARS-CoV-2 able to effect ~5000-fold reduction in viral RNA at 48 h. Ivermectin therefore warrants further investigation for possible benefits in humans.
ivy95jpw
ivy95jpw
2020-06-30
10.1016/j.antiviral.2020.104787
1.5
Discovery of baicalin and baicalein as novel, natural product inhibitors of SARS-CoV-2 3CL protease in vitro
Human infections with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) cause coronavirus disease 19 (COVID-19) and there is currently no cure. The 3C-like protease (3CLpro), a highly conserved protease indispensable for replication of coronaviruses, is a promising target for development of broad-spectrum antiviral drugs. To advance the speed of drug discovery and development, we investigated the inhibition of SARS-CoV-2 3CLpro by natural products derived from Chinese traditional medicines. Baicalin and baicalein were identified as the first non-covalent, non-peptidomimetic inhibitors of SARS-CoV-2 3CLpro and exhibited potent antiviral activities in a cell-based system. Remarkably, the binding mode of baicalein with SARS-CoV-2 3CLpro determined by X-ray protein crystallography is distinctly different from those of known inhibitors. Baicalein is perfectly ensconced in the core of the substrate-binding pocket by interacting with two catalytic residues, the crucial S1/S2 subsites and the oxyanion loop, acting as a “shield” in front of the catalytic dyad to prevent the peptide substrate approaching the active site. The simple chemical structure, unique mode of action, and potent antiviral activities in vitro, coupled with the favorable safety data from clinical trials, emphasize that baicalein provides a great opportunity for the development of critically needed anti-coronaviral drugs.
ixun0c8g
ixun0c8g
2020-04-14
10.1101/2020.04.13.038687
3
An Urgent Need for “Common Cold Units” to Study COVID-19
ixz1835j
ixz1835j
2020-04-09
10.4269/ajtmh.20-0246
4
Energetics based epitope screening in SARS CoV-2 (COVID 19) spike glycoprotein by Immuno-informatic analysis aiming to a suitable vaccine development
The recent outbreak by SARS-CoV-2 has generated a chaos in global health and economy and claimed/infected a large number of lives. Closely resembling with SARS CoV, the present strain has manifested exceptionally higher degree of spreadability, virulence and stability possibly due to some unidentified mutations. The viral spike glycoprotein is very likely to interact with host Angiotensin-Converting Enzyme 2 (ACE2) and transmits its genetic materials and hijacks host machinery with extreme fidelity for self propagation. Few attempts have been made to develop a suitable vaccine or ACE2 blocker or virus-receptor inhibitor within this short period of time. Here, attempt was taken to develop some therapeutic and vaccination strategies with a comparison of spike glycoproteins among SARS-CoV, MERS-CoV and the SARS-CoV-2. We verified their structure quality (SWISS-MODEL, Phyre2, Pymol) topology (ProFunc), motifs (MEME Suite, GLAM2Scan), gene ontology based conserved domain (InterPro database) and screened several epitopes (SVMTrip) of SARS CoV-2 based on their energetics, IC50 and antigenicity with regard to their possible glycosylation and MHC/paratopic binding (Vaxigen v2.0, HawkDock, ZDOCK Server) effects. We screened here few pairs of spike protein epitopic regions and selected their energetic, IC50, MHC II reactivity and found some of those to be very good target for vaccination. A possible role of glycosylation on epitopic region showed profound effects on epitopic recognition. The present work might be helpful for the urgent development of a suitable vaccination regimen against SARS CoV-2.
iy4knx7j
iy4knx7j
2020-04-05
10.1101/2020.04.02.021725
3
An overview of coronaviruses including the SARS-2 coronavirus – Molecular biology, epidemiology and clinical implications
Abstract Coronavirus infections have emerged as epidemic and pandemic threats in last two decades. After the H1N1 influenza pandemic in 2009, recently diagnosed novel betacoronavirus or severe acute respiratory syndrome coronavirus (SARS-CoV)-2 has spread across 203 countries and territories in all 5 major continents. World Health Organization (WHO) declared this as a public health emergency of international concern on January 30, 2020. Subsequently on February 11, 2020 a new name was given to this disease i.e. COVID-19 by an expert group from WHO. As of April 12, 2020, 10:00 CET, GMT+2:00, 1,696,588 confirmed cases and 105,952 confirmed deaths have been reported to the WHO. (Coronavirus disease 2019, situation report 83). It possibly originated from a small animal market in Wuhan, China. A cluster of patients were admitted with unusual pneumonia not responding to treatment in various hospitals. Epidemiological, genomic analysis and correlation with other coronaviruses led to the isolation of new coronavirus, closely resembling the bat coronaviruses, from such patients in Wuhan. They were identified as the SARS-CoV-2. This virus infection presents as influenza like illness in the affected people. Fever, cough, respiratory distress with fatigue, diarrhea, nausea and vomiting are common symptoms seen in adults. This may progress on to respiratory distress, hypoxia, need for oxygen supplementation and ventilator support as seen in patients in the SARS-CoV-1 epidemic (2003) in Guangdong, China. The transmissibility of SARS-CoV-1 was less as compared to SARS-CoV-2 infection, and it was well controlled with good public health efforts. The present COVID-19 epidemic is still in the acceleration phase of 3 and 4 in various countries. Without any effective antiviral agents available at present, the need of the hour is early case detection, isolation of cases, use of good preventive care measures by the household contacts and in the hospital set up. The results of ongoing clinical trials on hydroxychloroquine, azithromycin alone or in combination and a new antiviral agent remdesivir may help to treat some of the infections. A need for effective vaccine is being seen an as good preventive strategy in this pandemic. However the results of clinical trials and incorporation of vaccines in public health programs is a long way to go.
izltn367
izltn367
2020-04-09
10.1016/j.cmrp.2020.04.001
3
Coronaviruses and their therapy
Abstract Coronaviruses may cause respiratory, enteric and central nervous system diseases in many species, including humans. Until recently, the relatively low burden of disease in humans caused by few of these viruses hampered development of coronavirus specific therapeutics. However, the emergence of severe acute respiratory syndrome coronavirus (SARS-CoV) has prompted the discovery of such drugs. Subsequent studies in animal models demonstrated the efficacy of SARS-CoV specific monoclonal antibodies, pegylated-interferon-α and siRNAs against SARS-CoV. Furthermore, several antivirals shown to be effective against other viruses were tested in vitro. Because of availability and shown efficacy, the use of interferons may be considered should SARS-CoV or a related coronavirus (re)-emerge. The more recent design of wide-spectrum inhibitors targeting the coronavirus main proteases may lead to the discovery of new antivirals against multiple coronavirus induced diseases.
j0496jb7
j0496jb7
2006-09-30
10.1016/j.antiviral.2006.05.019
1
Nonhuman Primate Models of Immunosenescence
Due to a dramatic increase in life expectancy, the number of individuals aged 65 and older is rapidly rising. This presents considerable challenges to our health care system since advanced age is associated with a higher susceptibility to infectious diseases due to immune senescence. However, the mechanisms underlying age-associated dysregulated immunity are still incompletely understood. Advancement in our comprehension of mechanisms of immune senescence and development of interventions to improve health span requires animal models that closely recapitulate the physiological changes that occur with aging in humans. Nonhuman primates (NHPs) are invaluable preclinical models to study the underlying causal mechanism of pathogenesis due to their outbred nature, high degree of genetic and physiological similarity to humans, and their susceptibility to human pathogens. In this chapter, we review NHP models available for biogerontology research, advantages and challenges they present, and advances they facilitated. Furthermore, we emphasize the utility of NHPs in characterizing immune senescence, evaluating interventions to reverse aging of the immune system, and development of vaccine strategies that are better suited for this vulnerable population.
j0exlr7c
j0exlr7c
2019-04-11
10.1007/978-3-319-99375-1_80
1.5
COVID-19 spike-host cell receptor GRP78 binding site prediction
Summary Objectives Understanding the novel coronavirus (COVID-19) mode of host cell recognition may help to fight the disease and save lives. The spike protein of coronaviruses is the main driving force for host cell recognition. Methods In this study, the COVID-19 spike binding site to the cell-surface receptor (Glucose Regulated Protein 78 (GRP78)) is predicted using combined molecular modeling docking and structural bioinformatics. The COVID-19 spike protein is modeled using its counterpart, the SARS spike. Results Sequence and structural alignments show that four regions, in addition to its cyclic nature have sequence and physicochemical similarities to the cyclic Pep42. Protein-protein docking was performed to test the four regions of the spike that fit tightly in the GRP78 Substrate Binding Domain β (SBDβ). The docking pose revealed the involvement of the SBDβ of GRP78 and the receptor-binding domain of the coronavirus spike protein in recognition of the host cell receptor. Conclusions We reveal that the binding is more favorable between regions III (C391-C525) and IV (C480-C488) of the spike protein model and GRP78. Region IV is the main driving force for GRP78 binding with the predicted binding affinity of -9.8 kcal/mol. These nine residues can be used to develop therapeutics specific against COVID-19.
j10308i3
j10308i3
2020-05-31
10.1016/j.jinf.2020.02.026
1
COVID-19 containment: China provides important lessons for global response
The world must act fast to contain wider international spread of the epidemic of COVID-19 now. The unprecedented public health efforts in China have contained the spread of this new virus. Measures taken in China are currently proven to reduce human-to-human transmission successfully. We summarized the effective intervention and prevention measures in the fields of public health response, clinical management, and research development in China, which may provide vital lessons for the global response. It is really important to take collaborative actions now to save more lives from the pandemic of COVID-19.
j2mvicsa
j2mvicsa
2020-03-25
10.1007/s11684-020-0766-9
3
SARS: Systematic Review of Treatment Effects
BACKGROUND: The SARS outbreak of 2002–2003 presented clinicians with a new, life-threatening disease for which they had no experience in treating and no research on the effectiveness of treatment options. The World Health Organization (WHO) expert panel on SARS treatment requested a systematic review and comprehensive summary of treatments used for SARS-infected patients in order to guide future treatment and identify priorities for research. METHODS AND FINDINGS: In response to the WHO request we conducted a systematic review of the published literature on ribavirin, corticosteroids, lopinavir and ritonavir (LPV/r), type I interferon (IFN), intravenous immunoglobulin (IVIG), and SARS convalescent plasma from both in vitro studies and in SARS patients. We also searched for clinical trial evidence of treatment for acute respiratory distress syndrome. Sources of data were the literature databases MEDLINE, EMBASE, BIOSIS, and the Cochrane Central Register of Controlled Trials (CENTRAL) up to February 2005. Data from publications were extracted and evidence within studies was classified using predefined criteria. In total, 54 SARS treatment studies, 15 in vitro studies, and three acute respiratory distress syndrome studies met our inclusion criteria. Within in vitro studies, ribavirin, lopinavir, and type I IFN showed inhibition of SARS-CoV in tissue culture. In SARS-infected patient reports on ribavirin, 26 studies were classified as inconclusive, and four showed possible harm. Seven studies of convalescent plasma or IVIG, three of IFN type I, and two of LPV/r were inconclusive. In 29 studies of steroid use, 25 were inconclusive and four were classified as causing possible harm. CONCLUSIONS: Despite an extensive literature reporting on SARS treatments, it was not possible to determine whether treatments benefited patients during the SARS outbreak. Some may have been harmful. Clinical trials should be designed to validate a standard protocol for dosage and timing, and to accrue data in real time during future outbreaks to monitor specific adverse effects and help inform treatment.
j35w1vsw
j35w1vsw
2006-09-12
10.1371/journal.pmed.0030343
0.5
An orally bioavailable broad-spectrum antiviral inhibits SARS-CoV-2 in human airway epithelial cell cultures and multiple coronaviruses in mice
Coronaviruses (CoVs) traffic frequently between species resulting in novel disease outbreaks, most recently exemplified by the newly emerged SARS-CoV-2, the causative agent of COVID-19. Herein, we show that the ribonucleoside analog β-D-N(4)-hydroxycytidine (NHC, EIDD-1931) has broad spectrum antiviral activity against SARS-CoV-2, MERS-CoV, SARS-CoV, and related zoonotic group 2b or 2c Bat-CoVs, as well as increased potency against a coronavirus bearing resistance mutations to the nucleoside analog inhibitor remdesivir. In mice infected with SARS-CoV or MERS-CoV, both prophylactic and therapeutic administration of EIDD-2801, an orally bioavailable NHC-prodrug (β-D-N(4)-hydroxycytidine-5′-isopropyl ester), improved pulmonary function, and reduced virus titer and body weight loss. Decreased MERS-CoV yields in vitro and in vivo were associated with increased transition mutation frequency in viral but not host cell RNA, supporting a mechanism of lethal mutagenesis in CoV. The potency of NHC/EIDD-2801 against multiple coronaviruses and oral bioavailability highlight its potential utility as an effective antiviral against SARS-CoV-2 and other future zoonotic coronaviruses.
j3b964oz
j3b964oz
2020-04-06
10.1126/scitranslmed.abb5883
2
Novel coronavirus (COVID‑19) epidemic: a veterinary perspective.
j3lk6l8u
j3lk6l8u
2020-02-12
10.12834/vetit.2173.11599.1
1.5
Risk of hospitalization and death from COVID-19 infection in patients with chronic plaque psoriasis receiving a biological treatment and renal transplanted recipients in maintenance immunosuppressive treatment
j4b2534p
j4b2534p
2020-04-21
10.1016/j.jaad.2020.04.085
3.5
Inhibition of SARS-CoV-2 infection (previously 2019-nCoV) by a highly potent pan-coronavirus fusion inhibitor targeting its spike protein that harbors a high capacity to mediate membrane fusion
The recent outbreak of coronavirus disease (COVID-19) caused by SARS-CoV-2 infection in Wuhan, China has posed a serious threat to global public health. To develop specific anti-coronavirus therapeutics and prophylactics, the molecular mechanism that underlies viral infection must first be confirmed. Therefore, we herein used a SARS-CoV-2 spike (S) protein-mediated cell-cell fusion assay and found that SARS-CoV-2 showed plasma membrane fusion capacity superior to that of SARS-CoV. We solved the X-ray crystal structure of six-helical bundle (6-HB) core of the HR1 and HR2 domains in SARS-CoV-2 S protein S2 subunit, revealing that several mutated amino acid residues in the HR1 domain may be associated with enhanced interactions with HR2 domain. We previously developed a pan-coronavirus fusion inhibitor, EK1, which targeted HR1 domain and could inhibit infection by divergent human coronaviruses tested, including SARS-CoV and MERS-CoV. We then generated a series of lipopeptides and found that the EK1C4 was the most potent fusion inhibitor against SARS-CoV-2 S protein-mediated membrane fusion and pseudovirus infection with IC50s of 1.3 and 15.8 nM, about 241- and 149-fold more potent than that of EK1 peptide, respectively. EK1C4 was also highly effective against membrane fusion and infection of other human coronavirus pseudoviruses tested, including SARS-CoV and MERS-CoV, as well as SARSr-CoVs, potently inhibiting replication of 4 live human coronaviruses, including SARS-CoV-2. Intranasal application of EK1C4 before or after challenge with HCoV-OC43 protected mice from infection, suggesting that EK1C4 could be used for prevention and treatment of infection by currently circulating SARS-CoV-2 and emerging SARSr-CoVs.
j5bepvvw
j5bepvvw
2020-03-12
10.1101/2020.03.09.983247
1
Influenza-Omics and the Host Response: Recent Advances and Future Prospects
Influenza A viruses (IAV) continually evolve and have the capacity to cause global pandemics. Because IAV represents an ongoing threat, identifying novel therapies and host innate immune factors that contribute to IAV pathogenesis is of considerable interest. This review summarizes the relevant literature as it relates to global host responses to influenza infection at both the proteome and transcriptome level. The various-omics infection systems that include but are not limited to ferrets, mice, pigs, and even the controlled infection of humans are reviewed. Discussion focuses on recent advances, remaining challenges, and knowledge gaps as it relates to influenza-omics infection outcomes.
j5rlgbl8
j5rlgbl8
2017-06-10
10.3390/pathogens6020025
2.5
Treatment options for COVID-19: the reality and challenges
Abstract An outbreak related to the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was first reported in Wuhan, China in December 2019. An extremely high potential for dissemination resulted in the global coronavirus disease 2019 (COVID-19) pandemic in 2020. Despite the worsening trends of COVID-19, no drugs are validated to have significant efficacy in clinical treatment of COVID-19 patients in large-scale studies. Remdesivir is considered the most promising antiviral agent; it works by inhibiting the activity of RNA-dependent RNA polymerase (RdRp). A large-scale study investigating the clinical efficacy of remdesivir (200 mg on day 1, followed by 100 mg once daily) is on-going. The other excellent anti-influenza RdRp inhibitor favipiravir is also being clinically evaluated for its efficacy in COVID-19 patients. The protease inhibitor lopinavir/ritonavir (LPV/RTV) alone is not shown to provide better antiviral efficacy than standard care. However, the regimen of LPV/RTV plus ribavirin was shown to be effective against SARS-CoV in vitro. Another promising alternative is hydroxychloroquine (200 mg thrice daily) plus azithromycin (500 mg on day 1, followed by 250 mg once daily on day 2-5), which showed excellent clinical efficacy on Chinese COVID-19 patients and anti-SARS-CoV-2 potency in vitro. The roles of teicoplanin (which inhibits the viral genome exposure in cytoplasm) and monoclonal and polyclonal antibodies in the treatment of SARS-CoV-2 are under investigation. Avoiding the prescription of non-steroidal anti-inflammatory drugs, angiotensin converting enzyme inhibitors, or angiotensin II type I receptor blockers is advised for COVID-19 patients.
j8n06hzx
j8n06hzx
2020-04-04
10.1016/j.jmii.2020.03.034
1
Identification of potential inhibitors against SARS-CoV-2 by targeting proteins responsible for envelope formation and virion assembly using docking based virtual screening, and pharmacokinetics approaches
WHO has declared the outbreak of COVID-19 as a public health emergency of international concern. The ever-growing new cases have called for an urgent emergency for specific anti-COVID-19 drugs. Three structural proteins (Membrane, Envelope and Nucleocapsid protein) play an essential role in the assembly and formation of the infectious virion particles. Thus, the present study was designed to identify potential drug candidates from the unique collection of 548 anti-viral compounds (natural and synthetic anti-viral), which target SARS-CoV-2 structural proteins. High-end molecular docking analysis was performed to characterize the binding affinity of the selected drugs-the ligand, with the SARS-CoV-2 structural proteins, while high-level Simulation studies analyzed the stability of drug-protein interactions. The present study identified rutin, a bioflavonoid and the antibiotic, doxycycline, as the most potent inhibitor of SARS-CoV-2 envelope protein. Caffeic acid and ferulic acid were found to inhibit SARS-CoV-2 membrane protein while the anti-viral agent's simeprevir and grazoprevir showed a high binding affinity for nucleocapsid protein. All these compounds not only showed excellent pharmacokinetic properties, absorption, metabolism, minimal toxicity and bioavailability but were also remain stabilized at the active site of proteins during the MD simulation. Thus, the identified lead compounds may act as potential molecules for the development of effective drugs against SARS-CoV-2 by inhibiting the envelope formation, virion assembly and viral pathogenesis.
j92mfwkj
j92mfwkj
2020
5
AI-Driven Tools for Coronavirus Outbreak: Need of Active Learning and Cross-Population Train/Test Models on Multitudinal/Multimodal Data
The novel coronavirus (COVID-19) outbreak, which was identified in late 2019, requires special attention because of its future epidemics and possible global threats. Beside clinical procedures and treatments, since Artificial Intelligence (AI) promises a new paradigm for healthcare, several different AI tools that are built upon Machine Learning (ML) algorithms are employed for analyzing data and decision-making processes. This means that AI-driven tools help identify COVID-19 outbreaks as well as forecast their nature of spread across the globe. However, unlike other healthcare issues, for COVID-19, to detect COVID-19, AI-driven tools are expected to have active learning-based cross-population train/test models that employs multitudinal and multimodal data, which is the primary purpose of the paper.
j97ugs3y
j97ugs3y
2020-03-18
10.1007/s10916-020-01562-1
1.5
SARS-CoV-2 proteome microarray for mapping COVID-19 antibody interactions at amino acid resolution
COVID-19 has quickly become a worldwide pandemic, which has significantly impacted the economy, education, and social interactions. Understanding the humoral antibody response to SARS-CoV-2 proteins may help identify biomarkers that can be used to detect and treat COVID-19 infection. However, no immuno-proteomics platform exists that can perform such proteome-wide analysis. To address this need, we created a SARS-CoV-2 proteome microarray to analyze antibody interactions at amino acid resolution by spotting peptides 15 amino acids long with 5-amino acid offsets representing full-length SARS-CoV-2 proteins. Moreover, the array processing time is short (1.5 hours), the dynamic range is ~2 orders of magnitude, and the lowest limit of detection is 94 pg/mL. Here, the SARS-CoV-2 proteome array reveals that antibodies commercially available for SARS-CoV-1 proteins can also target SARS-CoV-2 proteins. These readily available reagents could be used immediately in COVID-19 research. Second, IgM and IgG immunogenic epitopes of SARS-CoV-2 proteins were profiled in the serum of ten COVID-19 patients. Such epitope biomarkers provide insight into the immune response to COVID-19 and are potential targets for COVID-19 diagnosis and vaccine development. Finally, serological antibodies that may neutralize viral entry into host cells via the ACE2 receptor were identified. Further investigation into whether these antibodies can inhibit the propagation of SARS-CoV-2 is warranted. Antibody and epitope profiling in response to COVID-19 is possible with our peptide-based SARS-COV-2 proteome microarray. The data gleaned from the array could provide invaluable information to the scientific community to understand, detect, and treat COVID-19.
j9armxm9
j9armxm9
2020-04-13
10.1101/2020.03.26.994756
1
Tafenoquine inhibits replication of SARS-Cov-2 at pharmacologically relevant concentrations in vitro
Tafenoquine [TQ] exhibited EC50/90s of ~ 2.6/5.1 μM against SARS-CoV-2 in VERO E6 cells and was 4-fold more potent than hydroxychloroquine [HCQ]. Time-of-addition experiments were consistent with a different mechanism for TQ v HCQ. Physiologically based pharmacokinetic (PBPK) modeling suggested that lung unbound concentrations of TQ in COVID-19 patients may exceed the EC90 for at least 8 weeks after administration. The therapeutic potential for TQ in management of COVID-19 should be further evaluated.
j9mz0ob5
j9mz0ob5
2020-07-12
10.1101/2020.07.12.199059
5
Chloroquine paradox may cause more damage than help fight COVID-19
Abstract Novel coronavirus disease 2019 (COVID-19) pandemic is the most recent health care crisis without specific prophylactic or therapeutic drugs. Antimalarial drug chloroquine (CHL) and its safer derivative hydroxychloroquine (HCHL) have been proposed to be repurposed to treat SARS coronavirus-2 (SARS-CoV-2), the causative agent of COVID-19. CHL/HCHL have anti-inflammatory activity and are used to treat rheumatoid arthritis, osteoarthritis and lupus. Although, CHL/HCHL have an anti-viral activity against several viruses in cell-cultures, the anti-viral activity in-vivo is questionable. Repurposing of CHL/HCHL to treat SARS-CoV-2 infection is appealing. However, there is empirical evidence from animal studies with other viruses suggesting that CHL/HCHL may have an untoward paradoxical effect. One thus cannot exclude the possibility that CHL may increase the severity of the disease and prove deleterious both for the patients and public health efforts to contain the highly contagious and explosive spread of SARS-CoV-2.
j9vmsfjw
j9vmsfjw
2020-04-17
10.1016/j.micinf.2020.04.004
2
Broad anti-coronaviral activity of FDA approved drugs against SARS-CoV-2 in vitro and SARS-CoV in vivo
SARS-CoV-2 emerged in China at the end of 2019 and has rapidly become a pandemic with roughly 2.7 million recorded COVID-19 cases and greater than 189,000 recorded deaths by April 23rd, 2020 (www.WHO.org). There are no FDA approved antivirals or vaccines for any coronavirus, including SARS-CoV-2. Current treatments for COVID-19 are limited to supportive therapies and off-label use of FDA approved drugs. Rapid development and human testing of potential antivirals is greatly needed. A quick way to test compounds with potential antiviral activity is through drug repurposing. Numerous drugs are already approved for human use and subsequently there is a good understanding of their safety profiles and potential side effects, making them easier to fast-track to clinical studies in COVID-19 patients. Here, we present data on the antiviral activity of 20 FDA approved drugs against SARS-CoV-2 that also inhibit SARS-CoV and MERS-CoV. We found that 17 of these inhibit SARS-CoV-2 at a range of IC50 values at non-cytotoxic concentrations. We directly follow up with seven of these to demonstrate all are capable of inhibiting infectious SARS-CoV-2 production. Moreover, we have evaluated two of these, chloroquine and chlorpromazine, in vivo using a mouse-adapted SARS-CoV model and found both drugs protect mice from clinical disease.
jbc74lcu
jbc74lcu
2020-04-27
10.1101/2020.03.25.008482
0.5
Coronavirus disease 2019 (COVID-19): current status and future perspectives
ABSTRACT Coronavirus disease 2019 (COVID-19) originated in the city of Wuhan, Hubei Province, Central China, and has spread quickly to 72 countries to date. COVID-19 is caused by a novel coronavirus, named severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) [previously provisionally known as 2019 novel coronavirus (2019-nCoV)]. At present, the newly identified SARS-CoV-2 has caused a large number of deaths with tens of thousands of confirmed cases worldwide, posing a serious threat to public health. However, there are no clinically approved vaccines or specific therapeutic drugs available for COVID-19. Intensive research on the newly emerged SARS-CoV-2 is urgently needed to elucidate the pathogenic mechanisms and epidemiological characteristics and to identify potential drug targets, which will contribute to the development of effective prevention and treatment strategies. Hence, this review will focus on recent progress regarding the structure of SARS-CoV-2 and the characteristics of COVID-19, such as the aetiology, pathogenesis and epidemiological characteristics.
jbtrdvhe
jbtrdvhe
2020-03-29
10.1016/j.ijantimicag.2020.105951
1
Animal models of Middle East Respiratory Syndrome coronavirus infection
The emergence of the Middle East respiratory syndrome coronavirus (MERS-CoV) in 2012 marked the second time that a new, highly pathogenic coronavirus has emerged in the human population in the 21(st) century. In this review, we discuss the current state of knowledge of animal models of MERS-CoV infection. Commonly used laboratory animal species such as Syrian hamsters, mice and ferrets are not susceptible to MERS-CoV, due to differences in the MERS-CoV receptor dipeptyl peptidase 4 (DPP4). The initially developed animal models comprise two nonhuman primate species, the rhesus macaque and the common marmoset. Rhesus macaques develop a mild to moderate respiratory disease upon inoculation, reminiscent of milder MERS cases, whereas marmosets develop a moderate to severe respiratory disease, recapitulating the severe disease observed in some patients. Dromedary camels, considered to be the reservoir for MERS-CoV, develop a mild upper respiratory tract infection with abundant viral shedding. Although normal mice are not susceptible to MERS-CoV, expression of the human DPP4 (hDPP4) overcomes the lack of susceptibility. Transgenic hDPP4 mice develop severe and lethal respiratory disease upon inoculation with MERS-CoV. These hDPP4 transgenic mice are potentially the ideal first line animal model for efficacy testing of therapeutic and prophylactic countermeasures. Further characterization of identified countermeasures would ideally be performed in the common marmoset model, due to the more severe disease outcome. This article forms part of a symposium in Antiviral Research on “From SARS to MERS: research on highly pathogenic human coronaviruses.”
jc5rdiwq
jc5rdiwq
2015-10-01
10.1016/j.antiviral.2015.07.005
1.5
Therapeutic Application of Chloroquine in Clinical Trials for COVID-19
The novel corona virus disease -2019 (COVID-19) pandemic has caused a massive global public health havoc. Recent clinical trials carried out in China has found a promising therapeutic application of chloroquine and hydroxychloroquine for COVID-19. This study meticulously evaluated the various dosages of chloroquine and hydroxychloroquine utilized in clinical trials registered in Chinese and US clinical trial registries for the treatment of pneumonia caused by SARS-CoV-2.
jc9ugexn
jc9ugexn
2020-03-27
10.1101/2020.03.22.20040964
1
High-Throughput Human Primary Cell-Based Airway Model for Evaluating Influenza, Coronavirus, or other Respiratory Viruses in vitro
Influenza and other respiratory viruses represent a significant threat to public health, national security, and the world economy, and can lead to the emergence of global pandemics such as the current COVID-19 crisis. One of the greatest barriers to the development of effective therapeutic agents to treat influenza, coronaviruses, and many other infections of the respiratory tract is the absence of a robust preclinical model. Preclinical studies currently rely on high-throughput, low-fidelity in vitro screening with cell lines and/or low-throughput animal models that often provide a poor correlation to human clinical responses. Here, we introduce a human primary airway epithelial cell-based model integrated into a high-throughput platform where tissues are cultured at an air-liquid interface (PREDICT96-ALI). We present results on the application of this platform to influenza and coronavirus infections, providing multiple readouts capable of evaluating viral infection kinetics and potentially the efficacy of therapeutic agents in an in vitro system. Several strains of influenza A virus are shown to successfully infect the human primary cell-based airway tissue cultured at an air-liquid interface (ALI), and as a proof-of-concept, the effect of the antiviral oseltamivir on one strain of Influenza A is evaluated. Human coronaviruses NL63 (HCoV-NL63) and SARS-CoV-2 enter host cells via ACE2 and utilize the protease TMPRSS2 for protein priming, and we confirm expression of both in our ALI model. We also demonstrate coronavirus infection in this system with HCoV-NL63, observing sufficient viral propagation over 96 hours post-infection to indicate successful infection of the primary cell-based model. This new capability has the potential to address a gap in the rapid assessment of therapeutic efficacy of various small molecules and antiviral agents against influenza and other respiratory viruses including coronaviruses.
jd0dmp46
jd0dmp46
2020-05-23
10.1101/2020.05.23.112797
4
Medication for COVID-19-an Overview of Approaches Currently Under Study
BACKGROUND: With the worldwide spread of SARS-CoV-2 infection, it is becoming increasingly urgent to develop a vaccine to prevent COVID-19, as well as effective drugs to treat it. METHODS: This article is based on a selective literature search in PubMed and ClinicalTrials.gov, followed by an assessment of the ongoing clinical trials that were revealed by the search. RESULTS: A number of substances have been found to prevent the reproduction of SARS-CoV-2 in vitro. These include virustatic agents that have already been approved for the treatment of other types of viral infection, as well as drugs that are currently used for entirely different purposes. High in vitro activity has been found for the nucleotide analogue remdesivir, for the antimalarial drug chloroquine, and for nitazoxanide, a drug used to treat protozoan infections. Because the virus enters human cells by way of the membrane-associated angiotensin converting enzyme 2 (ACE2), keeping the virus from docking to this receptor is a conceivable treatment approach. Transmembrane protease serine 2 (TMPRSS2) plays a role in the fusion of the virus with cells; inhibitors of this enzyme are known as well. The potential therapeutic efficacy and tolerability of these and other active substances remain to be investigated in clinical trials. At present, more than 80 trials on COVID-10 have already been registered with Clinical- Trials.gov. Some initial findings should already be available in late April 2020. CONCLUSION: Clinical trials are now indispensable in order to determine the true clinical benefits and risks of the substances that have been found to be active against SARSCoV- 2 in vitro. There is not yet any recommendation for the therapeutic use of any particular agent beyond standard supportive treatment.
jd1b7asr
jd1b7asr
2020
5
Molecular detection of SARS-CoV-2 in formalin fixed paraffin embedded specimens.
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the cause of human coronavirus disease 2019 (COVID-19), emerged in Wuhan, China in December 2019. The virus rapidly spread globally, resulting in a public-health crisis including more than 3.1 million cases and 224,000 deaths as of May 1, 2020. Here, we describe the identification and evaluation of commercially available reagents and assays for the molecular detection of SARS-CoV-2 in infected formalin fixed paraffin embedded (FFPE) cell pellets. We identified a suitable rabbit polyclonal anti-SARS-CoV spike protein antibody and a mouse monoclonal anti-SARS-CoV nucleocapsid protein (NP) antibody for cross detection of the respective SARS-CoV-2 proteins by immunohistochemistry (IHC) and immunofluorescence assay (IFA). Next, we established RNAscope in situ hybridization (ISH) to detect SARS-CoV-2 RNA. Furthermore, we established a multiplex fluorescence ISH (mFISH) to detect positive-sense SARS-CoV-2 RNA and negative-sense SARS-CoV-2 RNA (a replicative intermediate indicating viral replication). Finally, we developed a dual staining assay using IHC and ISH to detect SARS-CoV-2 antigen and RNA in the same FFPE section. These reagents and assays will accelerate COVID-19 pathogenesis studies in humans and in COVID-19 animal models.
jf3si5d6
jf3si5d6
2020-05-07
10.1172/jci.insight.139042
3
Participation of the phosphatidylinositol 3-kinase/Akt pathway in Junín virus replication in vitro
Abstract In this paper we demonstrate that infection of cell cultures with the arenavirus Junín (JUNV), agent of the argentine haemorrhagic fever, leads to the activation of PI3K/Akt signalling pathway. Phosphorylation of Akt occurs early during JUNV infection of Vero cells and is blocked by the PI3K inhibitor, Ly294002. Infection of cells with UV-irradiated JUNV redeemed the pattern of stimulation observed for infectious virus indicating that an early stage of multiplication cycle would be enough to trigger activation. Treatment of cells with chlorpromazine abrogated phosphorylation of Akt upon JUNV infection suggesting virus internalization as responsible for activation. Inhibition of Akt phosphorylation by Ly294002 impaired viral protein synthesis and expression leading to a reduced infectious virus yield without blocking the onset of persistent stage of infection. This impairment is linked to a reduced amount of virus bound to cells probably due to a blockage on the recycling of transferrin cell-receptor, employed by the virus to adsorb to the cell surface. Early Akt activation was also observed in BHK-21 and A549 JUNV infected cells suggesting an important role of PI3K/Akt signalling in JUNV multiplication in vitro.
jfg80kj6
jfg80kj6
2009-10-31
10.1016/j.virusres.2009.07.004
3.5
Using Partial Differential Equation with Google Mobility Data to Model COVID-19 in Arizona
The outbreak of COVID-19 disrupts the life of many people in the world. The state of Arizona in the U.S. emerges as one of the country's newest COVID-19 hot spots. Accurate forecasting for COVID-19 cases will help governments to implement necessary measures and convince more people to take personal precautions to combat the virus. It is difficult to accurately predict the COVID-19 cases due to many human factors involved. This paper aims to provide a forecasting model for COVID-19 cases with the help of human activity data from the Google Community Mobility Reports. To achieve this goal, a specific partial differential equation (PDE) is developed and validated with the COVID-19 data from the New York Times at the county level in the state of Arizona in the U.S. The proposed model describes the combined effects of transboundary spread among county clusters in Arizona and human actives on the transmission of COVID-19. The results show that the prediction accuracy of this model is well acceptable (above 94\%). Furthermore, we study the effectiveness of human precautions such as wearing face masks and practicing social distancing on the decrease of COVID-19 cases at the local level. The localized analytical results can be used to help to slow down the spread of COVID-19 in Arizona. To the best of our knowledge, this work is the first attempt to apply PDE models on COVID-19 prediction with the Google Community Mobility Reports.
jfiqj1mb
jfiqj1mb
2020-06-30
5
Inferring Infection Patterns Based on a Connectivity Map of Host Transcriptional Responses
Host responses to infections represent an important pathogenicity determiner, and delineation of host responses can elucidate pathogenesis processes and inform the development of anti-infection therapies. Low cost, high throughput, easy quantitation, and rich descriptions have made gene expression profiling generated by DNA microarrays an optimal approach for describing host transcriptional responses (HTRs). However, efforts to characterize the landscape of HTRs to diverse pathogens are far from offering a comprehensive view. Here, we developed an HTR Connectivity Map based on systematic assessment of pairwise similarities of HTRs to 50 clinically important human pathogens using 1353 gene-expression profiles generated from >60 human cells/tissues. These 50 pathogens were further partitioned into eight robust “HTR communities” (i.e., groups with more consensus internal HTR similarities). These communities showed enrichment in specific infection attributes and differential gene expression patterns. Using query signatures of HTRs to external pathogens, we demonstrated four distinct modes of HTR associations among different pathogens types/class, and validated the reliability of the HTR community divisions for differentiating and categorizing pathogens from a host-oriented perspective. These findings provide a first-generation HTR Connectivity Map of 50 diverse pathogens, and demonstrate the potential for using annotated HTR community to detect functional associations among infectious pathogens.
jgwvjkbj
jgwvjkbj
2015-10-28
10.1038/srep15820
1
Molecular mechanisms of severe acute respiratory syndrome (SARS)
Severe acute respiratory syndrome (SARS) is a new infectious disease caused by a novel coronavirus that leads to deleterious pulmonary pathological features. Due to its high morbidity and mortality and widespread occurrence, SARS has evolved as an important respiratory disease which may be encountered everywhere in the world. The virus was identified as the causative agent of SARS due to the efforts of a WHO-led laboratory network. The potential mutability of the SARS-CoV genome may lead to new SARS outbreaks and several regions of the viral genomes open reading frames have been identified which may contribute to the severe virulence of the virus. With regard to the pathogenesis of SARS, several mechanisms involving both direct effects on target cells and indirect effects via the immune system may exist. Vaccination would offer the most attractive approach to prevent new epidemics of SARS, but the development of vaccines is difficult due to missing data on the role of immune system-virus interactions and the potential mutability of the virus. Even in a situation of no new infections, SARS remains a major health hazard, as new epidemics may arise. Therefore, further experimental and clinical research is required to control the disease.
jh9e85c0
jh9e85c0
2005-01-20
10.1186/1465-9921-6-8
2
Potential Neutralizing Antibodies Discovered for Novel Corona Virus Using Machine Learning
The fast and untraceable virus mutations take lives of thousands of people before the immune system can produce the inhibitory antibody. Recent outbreak of novel coronavirus infected and killed thousands of people in the world. Rapid methods in finding peptides or antibody sequences that can inhibit the viral epitopes of COVID-19 will save the life of thousands. In this paper, we devised a machine learning (ML) model to predict the possible inhibitory synthetic antibodies for Corona virus. We collected 1933 virus-antibody sequences and their clinical patient neutralization response and trained an ML model to predict the antibody response. Using graph featurization with variety of ML methods, we screened thousands of hypothetical antibody sequences and found 8 stable antibodies that potentially inhibit COVID-19. We combined bioinformatics, structural biology, and Molecular Dynamics (MD) simulations to verify the stability of the candidate antibodies that can inhibit the Corona virus.
jj7hrv78
jj7hrv78
2020-03-18
2
In search for the hotspots of Disease X: A biogeographic approach to mapping the predictive risk of WHO s Blueprint Priority Diseases
Anthropization of natural habitats including climate change along with overpopulation and global travel have been contributing to emerging infectious diseases outbreaks. The recent COVID-19 outbreak in Wuhan, highlights such threats to human health, social stability and global trade and economy. We used species distribution modelling and environmental data from satellite imagery to model Blueprint Priority Diseases occurrences. We constructed classical regression and Support Vector Machine models based on environmental predictor variables such as landscape, tree cover loss, climatic covariates. Models were evaluated and a weighed mean was used to map the predictive risk of disease emergence. We mapped the predictive risk for filovirus, Nipah, Rift Valley Fever and coronavirus diseases. Elevation, tree cover loss and climatic covariates were found to significant factors influencing disease emergence. We also showed the relevance of disease biogeography and in the identification potential hotspots for Disease X in regions in Uganda and China.
jjbez46k
jjbez46k
2020-03-30
10.1101/2020.03.27.20044156
1.5
Partial RdRp sequences offer a robust method for Coronavirus subgenus classification
The recent reclassification of the Riboviria, and the introduction of multiple new taxonomic categories including both subfamilies and subgenera for coronaviruses (family Coronaviridae, subfamily Orthocoronavirinae) represents a major shift in how official classifications are used to designate specific viral lineages. While the newly defined subgenera provide much-needed standardisation for commonly cited viruses of public health importance, no method has been proposed for the assignment of subgenus based on partial sequence data, or for sequences that are divergent from the designated holotype reference genomes. Here, we describe the genetic variation of a partial region of the coronavirus RNA-dependent RNA polymerase (RdRp), which is one of the most used partial sequence loci for both detection and classification of coronaviruses in molecular epidemiology. We infer Bayesian phylogenies from more than 7000 publicly available coronavirus sequences and examine clade groupings relative to all subgenus holotype sequences. Our phylogenetic analyses are largely coherent with genome-scale analyses based on designated holotype members for each subgenus. Distance measures between sequences form discrete clusters between taxa, offering logical threshold boundaries that can attribute subgenus or indicate sequences that are likely to belong to unclassified subgenera both accurately and robustly. We thus propose that partial RdRp sequence data of coronaviruses is sufficient for the attribution of subgenus-level taxonomic classifications and we supply the R package, “MyCoV”, which provides a method for attributing subgenus and assessing the reliability of the attribution. The analysis of polymerase chain reaction amplicons derived from biological samples is the most common modern method for detection and classification of infecting viral agents, such as Coronaviruses. Recent updates to the official standard for taxonomic classification of Coronaviruses, however, may leave researchers unsure as to whether the viral sequences they obtain by these methods can be classified into specific viral taxa due to variations in the sequences when compared to type strains. Here, we present a plausible method for defining genetic dissimilarity cut-offs that will allow researchers to state which taxon their virus belongs to and with what level of certainty. To assist in this, we also provide the R package ‘MyCoV’ which classifies user generated sequences.
jjraqr85
jjraqr85
2020-03-06
10.1101/2020.03.02.974311
1.5
A model to forecast regional demand for COVID-19 related hospital beds
COVID-19 threatens to overwhelm hospital facilities throughout the United States. We created an interactive, quantitative model that forecasts demand for COVID-19 related hospitalization based on county-level population characteristics, data from the literature on COVID-19, and data from online repositories. Using this information as well as user inputs, the model estimates a time series of demand for intensive care beds and acute care beds as well as the availability of those beds. The online model is designed to be intuitive and interactive so that local leaders with limited technical or epidemiological expertise may make decisions based on a variety of scenarios. This complements high-level models designed for public consumption and technically sophisticated models designed for use by epidemiologists. The model is actively being used by several academic medical centers and policy makers, and we believe that broader access will continue to aid community and hospital leaders in their response to COVID-19. Link to online model: https://surf.stanford.edu/covid-19-tools/covid-19/
jjtsd4n3
jjtsd4n3
2020-03-30
10.1101/2020.03.26.20044842
1.5
Computational analysis suggests putative intermediate animal hosts of the SARS-CoV-2
The authors have withdrawn their manuscript whilst they wish to perform additional experiments to validate their conclusions further. Therefore, the authors do not wish this work to be cited as reference for the project. If you have any questions, please contact the corresponding author for more details.
jkm496ip
jkm496ip
2020-04-15
10.1101/2020.04.04.025080
1.5
Panel 7 – Pathogenesis of otitis media – a review of the literature between 2015 and 2019
Abstract Objective To perform a comprehensive review of the literature from July 2015 to June 2019 on the pathogenesis of otitis media. Bacteria, viruses and the role of the microbiome as well as the host response are discussed. Directions for future research are also suggested. Data sources PubMed database of the National Library of Medicine. Review methods PubMed was searched for any papers pertaining to OM pathogenesis between July 2015 and June 2019. If in English, abstracts were assessed individually for their relevance and included in the report. Members of the panel drafted the report based on these searches and on new data presented at the 20th International Symposium on Recent Advances in Otitis Media. Conclusions The main themes that arose in OM pathogenesis were around the need for symptomatic viral infections to develop disease. Different populations potentially having different mechanisms of pathogenesis. Novel bacterial otopathogens are emerging and need to be monitored. Animal models need to continue to be developed and used to understand disease pathogenesis. Implications for Practice The findings in the pathogenesis panel have several implications for both research and clinical practice. The most urgent areas appear to be to continue monitoring the emergence of novel otopathogens, and the need to develop prevention and preventative therapies that do not rely on antibiotics and protect against the development of the initial OM episode.
jkm5ans8
jkm5ans8
2020-03-31
10.1016/j.ijporl.2019.109838
2.5
COVID-19: a new challenge for human beings
jlslbsp2
jlslbsp2
2020-03-31
10.1038/s41423-020-0407-x
3.5
SAveRUNNER: a network-based algorithm for drug repurposing and its application to COVID-19
The novelty of new human coronavirus COVID-19/SARS-CoV-2 and the lack of effective drugs and vaccines gave rise to a wide variety of strategies employed to fight this worldwide pandemic. Many of these strategies rely on the repositioning of existing drugs that could shorten the time and reduce the cost compared to de novo drug discovery. In this study, we presented a new network-based algorithm for drug repositioning, called SAveRUNNER (Searching off-lAbel dRUg aNd NEtwoRk), which predicts drug-disease associations by quantifying the interplay between the drug targets and the disease-specific proteins in the human interactome via a novel network-based similarity measure that prioritizes associations between drugs and diseases locating in the same network neighborhoods. Specifically, we applied SAveRUNNER on a panel of 14 selected diseases with a consolidated knowledge about their disease-causing genes and that have been found to be related to COVID-19 for genetic similarity, comorbidity, or for their association to drugs tentatively repurposed to treat COVID-19. Focusing specifically on SARS subnetwork, we identified 282 repurposable drugs, including some the most rumored off-label drugs for COVID-19 treatments, as well as a new combination therapy of 5 drugs, actually used in clinical practice. Furthermore, to maximize the efficiency of putative downstream validation experiments, we prioritized 24 potential anti-SARS-CoV repurposable drugs based on their network-based similarity values. These top-ranked drugs include ACE-inhibitors, monoclonal antibodies, and thrombin inhibitors. Finally, our findings were in-silico validated by performing a gene set enrichment analysis, which confirmed that most of the network-predicted repurposable drugs may have a potential treatment effect against human coronavirus infections.
jozd45ch
jozd45ch
2020-06-04
4
The SARS-CoV-2 exerts a distinctive strategy for interacting with the ACE2 human receptor
The COVID-19 disease has plagued over 110 countries and has resulted in over 4,000 deaths within 10 weeks. We compare the interaction between the human ACE2 receptor and the SARS-CoV-2 spike protein with that of other pathogenic coronaviruses using molecular dynamics simulations. SARS-CoV, SARS-CoV-2, and HCoV-NL63 recognize ACE2 as the natural receptor but present a distinct binding interface to ACE2 and a different network of residue-residue contacts. SARS-CoV and SARS-CoV-2 have comparable binding affinities achieved by balancing energetics and dynamics. The SARS-CoV-2–ACE2 complex contains a higher number of contacts, a larger interface area, and decreased interface residue fluctuations relative to SARS-CoV. These findings expose an exceptional evolutionary exploration exerted by coronaviruses toward host recognition. We postulate that the versatility of cell receptor binding strategies has immediate implications on therapeutic strategies. One Sentence Summary Molecular dynamics simulations reveal a temporal dimension of coronaviruses interactions with the host receptor.
jpkxjn6e
jpkxjn6e
2020-03-12
10.1101/2020.03.10.986398
1
Emergency tracheostomy during COVID 19 Pandemic in a head and neck surgical oncology unit
• Awake, Emergency, Intervention for an Unsecured 'Unable to intubate' Critical upper airway obstruction is a surgical challenge. • Aerosolization and risk COVID 19 transmission add to the already existing difficulty of surgical restoration of critical airway obstruction. • Adequate personal protection, rapid restoration of the airway with the minimum aerosol generation, and prevention of COVID 19 dissemination are keys to the success of Emergency Tracheostomy during the Pandemic.
jqgyln7b
jqgyln7b
2020-05-08
10.1016/j.oraloncology.2020.104784
3.5
COVID-19 and the Renin-Angiotensin System
jr8d6lud
jr8d6lud
2020-03-27
10.1016/j.ekir.2020.03.024
1.5
A roadmap for MERS-CoV research and product development: report from a World Health Organization consultation
As part of the World Health Organization (WHO) R&D Blueprint initiative, leading stakeholders on Middle East respiratory syndrome coronavirus (MERS-CoV) convened to agree on strategic public-health goals and global priority research activities that are needed to combat MERS-CoV. SUPPLEMENTARY INFORMATION: The online version of this article (doi:10.1038/nm.4131) contains supplementary material, which is available to authorized users.
js2ppypr
js2ppypr
2016-07-07
10.1038/nm.4131
1
Coronavirus disease 2019 (COVID-19) pandemic and pregnancy
The current coronavirus disease 2019 (COVID-19) pneumonia pandemic, caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is spreading globally at an accelerated rate, with a basic reproduction number (R0) of 2–2.5, indicating that 2–3 persons will be infected from an index patient. A serious public health emergency, it is particularly deadly in vulnerable populations and communities in which healthcare providers are insufficiently prepared to manage the infection. As of March 16, 2020, there are more than 180,000 confirmed cases of COVID-19 worldwide, with more than 7000 related deaths. The SARS-CoV-2 virus has been isolated from asymptomatic individuals, and affected patients continue to be infectious 2 weeks after cessation of symptoms. The substantial morbidity and socioeconomic impact have necessitated drastic measures across all continents, including nationwide lockdowns and border closures. Pregnant women and their fetuses represent a high-risk population during infectious disease outbreaks. To date, the outcomes of 55 pregnant women infected with COVID-19 and 46 neonates have been reported in the literature, with no definite evidence of vertical transmission. Physiological and mechanical changes in pregnancy increase susceptibility to infections in general, particularly when the cardiorespiratory system is affected, and encourage rapid progression to respiratory failure in the gravida. Furthermore, the pregnancy bias toward T-helper 2 (Th2) system dominance, which protects the fetus, leaves the mother vulnerable to viral infections, which are more effectively contained by the Th1 system. These unique challenges mandate an integrated approach to pregnancies affected by SARS-CoV-2. Here we present a review of COVID-19 in pregnancy, bringing together the various factors integral to the understanding of pathophysiology and susceptibility, diagnostic challenges with real-time reverse transcription polymerase chain reaction (RT-PCR) assays, therapeutic controversies, intrauterine transmission, and maternal−fetal complications. We discuss the latest options in antiviral therapy and vaccine development, including the novel use of chloroquine in the management of COVID-19. Fetal surveillance, in view of the predisposition to growth restriction and special considerations during labor and delivery, is addressed. In addition, we focus on keeping frontline obstetric care providers safe while continuing to provide essential services. Our clinical service model is built around the principles of workplace segregation, responsible social distancing, containment of cross-infection to healthcare providers, judicious use of personal protective equipment, and telemedicine. Our aim is to share a framework that can be adopted by tertiary maternity units managing pregnant women in the flux of a pandemic while maintaining the safety of the patient and healthcare provider at its core.
jslfu3qt
jslfu3qt
2020-03-23
10.1016/j.ajog.2020.03.021
1
Should COVID-19 Concern Nephrologists? Why and to What Extent? The Emerging Impasse of Angiotensin Blockade
Here, we review the most recent findings on the effects of SARS-CoV-2 infection on kidney diseases, including acute kidney injury, and examine the potential effects of ARBs on the outcomes of patients with COVID-19. Lastly, we discuss the clinical management of COVID-19 patients with existing chronic renal disorders, particularly those in dialysis and with kidney transplants.
jtbcomd6
jtbcomd6
2020-03-23
10.1159/000507305
2
Oncolytic viruses in cancer therapy
Abstract Oncolytic virotherapy is a promising form of gene therapy for cancer, employing nature’s own agents to find and destroy malignant cells. The purpose of this review is to provide an introduction to this very topical field of research and to point out some of the current observations, insights and ideas circulating in the literature. We have strived to acknowledge as many different oncolytic viruses as possible to give a broader picture of targeting cancer using viruses. Some of the newest additions to the panel of oncolytic viruses include the avian adenovirus, foamy virus, myxoma virus, yaba-like disease virus, echovirus type 1, bovine herpesvirus 4, Saimiri virus, feline panleukopenia virus, Sendai virus and the non-human coronaviruses. Although promising, virotherapy still faces many obstacles that need to be addressed, including the emergence of virus-resistant tumor cells.
jttif2z7
jttif2z7
2007-09-08
10.1016/j.canlet.2007.02.002
1
Development of Medical Countermeasures to Middle East Respiratory Syndrome Coronavirus
Preclinical development of and research on potential Middle East respiratory syndrome coronavirus (MERS-CoV) medical countermeasures remain preliminary; advancements are needed before most countermeasures are ready to be tested in human clinical trials. Research priorities include standardization of animal models and virus stocks for studying disease pathogenesis and efficacy of medical countermeasures; development of MERS-CoV diagnostics; improved access to nonhuman primates to support preclinical research; studies to better understand and control MERS-CoV disease, including vaccination studies in camels; and development of a standardized clinical trial protocol. Partnering with clinical trial networks in affected countries to evaluate safety and efficacy of investigational therapeutics will strengthen efforts to identify successful medical countermeasures.
jtx7ni9b
jtx7ni9b
2016-07-16
10.3201/eid2207.160022
0.5
Systemic Effects of Missense Mutations on SARS-CoV-2 Spike Glycoprotein Stability and Receptor Binding Affinity
The spike (S) glycoprotein of SARS-CoV-2 is responsible for the binding to the permissive cells. The receptor-binding domain (RBD) of SARS-CoV-2 S protein directly interacts with the human angiotensin-converting enzyme 2 (ACE2) on the host cell membrane. In this study, we used computational saturation mutagenesis approaches, including structure-based energy calculations and sequence-based pathogenicity predictions, to quantify the systemic effects of missense mutations on SARS-CoV-2 S protein structure and function. A total of 18,354 mutations in S protein were analyzed and we discovered that most of these mutations could destabilize the entire S protein and its RBD. Specifically, residues G431 and S514 in SARS-CoV-2 RBD are important for S protein stability. We analyzed 384 experimentally verified S missense variations and revealed that the dominant pandemic form, D614G, can stabilize the entire S protein. Moreover, many mutations in N-linked glycosylation sites can increase the stability of the S protein. In addition, we investigated 3,705 mutations in SARS-CoV-2 RBD and 11,324 mutations in human ACE2 and found that SARS-CoV-2 neighbor residues G496 and F497 and ACE2 residues D355 and Y41 are critical for the RBD-ACE2 interaction. The findings comprehensively provide potential target sites in the development of drugs and vaccines against COVID-19.
jty4ebdf
jty4ebdf
2020-05-23
10.1101/2020.05.21.109835
4.5
Broad Spectrum Antiviral Agent Niclosamide and Its Therapeutic Potential
[Image: see text] The recent outbreak of coronavirus disease 2019 (COVID-19) highlights an urgent need for therapeutics. Through a series of drug repurposing screening campaigns, niclosamide, an FDA-approved anthelminthic drug, was found to be effective against various viral infections with nanomolar to micromolar potency such as SARS-CoV, MERS-CoV, ZIKV, HCV, and human adenovirus, indicating its potential as an antiviral agent. In this brief review, we summarize the broad antiviral activity of niclosamide and highlight its potential clinical use in the treatment of COVID-19.
ju35nyir
ju35nyir
2020-03-03
10.1021/acsinfecdis.0c00052
1
Early detection of SARS-CoV-2 antibodies in COVID-19 patients as a serologic marker of infection
BACKGROUND: Thousands of medical staff had been infected with SARS-CoV-2 virus with hundreds of deaths reported. Such loss could be prevented if there is a serologic assay for SARS-CoV-2-specific antibodies for serological surveillance of its infection at the early stage of disease. METHODS: Using CHO cell expressed full length SARS-CoV-2 S1 protein as capturing antigen, a COVID-19/SARS-CoV-2 S1 serology ELISA kit was developed and validated with negative samples collected prior to the outbreaks or during the outbreak, and positive samples from patients confirmed with COVID-19. RESULTS: The specificity of the ELISA kit was 97.5%, as examined against total 412 normal human samples. The sensitivity was 97.1% by testing against 69 samples from hospitalized and/or recovered COVID-19 patients. The overall accuracy rate reached 97.3%. The assay was able to detect SARS-CoV-2 antibody on day one after the onset of COVID-19 disease. The average antibody levels increased during the hospitalization and after been discharged for two weeks. SARS-CoV-2 antibodies were detected in 28 out of 276 asymptomatic medical staff and one out of five nucleic acid test-negative “Close contacts” of COVID-19 patient. CONCLUSION: With the assays developed here, we can screen medical staff, in-coming patients, passengers and people who are in close contact with the confirmed patients to identify the “innocent viral spreaders”, protect the medical staff and stop the further spreading of the virus.
juooj31c
juooj31c
2020-05-01
10.1093/cid/ciaa523
3
Clinical observation and management of COVID-19 patients
Three leading infectious disease experts in China were invited to share their bedside observations in the management of COVID-19 patients. Professor Taisheng Li was sent to Wuhan to provide frontline medical care. He depicts the clinical course of SARS-CoV-2 infection. Furthermore, he observes the significant abnormality of coagulation function and proposes that the early intravenous immunoglobulin and low molecular weight heparin anticoagulation therapy are very important. Professor Hongzhou Lu, a leader in China to try various anti-viral drugs, expresses concern on the quality of the ongoing clinical trials as most trials are small in scale and repetitive in nature, and emphasizes the importance of the quick publication of clinical trial results. Regarding the traditional Chinese medicine, Professor Lu suggests to develop a creative evaluation system because of the complicated chemical compositions. Professor Wenhong Zhang is responsible for Shanghai's overall clinical management of the COVID-19 cases. He introduces the team approach to manage COVID-19 patients. For severe or critically ill patients, in addition to the respiratory supportive treatment, timely multiorgan evaluation and treatment is very crucial. The medical decisions and interventions are carefully tailored to the unique characteristics of each patient.
jx3alip6
jx3alip6
2020-03-25
10.1080/22221751.2020.1741327
1
Clinical benefit of remdesivir in rhesus macaques infected with SARS-CoV-2
Effective therapeutics to treat COVID-19 are urgently needed. While many investigational, approved, and repurposed drugs have been suggested, preclinical data from animal models can guide the search for effective treatments by ruling out treatments without in vivo efficacy. Remdesivir (GS-5734) is a nucleotide analog prodrug with broad antiviral activity1,2, that is currently investigated in COVID-19 clinical trials and recently received Emergency Use Authorization from the US Food and Drug Administration3,4. In animal models, remdesivir treatment was effective against MERS-CoV and SARS-CoV infection.2,5,6 In vitro, remdesivir inhibited replication of SARS-CoV-2.7,8 Here, we investigated the efficacy of remdesivir treatment in a rhesus macaque model of SARS-CoV-2 infection9. In contrast to vehicle-treated animals, animals treated with remdesivir did not show signs of respiratory disease and had reduced pulmonary infiltrates on radiographs and reduced virus titers in bronchoalveolar lavages 12hrs after the first treatment administration. Virus shedding from the upper respiratory tract was not reduced by remdesivir treatment. At necropsy, lung viral loads of remdesivir-treated animals were lower and there was a reduction in damage to the lungs. Thus, therapeutic remdesivir treatment initiated early during infection had a clinical benefit in SARS-CoV-2-infected rhesus macaques. Although the rhesus macaque model does not represent the severe disease observed in a proportion of COVID-19 patients, our data support early remdesivir treatment initiation in COVID-19 patients to prevent progression to pneumonia.
jxbch44o
jxbch44o
2020
4
Severe acute respiratory syndrome (SARS) in intensive care units (ICUs): limiting the risk to healthcare workers
Abstract The global epidemic of severe acute respiratory syndrome (SARS) during the first half of 2003 resulted in over 8000 cases with more than 800 deaths. Many of those who eventually died, did so in the critical (intensive) care units of various hospitals around the world, and many secondary cases of SARS arose in healthcare workers looking after such patients in these units. Research on SARS coronavirus (SARS CoV) demonstrated that this virus belongs to the same family of viruses, the Coronaviridae that causes the common cold, with some important differences. Properties of this virus have been discovered which can be used to develop important infection control policies within hospitals to limit the number of secondary cases. These properties include environmental survival, transmissibility, viral load in various organs and fluids and periods of symptomatic illness during which infectivity is greatest. Various barrier methods were used throughout the epidemic to protect healthcare workers from SARS, with varying degrees of success. Treatment of SARS patients has mainly involved steroid therapy, with or without ribavirin, but there is no consensus on the best treatment protocol, as yet. This review focuses on the implications of SARS for healthcare workers and patients on critical care units.
jxr0phr1
jxr0phr1
2004-08-31
10.1016/j.cacc.2004.05.003
1
Viruses and Bats
k02lpwm0
k02lpwm0
2019-09-21
10.3390/v11100884
1.5
The Current and Future State of Vaccines, Antivirals and Gene Therapies Against Emerging Coronaviruses
Emerging coronaviruses (CoV) are constant global public health threats to society. Multiple ongoing clinical trials for vaccines and antivirals against CoVs showcase the availability of medical interventions to both prevent and treat the future emergence of highly pathogenic CoVs in human. However, given the diverse nature of CoVs and our close interactions with wild, domestic and companion animals, the next epidemic zoonotic CoV could resist the existing vaccines and antivirals developed, which are primarily focused on Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV) and Middle East Respiratory Syndrome Coronavirus (MERS CoV). In late 2019, the novel CoV (SARS-CoV-2) emerged in Wuhan, China, causing global public health concern. In this review, we will summarize the key advancements of current vaccines and antivirals against SARS-CoV and MERS-CoV as well as discuss the challenge and opportunity in the current SARS-CoV-2 crisis. At the end, we advocate the development of a “plug-and-play” platform technologies that could allow quick manufacturing and administration of broad-spectrum countermeasures in an outbreak setting. We will discuss the potential of AAV-based gene therapy technology for in vivo therapeutic antibody delivery to combat SARS-CoV-2 outbreak and the future emergence of severe CoVs.
k0jy5d67
k0jy5d67
2020-04-24
10.3389/fmicb.2020.00658
3
Detection of SARS-CoV-2 in pets living with COVID-19 owners diagnosed during the COVID-19 lockdown in Spain: A case of an asymptomatic cat with SARS-CoV-2 in Europe
During April-May 2020, the presence of respiratory syndrome coronavirus 2 (SARS-CoV-2) in pets living with coronavirus disease 2019 (COVID-19) owners was analyzed. From 23 pets, a cat without clinical symptoms showed positive results for SARS-CoV-2 in oropharyngeal swab using three RT-qPCR assays (negative rectal swab). SARS-CoV-2 was not detected in the remaining pets. Our finding suggests that cats may act as asymptomatic dispersers of SARS-CoV-2, although viral transmission from animals to humans seems unlikely.
k0mhfs1h
k0mhfs1h
2020-05-21
10.1101/2020.05.14.20101444
4.5
A data-driven assessment of early travel restrictions related to the spreading of the novel COVID-19 within mainland China
Two months after it was firstly reported, the novel coronavirus disease COVID-19 has already spread worldwide. However, the vast majority of reported infections have occurred in China. To assess the effect of early travel restrictions adopted by the health authorities in China, we have implemented an epidemic metapopulation model that is fed with mobility data corresponding to 2019 and 2020. This allows to compare two radically different scenarios, one with no travel restrictions and another in which mobility is reduced by a travel ban. Our findings indicate that i) travel restrictions are an effective measure in the short term, however, ii) they are ineffective when it comes to completely eliminate the disease. The latter is due to the impossibility of removing the risk of seeding the disease to other regions. Our study also highlights the importance of developing more realistic models of behavioral changes when a disease outbreak is unfolding.
k13cchxn
k13cchxn
2020-03-08
10.1101/2020.03.05.20031740
2.5
Coronavirus disease 2019 (COVID-19): A literature review
Abstract In early December 2019, an outbreak of coronavirus disease 2019 (COVID-19), caused by a novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), occurred in Wuhan City, Hubei Province, China. On January 30, 2020 the World Health Organization declared the outbreak as a Public Health Emergency of International Concern. As of February 14, 2020, 49,053 laboratory-confirmed and 1,381 deaths have been reported globally. Perceived risk of acquiring disease has led many governments to institute a variety of control measures. We conducted a literature review of publicly available information to summarize knowledge about the pathogen and the current epidemic. In this literature review, the causative agent, pathogenesis and immune responses, epidemiology, diagnosis, treatment and management of the disease, control and preventions strategies are all reviewed.
k2ixwz9w
k2ixwz9w
2020-04-08
10.1016/j.jiph.2020.03.019
4.5
MyD88 Is Required for Protection from Lethal Infection with a Mouse-Adapted SARS-CoV
A novel human coronavirus, SARS-CoV, emerged suddenly in 2003, causing approximately 8000 human cases and more than 700 deaths worldwide. Since most animal models fail to faithfully recapitulate the clinical course of SARS-CoV in humans, the virus and host factors that mediate disease pathogenesis remain unclear. Recently, our laboratory and others developed a recombinant mouse-adapted SARS-CoV (rMA15) that was lethal in BALB/c mice. In contrast, intranasal infection of young 10-week-old C57BL/6 mice with rMA15 results in a nonlethal infection characterized by high titer replication within the lungs, lung inflammation, destruction of lung tissue, and loss of body weight, thus providing a useful model to identify host mediators of protection. Here, we report that mice deficient in MyD88 (MyD88(−/−)), an adapter protein that mediates Toll-like receptor (TLR), IL-1R, and IL-18R signaling, are far more susceptible to rMA15 infection. The genetic absence of MyD88 resulted in enhanced pulmonary pathology and greater than 90% mortality by day 6 post-infection. MyD88(−/−) mice had significantly higher viral loads in lung tissue throughout the course of infection. Despite increased viral loads, the expression of multiple proinflammatory cytokines and chemokines within lung tissue and recruitment of inflammatory monocytes/macrophages to the lung was severely impaired in MyD88(−/−) mice compared to wild-type mice. Furthermore, mice deficient in chemokine receptors that contribute to monocyte recruitment to the lung were more susceptible to rMA15-induced disease and exhibited severe lung pathology similar to that seen in MyD88(−/−)mice. These data suggest that MyD88-mediated innate immune signaling and inflammatory cell recruitment to the lung are required for protection from lethal rMA15 infection.
k2mrd2rs
k2mrd2rs
2008-12-12
10.1371/journal.ppat.1000240
4
Inhibition of severe acute respiratory syndrome coronavirus replication in a lethal SARS-CoV BALB/c mouse model by stinging nettle lectin, Urtica dioica agglutinin
Urtica dioica agglutinin (UDA) is a small plant monomeric lectin, 8.7 kDa in size, with an N-acetylglucosamine specificity that inhibits viruses from Nidovirales in vitro. In the current study, we first examined the efficacy of UDA on the replication of different SARS-CoV strains in Vero 76 cells. UDA inhibited virus replication in a dose-dependent manner and reduced virus yields of the Urbani strain by 90% at 1.1 ± 0.4 µg/ml in Vero 76 cells. Then, UDA was tested for efficacy in a lethal SARS-CoV-infected BALB/c mouse model. BALB/c mice were infected with two LD(50) (575 PFU) of virus for 4 hours before the mice were treated intraperitoneally with UDA at 20, 10, 5 or 0 mg/kg/day for 4 days. Treatment with UDA at 5 mg/kg significantly protected the mice against a lethal infection with mouse-adapted SARS-CoV (p<0.001), but did not significantly reduce virus lung titers. All virus-infected mice receiving UDA treatments were also significantly protected against weight loss (p<0.001). UDA also effectively reduced lung pathology scores. At day 6 after virus exposure, all groups of mice receiving UDA had much lower lung weights than did the placebo-treated mice. Thus, our data suggest that UDA treatment of SARS infection in mice leads to a substantial therapeutic effect that protects mice against death and weight loss. Furthermore, the mode of action of UDA in vitro was further investigated using live SARS-CoV Urbani strain virus and retroviral particles pseudotyped with SARS-CoV spike (S). UDA specifically inhibited the replication of live SARS-CoV or SARS-CoV pseudotyped virus when added just before, but not after, adsorption. These data suggested that UDA likely inhibits SARS-CoV infection by targeting early stages of the replication cycle, namely, adsorption or penetration. In addition, we demonstrated that UDA neutralizes the virus infectivity, presumably by binding to the SARS-CoV spike (S) glycoprotein. Finally, the target molecule for inhibition of virus replication was partially characterized. When UDA was exposed to N-acetylglucosamine and then UDA was added to cells just prior to adsorption, UDA did not inhibit the virus infection. These data support the conclusion that UDA might bind to N-acetylglucosamine-like residues present on the glycosylated envelope glycoproteins, thereby preventing virus attachment to cells.
k2skui3u
k2skui3u
2011-04-01
10.1016/j.antiviral.2011.02.003
0.5
Immune responses and histopathological changes in rabbits immunized with inactivated SARS coronavirus
To evaluate the immunogenicity of inactivated SARS coronavirus (SARS-CoV), three groups of rabbits were immunized three times at 2-week intervals with inactivated vaccine + adjuvant, adjuvant, and normal saline respectively. Eight batchs of serum were sampled from the auricular vein at day 7 to day 51, and specific IgG antibody titers and neutralizing antibody titers were detected by indirect ELISA and micro-cytopathic effect neutralizing test. Antibody specificity was identified by proteinchip assay. Histopathological changes were detected by H&E staining. The results showed that, rabbits in the experimental group immunized with inactivated SARS-CoV all generated specific IgG antibodies with neutralizing activity, which suggested the inactivated SARS-CoV could preserve its antigenicity well and elicit an effective humoral immune responses. The peak titer value of specific IgG antibody and neutralizing antibody reached 1:40960 and 1:2560 respectively. In the experimental group, no obvious histopathological changes was detected in the H&E stained slides of heart, spleen, kidney and testis samples, but the livers had slight histopathological changes, and the lungs presented remarkable histopathological changes. These findings are of importance for SARS-CoV inactivated vaccine development.
k38xlki3
k38xlki3
2008-01-13
10.1007/s12250-007-0033-0
1.5
Glecaprevir and Maraviroc are high-affinity inhibitors of SARS-CoV-2 main protease: possible implication in COVID-19 therapy
Due to the lack of efficient therapeutic options and clinical trial limitations, the FDA-approved drugs can be a good choice to handle Coronavirus disease (COVID-19). Many reports have enough evidence for the use of FDA-approved drugs which have inhibitory potential against target proteins of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). Here, we utilized a structure-based drug design approach to find possible drug candidates from the existing pool of FDA-approved drugs and checked their effectiveness against the SARS-CoV-2. We performed virtual screening of the FDA-approved drugs against the main protease (Mpro) of SARS-CoV-2, an essential enzyme, and a potential drug target. Using well-defined computational methods, we identified Glecaprevir and Maraviroc (MVC) as the best inhibitors of SARS-CoV-2 Mpro. Both drugs bind to the substrate-binding pocket of SARS-CoV-2 Mpro and form a significant number of non-covalent interactions. Glecaprevir and MVC bind to the conserved residues of substrate-binding pocket of SARS-CoV-2 Mpro. This work provides sufficient evidence for the use of Glecaprevir and MVC for the therapeutic management of COVID-19 after experimental validation and clinical manifestations.
k4dphhfh
k4dphhfh
2020
5
Supporting pandemic response using genomics and bioinformatics: A case study on the emergent SARS‐CoV‐2 outbreak
Pre‐clinical responses to fast‐moving infectious disease outbreaks heavily depend on choosing the best isolates for animal models that inform diagnostics, vaccines and treatments. Current approaches are driven by practical considerations (e.g. first available virus isolate) rather than a detailed analysis of the characteristics of the virus strain chosen, which can lead to animal models that are not representative of the circulating or emerging clusters. Here, we suggest a combination of epidemiological, experimental and bioinformatic considerations when choosing virus strains for animal model generation. We discuss the currently chosen SARS‐CoV‐2 strains for international coronavirus disease (COVID‐19) models in the context of their phylogeny as well as in a novel alignment‐free bioinformatic approach. Unlike phylogenetic trees, which focus on individual shared mutations, this new approach assesses genome‐wide co‐developing functionalities and hence offers a more fluid view of the ‘cloud of variances’ that RNA viruses are prone to accumulate. This joint approach concludes that while the current animal models cover the existing viral strains adequately, there is substantial evolutionary activity that is likely not considered by the current models. Based on insights from the non‐discrete alignment‐free approach and experimental observations, we suggest isolates for future animal models.
k8m19by9
k8m19by9
2020-05-25
10.1111/tbed.13588
4.5
Pangolins Harbor SARS-CoV-2-Related Coronaviruses
The pandemic of coronavirus disease 2019 (COVID-19) caused by SARS-CoV-2 has posed a severe threat to global public health. Yet, the origin of SARS-CoV-2 remains mysterious. Several recent studies (e.g., Lam et al ., Xiao et al .) identified SARS-CoV-2-related viruses in pangolins, providing novel insights into the evolution and diversity of SARS-CoV-2-related viruses.
k9yus2sv
k9yus2sv
2020-04-06
10.1016/j.tim.2020.04.001
1
Potent Antiviral Activities of Type I Interferons to SARS-CoV-2 Infection
The historical outbreak of COVID-19 disease not only constitutes a global public health crisis, but also has a devastating social and economic impact. The disease is caused by a newly identified coronavirus, Severe Acute Respiratory Syndrome coronavirus 2 (SARS-CoV-2). There is an urgent need to identify antivirals to curtail the COVID-19 pandemic. Herein, we report the remarkable sensitivity of SARS-CoV-2 to recombinant human interferons α and β (IFNα/β). Treatment with IFN-α or IFN-β at a concentration of 50 international units (IU) per milliliter drastically reduce viral titers by 3.4 log or 4.5 log, respectively in Vero cells. The EC(50) of IFN-α and IFN-β treatment is 1.35 IU/ml and 0.76 IU/ml, respectively, in Vero cells. These results suggested that SARS-CoV-2 is more sensitive to many other human pathogenic viruses, including the SARS-CoV. Overall, our results demonstrate the potent efficacy of human Type I IFN in suppressing SARS-CoV-2 replication, a finding which could inform future treatment options for COVID-19.
kb3z3b8f
kb3z3b8f
2020-04-05
10.1101/2020.04.02.022764
3
Is it super-spreading?
If the covid-19 virus is transmitted largely by superspreaders, it might not go pandemic, reports Debora MacKenzie
kb8dz8hd
kb8dz8hd
2020-02-22
10.1016/s0262-4079(20)30375-4
2
Characterization of neutralizing antibodies from a SARS-CoV-2 infected individual
B cells specific for the SARS-CoV-2 S envelope glycoprotein spike were isolated from a COVID-19-infected subject using a stabilized spike-derived ectodomain (S2P) twenty-one days post-infection. Forty-four S2P-specific monoclonal antibodies were generated, three of which bound to the receptor binding domain (RBD). The antibodies were minimally mutated from germline and were derived from different B cell lineages. Only two antibodies displayed neutralizing activity against SARS-CoV-2 pseudo-virus. The most potent antibody bound the RBD in a manner that prevented binding to the ACE2 receptor, while the other bound outside the RBD. Our study indicates that the majority of antibodies against the viral envelope spike that were generated during the first weeks of COVID-19 infection are non-neutralizing and target epitopes outside the RBD. Antibodies that disrupt the SARS-CoV-2 spike-ACE2 interaction can potently neutralize the virus without undergoing extensive maturation. Such antibodies have potential preventive/therapeutic potential and can serve as templates for vaccine-design. IN BRIEF SARS-CoV-2 infection leads to expansion of diverse B cells clones against the viral spike glycoprotein (S). The antibodies bind S with high affinity despite being minimally mutated. Thus, the development of neutralizing antibody responses by vaccination will require the activation of certain naïve B cells without requiring extensive somatic mutation. Highlights Analysis of early B cell response to SARS-CoV-2 spike protein Most antibodies target non-neutralizing epitopes Potent neutralizing mAb blocks the interaction of the S protein with ACE2 Neutralizing antibodies are minimally mutated
kbt5gdyy
kbt5gdyy
2020-05-12
10.1101/2020.05.12.091298
4.5
Review on the study of spreading of the COVID-19 based on dynamic models/ 中华医学科研管理杂志
Objective@#To Summarize mathematical and statistical models used in the area of infectious diseases modelling, to provide ideas and suggestions for the model-based analysis and decision-making of COVID-19.@*Methods@#By reviewing the commonly used mathematical and statistical models in the analysis of infectious diseases, with a focus on the mathematical models of the severe acute respiratory syndrome coronavirus 2(SARS-CoV-2) that have been published and their practical effects.@*Results@#Infectious diseases modelling based on multi-source information has become the main research trend, and the published mathematical models of COVID-19 epidemic need to be improved in terms of accuracy and scalability.@*Conclusions@#It is recommended to build a more advanced mathematical/statistical model by allowing for the characteristics of new coronaviruses and to use more informative data to improve the analysis and decision-making of the new epidemic.
kbulgxoa
kbulgxoa
2020
1
Computational target-based drug repurposing of elbasvir, an antiviral drug predicted to bind multiple SARS-CoV-2 proteins.
Coronavirus disease 19 (COVID-19) is a severe acute respiratory syndrome caused by SARS-CoV-2 (2019-nCoV). While no drugs have yet been approved to treat this disease, small molecules effective against other viral infections are under clinical evaluation for therapeutic abatement of SARS-CoV-2 infections. Ongoing clinical trials include Kaletra (a combination of two protease inhibitors approved for HIV treatment), remdesivir (an investigational drug targeting RNA-dependent RNA polymerase [RdRP] of SARS-CoV-2), and hydroxychloroquine (an approved anti-malarial and immuno-modulatory drug). Since SARS-CoV-2 replication depends on three virally encoded proteins (RdRP, papain-like proteinase, and helicase), we screened 54 FDA-approved antiviral drugs and ~3300 investigational drugs for binding to these proteins using targeted and unbiased docking simulations and computational modeling. Elbasvir, a drug approved for treating hepatitis C, is predicted to bind stably and preferentially to all three proteins. At the therapeutic dosage, elbasvir has low toxicity (liver enzymes transiently elevated in 1% of subjects) and well-characterized drug-drug interactions. We predict that treatment with elbasvir, alone or in combination with other drugs such as grazoprevir, could efficiently block SARS-CoV-2 replication. The concerted action of elbasvir on at least three targets essential for viral replication renders viral mutation to drug resistance extremely unlikely.
kc2r034w
kc2r034w
2020-04-08
10.26434/chemrxiv.12084822.v2
4
Inhibition of SARS Coronavirus Infection In Vitro with Clinically Approved Antiviral Drugs
Severe acute respiratory syndrome (SARS) is an infectious disease caused by a newly identified human coronavirus (SARS-CoV). Currently, no effective drug exists to treat SARS-CoV infection. In this study, we investigated whether a panel of commercially available antiviral drugs exhibit in vitro anti–SARS-CoV activity. A drug-screening assay that scores for virus-induced cytopathic effects on cultured cells was used. Tested were 19 clinically approved compounds from several major antiviral pharmacologic classes: nucleoside analogs, interferons, protease inhibitors, reverse transcriptase inhibitors, and neuraminidase inhibitors. Complete inhibition of cytopathic effects of SARS-CoV in culture was observed for interferon subtypes, β-1b, α-n1, α-n3, and human leukocyte interferon α. These findings support clinical testing of approved interferons for the treatment of SARS.
kcyao9i9
kcyao9i9
2004-04-16
10.3201/eid1004.030458
1
Harnessing the power of novel animal-free test methods for the development of COVID-19 drugs and vaccines
The COVID-19-inducing virus, SARS-CoV2, is likely to remain a threat to human health unless efficient drugs or vaccines become available. Given the extent of the current pandemic (people in over one hundred countries infected) and its disastrous effect on world economy (associated with limitations of human rights), speedy drug discovery is critical. In this situation, past investments into the development of new (animal-free) approach methods (NAM) for drug safety, efficacy, and quality evaluation can be leveraged. For this, we provide an overview of repurposing ideas to shortcut drug development times. Animal-based testing would be too lengthy, and it largely fails, when a pathogen is species-specific or if the desired drug is based on specific features of human biology. Fortunately, industry has already largely shifted to NAM, and some public funding programs have advanced the development of animal-free technologies. For instance, NAM can predict genotoxicity (a major aspect of carcinogenicity) within days, human antibodies targeting virus epitopes can be generated in molecular biology laboratories within weeks, and various human cell-based organoids are available to test virus infectivity and the biological processes controlling them. The European Medicines Agency (EMA) has formed an expert group to pave the way for the use of such approaches for accelerated drug development. This situation illustrates the importance of diversification in drug discovery strategies and clearly shows the shortcomings of an approach that invests 95% of resources into a single technology (animal experimentation) in the face of challenges that require alternative approaches. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s00204-020-02787-2) contains supplementary material, which is available to authorized users.
khfrd1nk
khfrd1nk
2020-05-23
10.1007/s00204-020-02787-2
4
Interaction of the spike protein RBD from SARS-CoV-2 with ACE2: Similarity with SARS-CoV, hot-spot analysis and effect of the receptor polymorphism
The spread of COVID-19 caused by the SARS-CoV-2 outbreak has been growing since its first identification in December 2019. The publishing of the first SARS-CoV-2 genome made a valuable source of data to study the details about its phylogeny, evolution, and interaction with the host. Protein-protein binding assays have confirmed that Angiotensin-converting enzyme 2 (ACE2) is more likely to be the cell receptor through which the virus invades the host cell. In the present work, we provide an insight into the interaction of the viral spike Receptor Binding Domain (RBD) from different coronavirus isolates with host ACE2 protein. By calculating the binding energy score between RBD and ACE2, we highlighted the putative jump in the affinity from a progenitor form of SARS-CoV-2 to the current virus responsible for COVID-19 outbreak. Our result was consistent with previously reported phylogenetic analysis and corroborates the opinion that the interface segment of the spike protein RBD might be acquired by SARS-CoV-2 via a complex evolutionary process rather than a progressive accumulation of mutations. We also highlighted the relevance of Q493 and P499 amino acid residues of SARS-CoV-2 RBD for binding to human ACE2 and maintaining the stability of the interface. Moreover, we show from the structural analysis that it is unlikely for the interface residues to be the result of genetic engineering. Finally, we studied the impact of eight different variants located at the interaction surface of ACE2, on the complex formation with SARS-CoV-2 RBD. We found that none of them is likely to disrupt the interaction with the viral RBD of SARS-CoV-2.
khl418zw
khl418zw
2020-05-14
10.1016/j.bbrc.2020.05.028
3.5
The FDA-approved gold drug auranofin inhibits novel coronavirus (SARS-COV-2) replication and attenuates inflammation in human cells
SARS-COV-2 has recently emerged as a new public health threat. Herein, we report that the FDA-approved drug, auranofin, inhibits SARS-COV-2 replication in human cells at low micro molar concentration. Treatment of cells with auranofin resulted in a 95% reduction in the viral RNA at 48 h after infection. Auranofin treatment dramatically reduced the expression of SARS-COV-2-induced cytokines in human cells. These data indicate that auranofin could be a useful drug to limit SARS-CoV-2 infection and associated lung injury due to its antiviral, anti-inflammatory and anti-reactive oxygen species (ROS) properties. Further animal studies are warranted to evaluate the safety and efficacy of auranofin for the management of SARS-COV-2 associated disease.
khrh289z
khrh289z
2020-05-19
10.1016/j.virol.2020.05.002
4
Computational simulations reveal the binding dynamics between human ACE2 and the receptor binding domain of SARS-CoV-2 spike protein
A novel coronavirus (the SARS-CoV-2) has been identified in January 2020 as the causal pathogen for COVID-19 pneumonia, an outbreak started near the end of 2019 in Wuhan, China. The SARS-CoV-2 was found to be closely related to the SARS-CoV, based on the genomic analysis. The Angiotensin converting enzyme 2 protein (ACE2) utilized by the SARS-CoV as a receptor was found to facilitate the infection of SARS-CoV-2 as well, initiated by the binding of the spike protein to the human ACE2. Using homology modeling and molecular dynamics (MD) simulation methods, we report here the detailed structure of the ACE2 in complex with the receptor binding domain (RBD) of the SARS-CoV-2 spike protein. The predicted model is highly consistent with the experimentally determined complex structures. Plausible binding modes between human ACE2 and the RBD were revealed from all-atom MD simulations. The simulation data further revealed critical residues at the complex interface and provided more details about the interactions between the SARS-CoV-2 RBD and human ACE2. Two mutants mimicking rat ACE2 were modeled to study the mutation effects on RBD binding to ACE2. The simulations showed that the N-terminal helix and the K353 of the human ACE2 alter the binding modes of the CoV2-RBD to the ACE2.
kifqgskc
kifqgskc
2020-03-27
10.1101/2020.03.24.005561
1.5
Low dose radiation therapy as a potential life saving treatment for COVID-19-induced acute respiratory distress syndrome (ARDS)
Abstract The new coronavirus COVID-19 disease caused by SARS-CoV-2 was declared as global public health emergency by WHO on Jan 30, 2020. Despite massive efforts from various governmental, health and medical organizations, the disease continues to spread globally with increasing fatality rates. Several experimental drugs have been approved by FDA with unknown efficacy and potential adverse effects. The exponentially spreading pandemic of COVID-19 deserves prime public health attention to evaluate yet unexplored arenas of management. We opine that one of these treatment options is low dose radiation therapy for severe and most critical cases. There is evidence in literature that low dose radiation induces an anti-inflammatory phenotype that can potentially afford therapeutic benefit against COVID-19- related complications that are associated with significant morbidity and mortality. Herein, we review the effects and putative mechanisms of low dose radiation that may be viable, useful and of value in counter-acting the acute inflammatory state induced by critical stage COVID-19.
kj7qpydc
kj7qpydc
2020-05-08
10.1016/j.radonc.2020.05.002
3.5
Development of remdesivir repositioning as a nucleotide analog against COVID-19 RNA dependent RNA polymerase
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative representative of a severe respiratory illness resulted in widespread human infections and deaths in nearly all of the countries since late 2019. There is no therapeutic FDA-approved drug against SARS-CoV-2 infection, although a combination of anti-viral drugs is directly being practiced in some countries. A broad-spectrum of antiviral agents are being currently evaluated in clinical trials, and in this review, we specifically focus on the application of Remdesivir (RVD) as a potential anti-viral compound against Middle East respiratory syndrome (MERS) -CoV, SARS-CoV and SARS-CoV-2. First, we overview the general information about SARS-CoV-2, followed by application of RDV as a nucleotide analogue which can potentially inhibits RNA-dependent RNA polymerase of COVs. Afterwards, we discussed the kinetics of SARS- or MERS-CoV proliferation in animal models which is significantly different compared to that in humans. Finally, some ongoing challenges and future perspective on the application of RDV either alone or in combination with other anti-viral agents against CoVs infection were surveyed to determine the efficiency of RDV in preclinical trials. As a result, this paper provides crucial evidence of the potency of RDV to prevent SARS-CoV-2 infections.Communicated by Ramaswamy H. Sarma.
kjc3j7yz
kjc3j7yz
2020
4
Rapid and accurate identification of COVID-19 infection through machine learning based on clinical available blood test results
Since the sudden outbreak of coronavirus disease 2019 (COVID-19), it has rapidly evolved into a momentous global health concern. Due to the lack of constructive information on the pathogenesis of COVID-19 and specific treatment, it highlights the importance of early diagnosis and timely treatment. In this study, 11 key blood indices were extracted through random forest algorithm to build the final assistant discrimination tool from 49 clinical available blood test data which were derived by commercial blood test equipments. The method presented robust outcome to accurately identify COVID-19 from a variety of suspected patients with similar CT information or similar symptoms, with accuracy of 0.9795 and 0.9697 for the cross-validation set and test set, respectively. The tool also demonstrated its outstanding performance on an external validation set that was completely independent of the modeling process, with sensitivity, specificity, and overall accuracy of 0.9512, 0.9697, and 0.9595, respectively. Besides, 24 samples from overseas infected patients with COVID-19 were used to make an in-depth clinical assessment with accuracy of 0.9167. After multiple verification, the reliability and repeatability of the tool has been fully evaluated, and it has the potential to develop into an emerging technology to identify COVID-19 and lower the burden of global public health. The proposed tool is well-suited to carry out preliminary assessment of suspected patients and help them to get timely treatment and quarantine suggestion. The assistant tool is now available online at http://lishuyan.lzu.edu.cn/COVID2019_2/.
kjovtgua
kjovtgua
2020-04-06
10.1101/2020.04.02.20051136
1
ACE2 receptor polymorphism: susceptibility to SARS-CoV-2, hypertension, multi-organ failure, and COVID-19 disease outcome
Abstract The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has emerged in Chinese people in December 2019 and has currently spread worldwide causing the COVID-19 pandemic with more than 150,000 deaths. In order for a SARS-CoV like virus circulating in wild life for a very long time to infect the index case-patient, a number of conditions must be met, foremost among which is the encounter with humans and the presence in homo sapiens of a cellular receptor allowing the virus to bind. Recently it was shown that the SARS-CoV-2 spike protein, binds to the human angiotensin I converting enzyme 2 (ACE2). This molecule is a peptidase expressed at the surface of lung epithelial cells and other tissues, that regulates the renin-angiotensin-aldosterone system. Humans are not equal with respect to the expression levels of the cellular ACE2. Moreover, ACE2 polymorphisms were recently described in human populations. Here we review the most recent evidence that ACE2 expression and/or polymorphism could influence both the susceptibility of people to SARS-CoV-2 infection and the outcome of the COVID-19 disease. Further exploration of the relationship between the virus, the peptidase function of ACE2 and the levels of angiotensin II in SARS-CoV-2 infected patients should help to better understand the pathophysiology of the disease and the multi-organ failures observed in severe COVID-19 cases, particularly heart failure.
kmd39z91
kmd39z91
2020-05-06
10.1016/j.jmii.2020.04.015
3
The anti-HIV Drug Nelfinavir Mesylate (Viracept) is a Potent Inhibitor of Cell Fusion Caused by the SARS-CoV-2 Spike (S) Glycoprotein Warranting further Evaluation as an Antiviral against COVID-19 infections
Coronaviruses belong to a group of enveloped, positive-single stranded RNA viruses that are known to cause severe respiratory distress in animals and humans. The current SARS coronavirus-2 (SARS CoV-2) pandemic has caused more than 2,000,000 infections globally and nearly 200,000 deaths. Coronaviruses enter susceptible cells via fusion of the viral envelope with the plasma membrane and/or via fusion of the viral envelope with endosomal membranes after endocytosis of the virus into endosomes. Previous results with SARS and MERS CoV have shown that the Spike (S) glycoprotein is a major determinant of virus infectivity and immunogenicity. Herein, we show that expression of SARS CoV-2 S (S-n) glycoprotein after transient transfection of African green monkey kidney (Vero) cells caused extensive cell fusion in comparison to limited cell fusion caused by the SARS S (S-o) glycoprotein. S-n expression was detected intracellularly and on transfected Vero cell surfaces and caused the formation of very large multinucleated cells (syncytia) by 48 hours post transfection. These results are in agreement with published pathology observations of extensive syncytial formation in lung tissues of COVID-19 patients. This differential S-n versus S-o-mediated cell fusion suggests that SARS-CoV-2 is able to spread from cell-to-cell much more efficiently than SARS effectively avoiding extracellular spaces and neutralizing antibodies. A systematic screening of several drugs for ability to inhibit S-n and S-o cell fusion revealed that the FDA approved HIV-protease inhibitor, nelfinavir mesylate (Viracept) drastically inhibited S-n and S-o-mediated cell fusion in a dose-dependent manner. Complete inhibition of cell fusion was observed at a 10 micromolar concentration. Computational modeling and in silico docking experiments suggested the possibility that nelfinavir may bind inside the S trimer structure, proximal to the S2 amino terminus directly inhibiting S-n and S-o-mediated membrane fusion. Also, it is possible that nelfinavir mesylate acts on cellular processes to inhibit S proteolytic processing. These results warrant further investigations of the potential of nelfinavir mesylate as an antiviral drug, especially at early times after SARS-CoV-2 symptoms appear.
kmmr6184
kmmr6184
2020-04-24
10.1101/2020.04.24.060376
2
SARS-CoV-2, COVID-19 and inherited arrhythmia syndromes
Abstract Ever since the first case was reported at the end of 2019, the SARS-COV-2 virus and associated lung disease COVID-19 has spread throughout the world and has become a pandemic. In particular, the high transmission rate of the virus has made it a threat to public health globally. Currently, there is no proven effective therapy against the virus, and the impact on other diseases is also uncertain, especially inherited arrhythmia syndrome. Arrhythmogenic effect of COVID-19 can be expected, potentially contributing to disease outcome. This may be of importance for patients with an increased risk for cardiac arrhythmias, either secondary to acquired conditions or co-morbidities or consequent to inherited syndromes. Management of patients with inherited arrhythmia syndromes such as Long QT syndrome, Brugada syndrome, Short QT syndrome and Catecholaminergic Polymorphic Ventricular Tachycardia in the setting of the COVID-19 pandemic may prove particularly challenging. Depending on the inherited defect involved, these patients may be susceptible to pro-arrhythmic effects of COVID-19-related issues such as fever, stress, electrolyte disturbances and use of antiviral drugs. We here describe the potential COVID-19 associated risks and therapeutic considerations for patients with distinct inherited arrhythmia syndromes and provide recommendations, pending local possibilities, for their monitoring and management during this pandemic.
kn1lcsia
kn1lcsia
2020-03-31
10.1016/j.hrthm.2020.03.024
2
Favipiravir and severe acute respiratory syndrome coronavirus 2 in hamster model
There is a need for safe and effective antiviral molecules with which to combat COVID-19 pandemics. Recently, in vitro inhibitory activity of favipiravir against SARS-CoV-2 was reported. Here, we used a Syrian hamster model to explore the pharmacokinetics of this molecule and its in vivo efficacy against SARS-CoV-2. Results revealed that high doses (700-1400mg/kg/day) significantly reduced virus replication in the lungs accompanied by clinical alleviation of the disease. However, these high doses were associated with significant toxicity in hamsters. Favipiravir pharmacokinetics displayed non-linear increase in plasma exposure between the doses and good lung penetration. Analysis of viral genomes in vivo showed that favipiravir induced a mutagenic effect. Whilst the plasma trough concentrations observed in this study were comparable with those previously found during human clinical trials, this potential toxicity requires further investigation to assess whether a tolerable dosing regimen can be found in humans that effectively reduces virus replication.
knpctp4p
knpctp4p
2020-07-07
10.1101/2020.07.07.191775
5
Simulation of the clinical and pathological manifestations of Coronavirus Disease 2019 (COVID-19) in golden Syrian hamster model: implications for disease pathogenesis and transmissibility
BACKGROUND: A physiological small animal model that resembles COVID-19 with low mortality is lacking. METHODS: Molecular docking on the binding between angiotensin-converting enzyme 2 (ACE2) of common laboratory mammals and the receptor-binding domain of the surface spike protein of SARS-CoV-2 suggested that the golden Syrian hamster is an option. Virus challenge, contact transmission, and passive immunoprophylaxis were performed. Serial organ tissues and blood were harvested for histopathology, viral load and titre, chemokine/cytokine assay, and neutralising antibody titre. RESULTS: The Syrian hamster could be consistently infected by SARS-CoV-2. Maximal clinical signs of rapid breathing, weight loss, histopathological changes from the initial exudative phase of diffuse alveolar damage with extensive apoptosis to the later proliferative phase of tissue repair, airway and intestinal involvement with virus nucleocapsid protein expression, high lung viral load, and spleen and lymphoid atrophy associated with marked cytokine activation were observed within the first week of virus challenge. The lung virus titre was between 105-107 TCID50/g. Challenged index hamsters consistently infected naïve contact hamsters housed within the same cage, resulting in similar pathology but not weight loss. All infected hamsters recovered and developed mean serum neutralising antibody titre &#8805;1:427 fourteen days post-challenge. Immunoprophylaxis with early convalescent serum achieved significant decrease in lung viral load but not in lung pathology. No consistent non-synonymous adaptive mutation of the spike was found in viruses isolated from infected hamsters. CONCLUSIONS: Besides satisfying the Koch's postulates, this readily available hamster model is an important tool for studying transmission, pathogenesis, treatment, and vaccination against SARS-CoV-2.
kol2c721
kol2c721
2020
4
Development and simulation of fully glycosylated molecular models of ACE2-Fc fusion proteins and their interaction with the SARS-CoV-2 spike protein binding domain
We develop fully glycosylated computational models of ACE2-Fc fusion proteins which are promising targets for a COVID-19 therapeutic. These models are tested in their interaction with fragments of the binding domain of the Spike Protein S1 of the SARS-CoV-2 virus. We see that some ACE2 glycans interact with S1 and glycans are influencing the conformation of the ACE2 receptor. Additionally, we optimize algorithms for protein glycosylation modelling in order to expedite future model development. All models and algorithms are openly available.
kp63sa3x
kp63sa3x
2020-05-06
10.1101/2020.05.05.079558
3
Potential Treatments for SARS‐CoV‐2 Infection
kp8iph2r
kp8iph2r
2020-05-21
10.1002/cld.969
4.5
Treatment of COVID-19: old tricks for new challenges
kpyti1ju
kpyti1ju
2020-03-16
10.1186/s13054-020-2818-6
2.5
Animal viruses of economic importance: Genetic variation, persistence, and prospects for their control
kq7n22wd
kq7n22wd
2002-11-14
10.1016/0163-7258(85)90033-6
1.5
Commentary on Ferguson, et al., “Impact of Non-pharmaceutical Interventions (NPIs) to Reduce COVID-19 Mortality and Healthcare Demand”
A recent manuscript (Ferguson et al. in Impact of non-pharmaceutical interventions (NPIs) to reduce COVID-19 mortality and healthcare demand, Imperial College COVID-19 Response Team, London, 2020. https://www.imperial.ac.uk/media/imperial-college/medicine/sph/ide/gida-fellowships/Imperial-College-COVID19-NPI-modelling-16-03-2020.pdf) from Imperial College modelers examining ways to mitigate and control the spread of COVID-19 has attracted much attention. In this paper, we will discuss a coarse taxonomy of models and explore the context and significance of the Imperial College and other models in contributing to the analysis of COVID-19.
kqntu6ej
kqntu6ej
2020-04-08
10.1007/s11538-020-00726-x
1.5
The role of ACEIs/ARBs in COVID-19: friend or foe?
kqs3qwfk
kqs3qwfk
2020-05-05
10.1016/j.mehy.2020.109810
5
Key residues of the receptor binding motif in the spike protein of SARS-CoV-2 that interact with ACE2 and neutralizing antibodies
Coronavirus disease 2019 (COVID-19), caused by the novel human coronavirus SARS-CoV-2, is currently a major threat to public health worldwide. The viral spike protein binds the host receptor angiotensin-converting enzyme 2 (ACE2) via the receptor-binding domain (RBD), and thus is believed to be a major target to block viral entry. Both SARS-CoV-2 and SARS-CoV share this mechanism. Here we functionally analyzed the key amino acid residues located within receptor binding motif of RBD that may interact with human ACE2 and available neutralizing antibodies. The in vivo experiments showed that immunization with either the SARS-CoV RBD or SARS-CoV-2 RBD was able to induce strong clade-specific neutralizing antibodies in mice; however, the cross-neutralizing activity was much weaker, indicating that there are distinct antigenic features in the RBDs of the two viruses. This finding was confirmed with the available neutralizing monoclonal antibodies against SARS-CoV or SARS-CoV-2. It is worth noting that a newly developed SARS-CoV-2 human antibody, HA001, was able to neutralize SARS-CoV-2, but failed to recognize SARS-CoV. Moreover, the potential epitope residues of HA001 were identified as A475 and F486 in the SARS-CoV-2 RBD, representing new binding sites for neutralizing antibodies. Overall, our study has revealed the presence of different key epitopes between SARS-CoV and SARS-CoV-2, which indicates the necessity to develop new prophylactic vaccine and antibody drugs for specific control of the COVID-19 pandemic although the available agents obtained from the SARS-CoV study are unneglectable.
kqzx9m82
kqzx9m82
2020-05-15
10.1038/s41423-020-0458-z
4
SARS
Severe acute respiratory syndrome (SARS) emerged in southern China in late 2002. It first spread within Guangdong Province and then to other parts of China. Via air travelers, it quickly reached various countries around the globe, causing several major hospital outbreaks. Within weeks, the causative agent, a previously unknown coronavirus (SARS-CoV), was identified, thanks to an unprecedented international effort led by the World Health Organization (WHO). Its origin was quickly traced to wild animals traded locally for culinary purposes. Masked palm civet and some other species seem to have acted as intermediate hosts. Since then, SARS-like coronaviruses were found in different bat species in China and elsewhere, and bats are now regarded as the wildlife reservoir for SARS-CoV. Fortunately, the SARS outbreak could be contained within months. Until July 2003, it had caused 8096 cases, with 774 deaths. Once adequate measures such as isolating patients and quarantining their contacts were strictly adhered to, further transmission between human beings could be interrupted. SARS is an example of how rapidly an infectious agent can spread in the modern world. At the same time, it should serve as a showcase of how international cooperation and modern science can help to combat the spread of infectious diseases.
kromgrnu
kromgrnu
2011-12-31
10.1016/b978-0-444-52272-6.00624-3
0.5
Potential Role of ACE2 in Coronavirus Disease 2019 (COVID-19) Prevention and Management
COVID-19 is the current public health threat all over the world. Unfortunately, there is no specific prevention and treatment strategy for this disease. We aim to explore the potential role of angiotensin-converting enzyme 2 (ACE2) in this regard through this literature review. As a crucial enzyme of renin-angiotensin-aldosterone system (RAAS), ACE2 not only mediates the virus entry but also affects the pathophysiological process of virus-induced acute lung injury (ALI), as well as other organs’ damage. As interaction of COVID-19 virus spike and ACE2 is essential for virus infection, COVID-19-specific vaccine based on spike protein, small molecule compound interrupting their interaction, human monoclonal antibody based on receptor-binding domain, and recombinant human ACE2 protein (rhuACE2) have aroused the interests of researchers. Meanwhile, ACE2 could catalyze angiotensin II (Ang II) to form angiotensin 1-7 (Ang 1-7), thus alleviates the harmful effect of Ang II and amplifies the protection effect of Ang1-7. ACE inhibitor and angiotensin II receptor blocker (ARB) have been shown to increase the level of expression of ACE2 and could be potential strategies in protecting lungs, heart, and kidneys. ACE2 plays a very important role in the pathogenesis and pathophysiology of COVID-19 infection. Strategies targeting ACE2 and its ligand, COVID-19 virus spike protein, may provide novel method in the prevention and management of novel coronavirus pneumonia.
ksintgvq
ksintgvq
2020-05-09
10.2478/jtim-2020-0003
4
SARS-CoV-2 Isolation and Propagation from Turkish COVID-19 patients
The novel coronavirus pneumonia, which was named later as Coronavirus Disease 2019 (COVID-19), is caused by the Severe Acute Respiratory Syndrome Coronavirus 2, namely SARS-CoV-2. It is a positive-strand RNA virus that is the seventh coronavirus known to infect humans. The COVID-19 outbreak presents enormous challenges for global health behind the pandemic outbreak. The first diagnosed patient in Turkey has been reported by the Republic of Turkey Ministry of Health on March 11, 2020. Today, over ninety thousand cases in Turkey, and two million cases around the world have been declared. Due to the urgent need for vaccine and anti-viral drug, isolation of the virus is crucial. Here, we report one of the first isolation and characterization studies of SARS-CoV-2 from nasopharyngeal and oropharyngeal specimens of diagnosed patients in Turkey. This study provides an isolation and replication methodology, and cell culture tropism of the virus that will be available to the research communities. Article Summary Scientists have isolated virus from Turkish COVID-19 patients. The isolation, propagation, and plaque and immune response assays of the virus described here will serve in following drug discovery and vaccine testing.
ksva9eah
ksva9eah
2020-04-24
10.1101/2020.04.23.056309
2
Proportional fault-tolerant data mining with applications to bioinformatics
The mining of frequent patterns in databases has been studied for several years, but few reports have discussed for fault-tolerant (FT) pattern mining. FT data mining is more suitable for extracting interesting information from real-world data that may be polluted by noise. In particular, the increasing amount of today’s biological databases requires such a data mining technique to mine important data, e.g., motifs. In this paper, we propose the concept of proportional FT mining of frequent patterns. The number of tolerable faults in a proportional FT pattern is proportional to the length of the pattern. Two algorithms are designed for solving this problem. The first algorithm, named FT-BottomUp, applies an FT-Apriori heuristic and finds all FT patterns with any number of faults. The second algorithm, FT-LevelWise, divides all FT patterns into several groups according to the number of tolerable faults, and mines the content patterns of each group in turn. By applying our algorithm on real data, two reported epitopes of spike proteins of SARS-CoV can be found in our resulting itemset and the proportional FT data mining is better than the fixed FT data mining for this application.
kt9sbn40
kt9sbn40
2009-02-19
10.1007/s10796-009-9158-z
1
Severe Acute Respiratory Syndrome: Developing a Research Response
When severe acute respiratory syndrome (SARS) first came to world attention in March 2003, it was immediately perceived to be a global threat with a pandemic potential. To help coordinate international research efforts, the National Institute of Allergy and Infectious Diseases convened a colloquium entitled SARS: Developing a Research Response on 30 May 2003. Breakout sessions intended to identify unmet research needs in 5 areas of SARS research—clinical research, epidemiology, diagnostics, therapeutics, and vaccines—are summarized here. Since this meeting, however, the identified research needs have been only partially met. Needs that have yet to be realized include reliable methods for early identification of individuals with SARS, a full description of SARS pathogenesis and immune response, and animal models that faithfully mimic SARS respiratory symptoms. It is also of the utmost importance that the global scientific community enhance mechanisms for international cooperation and planning for SARS research, as well as for other emerging infectious disease threats that are certain to arise in the future.
ktrh3seo
ktrh3seo
2004-02-16
10.1086/382225
1
Validation and verification of the Abbott RealTime SARS-CoV-2 assay analytical and clinical performance
BACKGROUND: High-throughput assays for the SARS-CoV-2 virus are critical to increasing test capacity and slowing the spread of COVID-19. Abbott Molecular developed and received emergency use authorization (EUA) to deploy the new RealTime SARS-CoV-2 assay, run on the automated m2000sp/rt system. OBJECTIVE: To evaluate analytical and clinical performance of the RealTime SARS-CoV-2 assay compared to the SARS-CoV-2 CDC-based laboratory developed test (LDT) in clinical use by the University of Washington Clinical Virology Laboratory (UW Virology). METHODS: RealTime SARS-CoV-2 assay limit of detection (LOD) was evaluated by testing two dilution panels of 60 replicates each. Cross-reactivity was evaluated by testing 24 clinical samples positive for various nonâSARS-CoV-2 respiratory viruses. Clinical performance was evaluated using 30 positive and 30 negative SARS-CoV-2 clinical samples previously tested using the UW Virology SARS-CoV-2 LDT. RESULTS: Exceeding the 100 copies/mL LOD reported in the RealTime SARS-CoV-2 assay EUA product insert, 19 of 20 replicates were detected at 50 copies/mL and 16 of 20 replicates were detected at 25 copies/mL. All clinical samples positive for 24 nonâSARS-CoV-2 respiratory viruses were SARS-CoV-2 negative on the RealTime SARS-CoV-2 assay. The assay had high sensitivity (93%) and specificity (100%) for detecting SARS-CoV-2 in clinical samples. Two positive samples that tested negative with the RealTime SARS-CoV-2 assay had cycle numbers of 35.94 or greater and required dilution prior to testing. One of these samples was also inconclusive on the SARS-CoV-2 LDT. CONCLUSION: The RealTime SARS-CoV-2 assay is acceptable for clinical use. With the high-throughput, fully automated m2000 system, this assay will accelerate the pace of SARS-CoV-2 testing.
kvjhv62p
kvjhv62p
2020
4.5
Are Animals a Neglected Transmission Route of SARS-CoV-2?
Little information on the SARS-CoV-2 virus in animals is available to date. Whereas no one husbandry animal case has been reported to date, which would have significant implications in food safety, companion animals play a role in COVID-19 epidemiology that opens up new questions. There is evidence that SARS-CoV-2 can infect felines, dogs and minks, and there is evidence of human-to-animal infection. Likewise, the S protein nucleotide sequence of the SARS-CoV-2 virus isolated in domestic animals and humans is identical, and the replication of the SARS-CoV-2 in cats is efficient. Besides, the epidemiological evidence for this current pandemic indicates that the spillover to humans was associated with close contact between man and exotic animals, very probably in Chinese wet markets, thus there is a growing general consensus that the exotic animal markets, should be strictly regulated. The examination of these findings and the particular role of animals in COVID-19 should be carefully analyzed in order to establish preparation and containment measures. Animal management and epidemiological surveillance must be also considered for COVID-19 control, and it can open up new questions regarding COVID-19 epidemiology and the role that animals play in it.
kvyvwhja
kvyvwhja
2020-06-18
10.3390/pathogens9060480
5
Coronavirus Disease 2019: Coronaviruses and Blood Safety
Abstract With the outbreak of unknown pneumonia in Wuhan, China, in December 2019, a new coronavirus, Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), aroused the attention of the entire world. The current outbreak of infections with SARS-CoV-2 is termed Coronavirus Disease 2019 (COVID-19). The World Health Organization declared COVID-19 in China as a Public Health Emergency of International Concern. Two other coronavirus infections—SARS in 2002-2003 and Middle East Respiratory Syndrome (MERS) in 2012—both caused severe respiratory syndrome in humans. All 3 of these emerging infectious diseases leading to a global spread are caused by β-coronaviruses. Although coronaviruses usually infect the upper or lower respiratory tract, viral shedding in plasma or serum is common. Therefore, there is still a theoretical risk of transmission of coronaviruses through the transfusion of labile blood products. Because more and more asymptomatic infections are being found among COVID-19 cases, considerations of blood safety and coronaviruses have arisen especially in endemic areas. In this review, we detail current evidence and understanding of the transmission of SARS-CoV, MERS–CoV, and SARS-CoV-2 through blood products as of February 10, 2020, and also discuss pathogen inactivation methods on coronaviruses.
kwq2y3il
kwq2y3il
2020-02-21
10.1016/j.tmrv.2020.02.003
1
Receptor utilization of angiotensin converting enzyme 2 (ACE2) indicates a narrower host range of SARS-CoV-2 than that of SARS-CoV
Coronavirus pandemics have become a huge threat to the public health worldwide in the recent decades. Typically, SARS-CoV caused SARS pandemic in 2003 and SARS-CoV-2 caused the COVID-19 pandemic recently. Both viruses have been reported to originate from bats. Thus, direct or indirect interspecies transmission from bats to humans is required for the viruses to cause pandemics. Receptor utilization is a key factor determining the host range of viruses which is critical to the interspecies transmission. Angiotensin converting enzyme 2 (ACE2) is the receptor of both SARS-CoV and SARS-CoV-2, but only ACE2s of certain animals can be utilized by the viruses. Here, we employed pseudovirus cell-entry assay to evaluate the receptor-utilizing capability of ACE2s of 20 animals by the two viruses and found that SARS-CoV-2 utilized less ACE2s than SARS-CoV, indicating a narrower host range of SARS-CoV-2. Meanwhile, pangolin CoV, another SARS-related coronavirus highly homologous to SARS-CoV-2 in its genome, yet showed similar ACE2 utilization profile with SARS-CoV rather than SARS-CoV-2. To clarify the mechanism underlying the receptor utilization, we compared the amino acid sequences of the 20 ACE2s and found 5 amino acid residues potentially critical for ACE2 utilization, including the N-terminal 20th and 42nd amino acids that may determine the different receptor utilization of SARS-CoV, SARS-CoV-2 and pangolin CoV. Our studies promote the understanding of receptor utilization of pandemic coronaviruses, potentially contributing to the virus tracing, intermediate host screening and epidemic prevention for pathogenic coronaviruses.
kx0n2oy5
kx0n2oy5
2020-06-13
10.1101/2020.06.13.149930
4
A novel severe acute respiratory syndrome coronavirus protein, U274, is transported to the cell surface and undergoes endocytosis.
The severe acute respiratory syndrome coronavirus (SARS-CoV) genome contains open reading frames (ORFs) that encode for several genes that are homologous to proteins found in all known coronaviruses. These are the replicase gene 1a/1b and the four structural proteins, nucleocapsid (N), spike (S), membrane (M), and envelope (E), and these proteins are expected to be essential for the replication of the virus. In addition, this genome also contains nine other potential ORFs varying in length from 39 to 274 amino acids. The largest among these is the first ORF of the second longest subgenomic RNA, and this protein (termed U274 in the present study) consists of 274 amino acids and contains three putative transmembrane domains. Using antibody specific for the C terminus of U274, we show U274 to be expressed in SARS-CoV-infected Vero E6 cells and, in addition to the full-length protein, two other processed forms were also detected. By indirect immunofluorescence, U274 was localized to the perinuclear region, as well as to the plasma membrane, in both transfected and infected cells. Using an N terminus myc-tagged U274, the topology of U274 and its expression on the cell surface were confirmed. Deletion of a cytoplasmic domain of U274, which contains Yxxphi and diacidic motifs, abolished its transport to the cell surface. In addition, U274 expressed on the cell surface can internalize antibodies from the culture medium into the cells. Coimmunoprecipitation experiments also showed that U274 could interact specifically with the M, E, and S structural proteins, as well as with U122, another protein that is unique to SARS-CoV.
kx1j99yw
kx1j99yw
2004
2.5
Coronaviruses and SARS-CoV-2: A Brief Overview
In late December 2019, several cases of pneumonia of unknown origin were reported from China, which in early January 2020 were announced to be caused by a novel coronavirus. The virus was later denominated severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and defined as the causal agent of Coronavirus Disease 2019 (COVID-19). Despite massive attempts to contain the disease in China, the virus has spread globally, and COVID-19 was declared a pandemic by the World Health Organization (WHO) in March 2020. Here we provide a short background on coronaviruses, and describe in more detail the novel SARS-CoV-2 and attempts to identify effective therapies against COVID-19.
kx5hihnr
kx5hihnr
2020-04-20
10.1213/ane.0000000000004845
2
COVID-19: A New Virus, but a Familiar Receptor and Cytokine Release Syndrome
Summary Zhou et al. (Nature) and Hoffmann et al. (Cell) identify ACE2 as a SARS-CoV-2 receptor, and the latter show its entry mechanism depends on cellular serine protease TMPRSS2. These results may explain proinflammatory cytokine release via the associated angiotestin II pathway and a possible therapeutic target via the IL-6-STAT3 axis.
ky0pva8y
ky0pva8y
2020-04-22
10.1016/j.immuni.2020.04.003
3
Should we mind for late neurologic manifestations from novel coronavirus?
kylls52u
kylls52u
2020-06-15
10.1016/j.clineuro.2020.106021
5
Cell entry mechanisms of SARS-CoV-2
A novel severe acute respiratory syndrome (SARS)-like coronavirus (SARS-CoV-2) is causing the global coronavirus disease 2019 (COVID-19) pandemic. Understanding how SARS-CoV-2 enters human cells is a high priority for deciphering its mystery and curbing its spread. A virus surface spike protein mediates SARS-CoV-2 entry into cells. To fulfill its function, SARS-CoV-2 spike binds to its receptor human ACE2 (hACE2) through its receptor-binding domain (RBD) and is proteolytically activated by human proteases. Here we investigated receptor binding and protease activation of SARS-CoV-2 spike using biochemical and pseudovirus entry assays. Our findings have identified key cell entry mechanisms of SARS-CoV-2. First, SARS-CoV-2 RBD has higher hACE2 binding affinity than SARS-CoV RBD, supporting efficient cell entry. Second, paradoxically, the hACE2 binding affinity of the entire SARS-CoV-2 spike is comparable to or lower than that of SARS-CoV spike, suggesting that SARS-CoV-2 RBD, albeit more potent, is less exposed than SARS-CoV RBD. Third, unlike SARS-CoV, cell entry of SARS-CoV-2 is preactivated by proprotein convertase furin, reducing its dependence on target cell proteases for entry. The high hACE2 binding affinity of the RBD, furin preactivation of the spike, and hidden RBD in the spike potentially allow SARS-CoV-2 to maintain efficient cell entry while evading immune surveillance. These features may contribute to the wide spread of the virus. Successful intervention strategies must target both the potency of SARS-CoV-2 and its evasiveness.
l19nsvun
l19nsvun
2020-05-26
10.1073/pnas.2003138117
4.5
Metagenomics detection and characterisation of viruses in faecal samples from Australian wild birds
We present an optimised metagenomics method for detection and characterisation of all virus types including single and double stranded DNA/RNA and enveloped and non-enveloped viruses. Initial evaluation included both spiked and non-spiked bird faecal samples as well as non-spiked human faecal samples. From the non-spiked bird samples (Australian Muscovy duck and Pacific black ducks) we detected 21 viruses, and we also present a summary of a few viruses detected in human faecal samples. We then present a detailed analysis of selected virus sequences in the avian samples that were somewhat similar to known viruses, and had good quality (Q20 or higher) and quantity of next-generation sequencing reads, and was of interest from a virological point of view, for example, avian coronavirus and avian paramyxovirus 6. Some of these viruses were closely related to known viruses while others were more distantly related with 70% or less identity to currently known/sequenced viruses. Besides detecting viruses, the technique also allowed the characterisation of host mitochondrial DNA present and thus identifying host species, while ribosomal RNA sequences provided insight into the “ribosomal activity microbiome”; of gut parasites; and of food eaten such as plants or insects, which we correlated to non-avian host associated viruses.
l2n0xvmd
l2n0xvmd
2018-06-06
10.1038/s41598-018-26851-1
1
Hijacking SARS-Cov-2/ACE2 receptor interaction by natural and semi-synthetic steroidal agents acting on functional pockets on receptor binding region
The coronavirus disease 2019 (COVID-19) is a respiratory tract infection caused by the severe acute respiratory syndrome coronavirus (SARS)-CoV-2. In the light of the urgent need to identify novel approaches to be used in the emergency phase, a largely explored strategy has been the repurpose of clinically available drugs as new antivirals, by targeting different viral proteins. In this paper, we describe a drug repurposing strategy based on a virtual screening of druggable pockets located in the central β-sheet core of the SARS-CoV-2 Spike protein RBD supported by in vitro tests identifying several steroidal derivatives as SARS-CoV-2 entry inhibitors. Our results demonstrate that several potential binding sites exist in the SARS CoV-2 S protein, and that the occupancy of these pockets reduces the ability of the S protein RBD to bind to the ACE2 consensus in vitro. In particular, natural occurring and clinically available steroids as glycyrrhetinic and oleanolic acids, as well as the bile acids derivatives glyco-UDCA and obeticholic acid have been shown to be effective in preventing virus entry in the case of low viral load. All together, these results might help to define novel approaches to reduce the viral load by using SARS-CoV-2 entry inhibitors.
l41lq2sc
l41lq2sc
2020-06-11
10.1101/2020.06.10.144964
4
Potent antiviral effect of protoporphyrin IX and verteporfin on SARS-CoV-2 infection
The infection of SARS-CoV-2 has spread to more than 200 countries and regions and the numbers of infected people and deaths worldwide are expected to continue to rise. Current treatment of COVID-19 is limited and mostly supportive. At present, there is no specific therapeutics against SARS-CoV-2. In this study, we discovered that protoporphyrin IX and verteporfin, two FDA-approved drugs for treatment of human diseases, had significant antiviral effect against SARS-CoV-2, with EC50 values for the reduction of viral RNA at nanomolar concentrations. Both drugs completely inhibited the cytopathic effect (CPE) produced by SARS-CoV-2 infection at lower drug concentrations than that of remdesivir. The selection indices of protoporphyrin IX and verteporfin are 952.74 and 368.93, respectively, suggesting wide safety margins. Both drugs were able to prevent SARS-CoV-2 infection as well as suppress established SARS-CoV-2 infection. The compounds share a porphyrin ring structure. Molecular docking indicates that the compounds may interact with viral receptor ACE2 and could block the cell-cell fusion mediated by ACE2 and viral S protein. Our finding suggests that protoporphyrin IX and verteporfin might be potential antivirals against SARS-CoV-2 infection and also sheds new light on the development of a novel class of small compounds against SARS-CoV-2.
l4ci8wr2
l4ci8wr2
2020-05-01
10.1101/2020.04.30.071290
3
Severe acute respiratory syndrome coronavirus-like virus in Chinese horseshoe bats.
Although the finding of severe acute respiratory syndrome coronavirus (SARS-CoV) in caged palm civets from live animal markets in China has provided evidence for interspecies transmission in the genesis of the SARS epidemic, subsequent studies suggested that the civet may have served only as an amplification host for SARS-CoV. In a surveillance study for CoV in noncaged animals from the wild areas of the Hong Kong Special Administration Region, we identified a CoV closely related to SARS-CoV (bat-SARS-CoV) from 23 (39%) of 59 anal swabs of wild Chinese horseshoe bats (Rhinolophus sinicus) by using RT-PCR. Sequencing and analysis of three bat-SARS-CoV genomes from samples collected at different dates showed that bat-SARS-CoV is closely related to SARS-CoV from humans and civets. Phylogenetic analysis showed that bat-SARS-CoV formed a distinct cluster with SARS-CoV as group 2b CoV, distantly related to known group 2 CoV. Most differences between the bat-SARS-CoV and SARS-CoV genomes were observed in the spike genes, ORF 3 and ORF 8, which are the regions where most variations also were observed between human and civet SARS-CoV genomes. In addition, the presence of a 29-bp insertion in ORF 8 of bat-SARS-CoV genome, not in most human SARS-CoV genomes, suggests that it has a common ancestor with civet SARS-CoV. Antibody against recombinant bat-SARS-CoV nucleocapsid protein was detected in 84% of Chinese horseshoe bats by using an enzyme immunoassay. Neutralizing antibody to human SARS-CoV also was detected in bats with lower viral loads. Precautions should be exercised in the handling of these animals.
l5ja7l6h
l5ja7l6h
2005
0.5
Epidemiology, virology, and clinical features of severe acute respiratory syndrome -coronavirus-2 (SARS-CoV-2; Coronavirus Disease-19)
A cluster of severe pneumonia of unknown etiology in Wuhan City, Hubei province in China emerged in December 2019. A novel coronavirus named severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) was isolated from lower respiratory tract sample as the causative agent. The current outbreak of infections with SARS-CoV-2 is termed Coronavirus Disease 2019 (COVID-19) by the World Health Organization (WHO). COVID-19 rapidly spread into at least 114 countries and killed more than 4,000 people by March 11 2020. WHO officially declared COVID-19 a pandemic on March 11, 2020. There have been 2 novel coronavirus outbreaks in the past 2 decades. The outbreak of severe acute respiratory syndrome (SARS) in 2002–2003 caused by SARS-CoV had a case fatality rate of around 10% (8,098 confirmed cases and 774 deaths), while Middle East respiratory syndrome (MERS) caused by MERS-CoV killed 861 people out of a total 2,502 confirmed cases between 2012 and 2019. The purpose of this review is to summarize known-to-date information about SARS-CoV-2, transmission of SARS-CoV-2, and clinical features.
l5q5wc06
l5q5wc06
2020-04-02
10.3345/cep.2020.00493
2
Antiviral Efficacies of FDA-Approved Drugs against SARS-CoV-2 Infection in Ferrets
Due to the urgent need of a therapeutic treatment for coronavirus (CoV) disease 2019 (COVID-19) patients, a number of FDA-approved/repurposed drugs have been suggested as antiviral candidates at clinics, without sufficient information. Furthermore, there have been extensive debates over antiviral candidates for their effectiveness and safety against severe acute respiratory syndrome CoV 2 (SARS-CoV-2), suggesting that rapid preclinical animal studies are required to identify potential antiviral candidates for human trials. To this end, the antiviral efficacies of lopinavir-ritonavir, hydroxychloroquine sulfate, and emtricitabine-tenofovir for SARS-CoV-2 infection were assessed in the ferret infection model. While the lopinavir-ritonavir-, hydroxychloroquine sulfate-, or emtricitabine-tenofovir-treated group exhibited lower overall clinical scores than the phosphate-buffered saline (PBS)-treated control group, the virus titers in nasal washes, stool specimens, and respiratory tissues were similar between all three antiviral-candidate-treated groups and the PBS-treated control group. Only the emtricitabine-tenofovir-treated group showed lower virus titers in nasal washes at 8 days postinfection (dpi) than the PBS-treated control group. To further explore the effect of immune suppression on viral infection and clinical outcome, ferrets were treated with azathioprine, an immunosuppressive drug. Compared to the PBS-treated control group, azathioprine-immunosuppressed ferrets exhibited a longer period of clinical illness, higher virus titers in nasal turbinate, delayed virus clearance, and significantly lower serum neutralization (SN) antibody titers. Taken together, all antiviral drugs tested marginally reduced the overall clinical scores of infected ferrets but did not significantly affect in vivo virus titers. Despite the potential discrepancy of drug efficacies between animals and humans, these preclinical ferret data should be highly informative to future therapeutic treatment of COVID-19 patients.
l611eisi
l611eisi
2020-05-22
10.1128/mbio.01114-20
4
Binding site analysis of potential protease inhibitors of COVID-19 using AutoDock
Recent outbreak of COVID-19 caused by SARS-CoV-2 in December 2019 raised global health concerns. Re-purposing the available protease inhibitor drugs for immediate use in treatment in SARS-CoV-2 infections could improve the currently available clinical management. The current study, aims to predict theoretical structure for protease of COVID-19 and to explore further whether this protein can serve as a target for protease inhibitor drugs such as remdesivir, nelfinavir, lopinavir, ritonavir and α-ketoamide. While the 3D structure of protease was predicted using SWISS MODEL server, molecular interaction studies between protein and ligands were performed using AutoDock software. The predicted protease model was reasonably good based on reports generated by different validation servers. The study further revealed that all the protease inhibitor drugs got docked with negative dock energy onto the target protein. Molecular interaction studies showed that protease structure had multiple active site residues for remdesivir, while for remaining ligands the structure had only one active site residue each. From the output of multiple sequence alignment, it is evident that ligand binding sites were conserved. The current in silico study thus, provides structural insights about the protease of COVID-19 and also its molecular interactions with some of the known protease inhibitors. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s13337-020-00585-z) contains supplementary material, which is available to authorized users.
l647du3s
l647du3s
2020-05-02
10.1007/s13337-020-00585-z
3.5
The possible mechanisms of action of 4-aminoquinolines (chloroquine/hydroxychloroquine) against Sars-Cov-2 infection (COVID-19): A role for iron homeostasis?
The anti-malarial drugs chloroquine (CQ) and primarily the less toxic hydroxychloroquine (HCQ) are currently used to treat autoimmune diseases for their immunomodulatory and anti-thrombotic properties. They have also been proposed for the treatment of several viral infections, due to their anti-viral effects in cell cultures and animal models, and, currently, for the treatment of coronavirus disease 2019 (COVID-19), the pandemic severe acute respiratory syndrome caused by coronavirus 2 (Sars-Cov-2) infection that is spreading all over the world. Although in some recent studies a clinical improvement in COVID-19 patients has been observed, the clinical efficacy of CQ and HCQ in COVID-19 has yet to be proven with randomized controlled studies, many of which are currently ongoing, also considering pharmacokinetics, optimal dosing regimen, therapeutic level and duration of treatment and taking into account patients with different severity degrees of disease. Here we review what is currently known on the mechanisms of action of CQ and HCQ as anti-viral, anti-inflammatory and anti-thrombotic drugs and discuss the up-to-date experimental evidence on the potential mechanisms of action of CQ/HCQ in Sars-Cov2 infection and the current clinical knowledge on their efficacy in the treatment of COVID-19 patients. Given the role of iron in several human viral infections, we also propose a different insight into a number of CQ and HCQ pharmacological effects, suggesting a potential involvement of iron homeostasis in Sars-Cov-2 infection and COVID-19 clinical course.
l6l24pco
l6l24pco
2020-05-13
10.1016/j.phrs.2020.104904
3
Preliminary Virtual Screening Studies to Identify GRP78 Inhibitors Which May Interfere with SARS-CoV-2 Infection
SARS-CoV-2 Spike protein was predicted by molecular docking to bind the host cell surface GRP78, which was suggested as a putative good molecular target to inhibit Covid-19. We aimed to confirm that GRP78 gene expression was increased in blood of SARS-CoV-2 (+) versus SARS-CoV-2 (−) pneumonia patients. In addition, we aimed to identify drugs that could be repurposed to inhibit GRP78, thus with potential anti-SARS-CoV-2 activity. Gene expression studies were performed in 10 SARS-CoV-2 (−) and 24 SARS-CoV-2 (+) pneumonia patients. A structure-based virtual screen was performed with 10,761 small molecules retrieved from DrugBank, using the GRP78 nucleotide binding domain and substrate binding domain as molecular targets. Results indicated that GRP78 mRNA levels were approximately four times higher in the blood of SARS-CoV-2 (+) versus SARS-CoV-2 (−) pneumonia patients, further suggesting that GRP78 might be a good molecular target to treat Covid-19. In addition, a total of 409 compounds were identified with potential as GRP78 inhibitors. In conclusion, we found preliminary evidence that further proposes GRP78 as a possible molecular target to treat Covid-19 and that many clinically approved drugs bind GRP78 as an off-target effect. We suggest that further work should be urgently carried out to confirm if GRP78 is indeed a good molecular target and if some of those drugs have potential to be repurposed for SARS-CoV-2 antiviral activity.
l7ohbk7c
l7ohbk7c
2020-06-25
10.3390/ph13060132
5
Infectivity, virulence, pathogenicity, host-pathogen interactions of SARS and SARS-CoV-2 in experimental animals: a systematic review
The outbreak of the SARS-CoV-2 in mainland China with subsequent human to human transmission worldwide had taken up the shape of a devastating pandemic. The ability of the virus to infect multiple species other than humans has currently been reported in experimental conditions. Non-human primates, felines, ferrets, rodents and host of other animals could previously be infected in experimental conditions with SARS-CoV and recently with SARS-CoV-2, both virus using Angiotensin-converting-enzyme 2 receptor for cellular entry. The variations in sequence homology of ACE2 receptor across species is identified as one of the factors determining virulence and pathogenicity in animals. The infection in experimental animals with SARS-CoV or SARS-CoV-2 on most occasions are asymptomatic, however, the virus could multiply within the respiratory tract and extra-pulmonary organs in most of the species. Here, we discuss about the pathogenicity, transmission, variations in angiotensin-converting-enzyme 2 receptor-binding across species and host pathogen interactions of SARS and SARS-CoV-2 in laboratory animals used in research.
l8qcqxzw
l8qcqxzw
2020-07-10
10.1007/s11259-020-09778-9
5
MERS-CoV pathogenesis and antiviral efficacy of licensed drugs in human monocyte-derived antigen-presenting cells
Middle East respiratory syndrome coronavirus (MERS-CoV) presents an emerging threat to public health worldwide by causing severe respiratory disease in humans with high virulence and case fatality rate (about 35%) since 2012. Little is known about the pathogenesis and innate antiviral response in primary human monocyte-derived macrophages (MDMs) and dendritic cells (MDDCs) upon MERS-CoV infection. In this study, we assessed MERS-CoV replication as well as induction of inflammatory cytokines and chemokines in MDMs and immature and mature MDDCs. Immature MDDCs and MDMs were permissive for MERS-CoV infection, while mature MDDCs were not, with stimulation of proinflammatory cytokine and chemokine upregulation in MDMs, but not in MDDCs. To further evaluate the antiviral activity of well-defined drugs in primary antigen presenting cells (APCs), three compounds (chloroquine, chlorpromazine and toremifine), each with broad-spectrum antiviral activity in immortalized cell lines, were evaluated in MDMs and MDDCs to determine their antiviral effect on MERS-CoV infection. While chloroquine was not active in these primary cells, chlorpromazine showed strong anti-MERS-CoV activity, but it was associated with high cytotoxicity narrowing the potential window for drug utilization. Unlike in established cells, toremifene had marginal activity when tested in antigen presenting cells, with high apparent cytotoxicity, also limiting its potential as a therapeutic option. These results demonstrate the value of testing drugs in primary cells, in addition to established cell lines, before initiating preclinical or clinical studies for MERS treatment and the importance of carefully assessing cytotoxicity in drug screen assays. Furthermore, these studies also highlight the role of APCs in stimulating a robust protective immune response to MERS-CoV infection.
l93978vq
l93978vq
2018-03-22
10.1371/journal.pone.0194868
1.5
Potential Antiviral Drugs for SARS-Cov-2 Treatment: Preclinical Findings and Ongoing Clinical Research.
Severe acute respiratory syndrome coronavirus 2 (SARS-Cov-2), initially termed 2019-new CoV (2019-nCoV), is a novel coronavirus responsible for the severe respiratory illness currently ongoing worldwide from the beginning of December 2019. This beta gene virus, very close to bat coronaviruses (bat-CoV-RaTG13) and bat-SL-CoVZC45, causes a severe disease, similar to those caused by Middle East respiratory syndrome (MERS)-CoV and SARS-CoV viruses, featured by low to moderate mortality rate. Unfortunately, the antiviral drugs commonly used in clinical practice to treat viral infections, are not applicable to SARS-Cov-2 and no vaccine is available. Thus, it is extremely necessary to identify new drugs suitable for the treatment of the 2019-nCoV outbreak. Different preclinical studies conducted on other coronaviruses suggested that promising clinical outcomes for 2019-nCoV should be obtained by using alpha-interferon, chloroquine phosphate, arabinol, remdesivir, lopinavir/ritonavir, and anti-inflammatory drugs. Moreover, clinical trials with these suitable drugs should be performed on patients affected by SARS-Cov-2 to prove their efficacy and safety. Finally, a very promising therapeutic drug, tocilizumab, is discussed; it is currently used to treat patients presenting COVID-19 pneumonia. Herein, we recapitulate these experimental studies to highlight the use of antiviral drugs for the treatment of SARS-Cov-2 disease.
lav2iavi
lav2iavi
2020-06-01
10.21873/invivo.11949
4.5
Lung tissue distribution of drugs as a key factor for COVID‐19 treatment
lb5cg801
lb5cg801
2020-05-18
10.1111/bph.15102
4
COVID-19 coronavirus vaccine design using reverse vaccinology and machine learning
To ultimately combat the emerging COVID-19 pandemic, it is desired to develop an effective and safe vaccine against this highly contagious disease caused by the SARS-CoV-2 coronavirus. Our literature and clinical trial survey showed that the whole virus, as well as the spike (S) protein, nucleocapsid (N) protein, and membrane protein, have been tested for vaccine development against SARS and MERS. We further used the Vaxign reverse vaccinology tool and the newly developed Vaxign-ML machine learning tool to predict COVID-19 vaccine candidates. The N protein was found to be conserved in the more pathogenic strains (SARS/MERS/COVID-19), but not in the other human coronaviruses that mostly cause mild symptoms. By investigating the entire proteome of SARS-CoV-2, six proteins, including the S protein and five non-structural proteins (nsp3, 3CL-pro, and nsp8–10) were predicted to be adhesins, which are crucial to the viral adhering and host invasion. The S, nsp3, and nsp8 proteins were also predicted by Vaxign-ML to induce high protective antigenicity. Besides the commonly used S protein, the nsp3 protein has not been tested in any coronavirus vaccine studies and was selected for further investigation. The nsp3 was found to be more conserved among SARS-CoV-2, SARS-CoV, and MERS-CoV than among 15 coronaviruses infecting human and other animals. The protein was also predicted to contain promiscuous MHC-I and MHC-II T-cell epitopes, and linear B-cell epitopes localized in specific locations and functional domains of the protein. Our predicted vaccine targets provide new strategies for effective and safe COVID-19 vaccine development.
ld0vo1rl
ld0vo1rl
2020-03-21
10.1101/2020.03.20.000141
1
Role of changes in SARS-CoV-2 spike protein in the interaction with the human ACE2 receptor: An in silico analysis
Many human viral diseases are a consequence of a zoonotic event. Some of the diseases caused by these zoonotic events have affected millions of people around the world, some of which have resulted in high rates of morbidity/mortality in humans. Changes in the viral proteins that function as ligands of the host receptor may promote the spillover between species. The most recent of these zoonotic events that have caused an ongoing epidemic of high magnitude is the Covid-19 epidemics caused by SARS-CoV-2. The aim of this study was to determine the mutation(s) in the sequence of the spike protein of the SARS-CoV-2 that might be favoring human to human transmission. An in silico approach was performed, and changes were detected in the S1 subunit of the receptor-binding domain of spike. The observed changes have significant effect on SARS-CoV-2 spike/ACE2 interaction and produce a reduction in the binding energy, compared to the one of the Bat-CoV to this receptor. The data presented in this study suggest a higher affinity of the SARS-Cov-2 spike protein to the human ACE2 receptor, compared to the one of Bat-CoV spike and ACE2. This could be the cause of the rapid viral spread of SARS-CoV-2 in humans.
ldf7uso2
ldf7uso2
2020-03-18
10.17179/excli2020-1167
1.5
Meeting report: 32nd International Conference on Antiviral Research
Abstract The 32nd International Conference on Antiviral Research (ICAR), sponsored by the International Society for Antiviral Research (ISAR), was held in Baltimore, Maryland, USA, on May 12–15, 2019. This report gives an overview of the conference on behalf of the Society. It provides a general review of the meeting and awardees, summarizing the presentations, and their main conclusions from the perspective of researchers active in many different areas of antiviral research and development. As in past years, ICAR promoted and showcased the most recent progress in antiviral research, and continued to foster collaborations and interactions in drug discovery and development. The 33rd ICAR will be held in Seattle, Washington, USA, March 30th-April 3rd, 2020.
ldk21iig
ldk21iig
2019-09-30
10.1016/j.antiviral.2019.104550
2.5
Repositioning of 8565 Existing Drugs for COVID-19
[Image: see text] The coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has infected over 7.1 million people and led to over 0.4 million deaths. Currently, there is no specific anti-SARS-CoV-2 medication. New drug discovery typically takes more than 10 years. Drug repositioning becomes one of the most feasible approaches for combating COVID-19. This work curates the largest available experimental data set for SARS-CoV-2 or SARS-CoV 3CL (main) protease inhibitors. On the basis of this data set, we develop validated machine learning models with relatively low root-mean-square error to screen 1553 FDA-approved drugs as well as another 7012 investigational or off-market drugs in DrugBank. We found that many existing drugs might be potentially potent to SARS-CoV-2. The druggability of many potent SARS-CoV-2 3CL protease inhibitors is analyzed. This work offers a foundation for further experimental studies of COVID-19 drug repositioning.
le3xa2p8
le3xa2p8
2020-06-16
10.1021/acs.jpclett.0c01579
4
Cell-Penetrating Peptides for Antiviral Drug Development
Viral diseases affect hundreds of millions of people worldwide, and the few available drugs to treat these diseases often come with limitations. The key obstacle to the development of new antiviral agents is their delivery into infected cells in vivo. Cell-penetrating peptides (CPPs) are short peptides that can cross the cellular lipid bilayer with the remarkable capability to shuttle conjugated cargoes into cells. CPPs have been successfully utilized to enhance the cellular uptake and intracellular trafficking of antiviral molecules, and thereby increase the inhibitory activity of potential antiviral proteins and oligonucleotide analogues, both in cultured cells and in animal models. This review will address the notable findings of these studies, highlighting some promising results and discussing the challenges CPP technology has to overcome for further clinical applications.
leaj1t3k
leaj1t3k
2010-03-02
10.3390/ph3030448
2
Current Drugs with Potential for Treatment of COVID-19: A Literature Review
PURPOSE: SARS-CoV-2 first emerged in China in December 2019 and rapidly spread worldwide. No vaccine or approved drug is available to eradicate the virus, however, some drugs that are indicated for other afflictions seems to be potentially beneficial to treat the infection albeit without unequivocal evidence. The aim of this article is to review the published background on the effectiveness of these drugs against COVID-19 Methods: A thorough literature search was conducted on recently published studies which have published between January 1 to March 25, 2020. PubMed, Google Scholar and Science Direct databases were searched Results: A total 22 articles were found eligible. 8 discuss about treatment outcomes from their applied drugs during treatment of COVID-19 patients, 4 report laboratory tests, one report animal trial and other 9 articles discuss recommendations and suggestions based on the treatment process and clinical outcomes of other diseases such as malaria, ebola, severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS). The data and/or recommendations are categorized in 4 classes: (a) anti-viral and anti-inflammatory drugs, (b) anti-malaria drugs, (c) traditional Chinese drugs and (d) other treatments/drugs. CONCLUSION: All examined treatments, although potentiality effective against COVID-19, need either appropriate drug development or clinical trial to be suitable for clinical use.
lfbdji6g
lfbdji6g
2020
3.5
Comparative pathogenesis of COVID-19, MERS, and SARS in a nonhuman primate model
The current pandemic coronavirus, SARS-CoV-2, was recently identified in patients with an acute respiratory syndrome, COVID-19. To compare its pathogenesis with that of previously emerging coronaviruses, we inoculated cynomolgus macaques with SARS-CoV-2 or MERS-CoV and compared the pathology and virology with historical reports of SARS-CoV infections. In SARS-CoV-2-infected macaques, virus was excreted from nose and throat in the absence of clinical signs, and detected in type I and II pneumocytes in foci of diffuse alveolar damage and in ciliated epithelial cells of nasal, bronchial, and bronchiolar mucosae. In SARS-CoV-infection, lung lesions were typically more severe, while they were milder in MERS-CoV infection, where virus was detected mainly in type II pneumocytes. These data show that SARS-CoV-2 causes COVID-19-like disease in macaques, and provides a new model to test preventive and therapeutic strategies.
lfeyqge5
lfeyqge5
2020-04-17
10.1126/science.abb7314
2
Zoonotic origins of human coronaviruses
Mutation and adaptation have driven the co-evolution of coronaviruses (CoVs) and their hosts, including human beings, for thousands of years. Before 2003, two human CoVs (HCoVs) were known to cause mild illness, such as common cold. The outbreaks of severe acute respiratory syndrome (SARS) and the Middle East respiratory syndrome (MERS) have flipped the coin to reveal how devastating and life-threatening an HCoV infection could be. The emergence of SARS-CoV-2 in central China at the end of 2019 has thrusted CoVs into the spotlight again and surprised us with its high transmissibility but reduced pathogenicity compared to its sister SARS-CoV. HCoV infection is a zoonosis and understanding the zoonotic origins of HCoVs would serve us well. Most HCoVs originated from bats where they are non-pathogenic. The intermediate reservoir hosts of some HCoVs are also known. Identifying the animal hosts has direct implications in the prevention of human diseases. Investigating CoV-host interactions in animals might also derive important insight on CoV pathogenesis in humans. In this review, we present an overview of the existing knowledge about the seven HCoVs, with a focus on the history of their discovery as well as their zoonotic origins and interspecies transmission. Importantly, we compare and contrast the different HCoVs from a perspective of virus evolution and genome recombination. The current CoV disease 2019 (COVID-19) epidemic is discussed in this context. In addition, the requirements for successful host switches and the implications of virus evolution on disease severity are also highlighted.
lfndq85x
lfndq85x
2020-03-15
10.7150/ijbs.45472
1.5
Severe acute respiratory syndrome coronavirus infection of golden Syrian hamsters.
Small animal models are needed in order to evaluate the efficacy of candidate vaccines and antivirals directed against the severe acute respiratory syndrome coronavirus (SARS CoV). We investigated the ability of SARS CoV to infect 5-week-old Golden Syrian hamsters. When administered intranasally, SARS CoV replicates to high titers in the lungs and nasal turbinates. Peak replication in the lower respiratory tract was noted on day 2 postinfection (p.i.) and was cleared by day 7 p.i. Low levels of virus were present in the nasal turbinates of a few hamsters at 14 days p.i. Viral replication in epithelial cells of the respiratory tract was accompanied by cellular necrosis early in infection, followed by an inflammatory response coincident with viral clearance, focal consolidation in pulmonary tissue, and eventual pulmonary tissue repair. Despite high levels of virus replication and associated pathology in the respiratory tract, the hamsters showed no evidence of disease. Neutralizing antibodies were detected in sera at day 7 p.i., and mean titers at day 28 p.i. exceeded 1:400. Hamsters challenged with SARS CoV at day 28 p.i. were completely protected from virus replication and accompanying pathology in the respiratory tract. Comparing these data to the mouse model, SARS CoV replicates to a higher titer and for a longer duration in the respiratory tract of hamsters and is accompanied by significant pathology that is absent in mice. Viremia and extrapulmonary spread of SARS CoV to liver and spleen, which are seen in hamsters, were not detected in mice. The hamster, therefore, is superior to the mouse as a model for the evaluation of antiviral agents and candidate vaccines against SARS CoV replication.
lgbexhfn
lgbexhfn
2005
1
Characterization and Inhibition of the Main Protease of Severe Acute Respiratory Syndrome Coronavirus
The main protease of SARS‐associated coronavirus (SARS‐CoV), also called 3C‐like protease (3CL(pro)), is vital for the viral replication. It cleaves the replicase polyproteins at 11 sites and is a promising drug target. Several groups of inhibitors have been identified through high‐throughput screening and rational drug design. In addition to the pharmaceutical applications, a mutant 3CL(pro) (T25G) with an expanded S1′ space has been demonstrated to tolerate larger residues at P1′, facilitating the cleavage behind the recognition sequence. This review summarizes current developments in anti‐SARS agents targeting 3CL(pro) and the application of the mutant protease as a tag‐cleavage endopeptidase.
lgrk3w7w
lgrk3w7w
2015-02-25
10.1002/cben.201400031
2.5
Interactions between antihyperglycemic drugs and the renin-angiotensin system: Putative roles in COVID-19. A mini-review
Abstract Background and aims: Diabetes mellitus is associated with a more severe course of coronavirus disease 2019 (COVID-19). The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) utilizes angiotensin-converting enzyme II (ACE2) receptor for host cell entry. We aimed to assess the interactions between antihyperglycemic drugs and the renin-angiotensin system (RAS) and their putative roles in COVID-19. Methods A literature search was performed using Pubmed to review the interrelationships between hyperglycemia, RAS and COVID-19, and the effects of antihyperglycemic medications. Results The RAS has an essential role in glucose homeostasis and may have a role in COVID-19-induced lung injury. Some antihyperglycemic medications modulate RAS and might hypothetically alleviate the deleterious effect of angiotensin II on lung injury. Furthermore, most antihyperglycemic medications showed anti-inflammatory effects in animal models of lung injury. Conclusions Some antihyperglycemic medications might have protective effects against COVID-19-induced lung injury. Early insulin therapy seems very promising in alleviating lung injury.
lh9tk4a4
lh9tk4a4
2020-05-05
10.1016/j.dsx.2020.04.040
3
Emerging infectious diseases: Focus on infection control issues for novel coronaviruses (Severe Acute Respiratory Syndrome-CoV and Middle East Respiratory Syndrome-CoV), hemorrhagic fever viruses (Lassa and Ebola), and highly pathogenic avian influenza viruses, A(H5N1) and A(H7N9)
Over the past several decades, we have witnessed the emergence of many new infectious agents, some of which are major public threats. New and emerging infectious diseases which are both transmissible from patient-to-patient and virulent with a high mortality include novel coronaviruses (SARS-CoV, MERS-CV), hemorrhagic fever viruses (Lassa, Ebola), and highly pathogenic avian influenza A viruses, A(H5N1) and A(H7N9). All healthcare facilities need to have policies and plans in place for early identification of patients with a highly communicable diseases which are highly virulent, ability to immediately isolate such patients, and provide proper management (e.g., training and availability of personal protective equipment) to prevent transmission to healthcare personnel, other patients and visitors to the healthcare facility.
ljggnelt
ljggnelt
2016-05-02
10.1016/j.ajic.2015.11.018
0.5
Prophylactic and therapeutic remdesivir (GS-5734) treatment in the rhesus macaque model of MERS-CoV infection
The continued emergence of Middle East Respiratory Syndrome (MERS) cases with a high case fatality rate stresses the need for the availability of effective antiviral treatments. Remdesivir (GS-5734) effectively inhibited MERS coronavirus (MERS-CoV) replication in vitro, and showed efficacy against Severe Acute Respiratory Syndrome (SARS)-CoV in a mouse model. Here, we tested the efficacy of prophylactic and therapeutic remdesivir treatment in a nonhuman primate model of MERS-CoV infection, the rhesus macaque. Prophylactic remdesivir treatment initiated 24 h prior to inoculation completely prevented MERS-CoV-induced clinical disease, strongly inhibited MERS-CoV replication in respiratory tissues, and prevented the formation of lung lesions. Therapeutic remdesivir treatment initiated 12 h postinoculation also provided a clear clinical benefit, with a reduction in clinical signs, reduced virus replication in the lungs, and decreased presence and severity of lung lesions. The data presented here support testing of the efficacy of remdesivir treatment in the context of a MERS clinical trial. It may also be considered for a wider range of coronaviruses, including the currently emerging novel coronavirus 2019-nCoV.
ljztowrp
ljztowrp
2020
3.5
Targeting viral entry as a strategy for broad-spectrum antivirals
The process of entry into a host cell is a key step in the life cycle of most viruses. In recent years, there has been a significant increase in our understanding of the routes and mechanisms of entry for a number of these viruses. This has led to the development of novel broad-spectrum antiviral approaches that target host cell proteins and pathways, in addition to strategies focused on individual viruses or virus families. Here we consider a number of these approaches and their broad-spectrum potential.
ll34i3eg
ll34i3eg
2019-09-12
10.12688/f1000research.19694.1
2.5
Deep Learning-based Detection for COVID-19 from Chest CT using Weak Label
Accurate and rapid diagnosis of COVID-19 suspected cases plays a crucial role in timely quarantine and medical treatment. Developing a deep learning-based model for automatic COVID-19 detection on chest CT is helpful to counter the outbreak of SARS-CoV-2. A weakly-supervised deep learning-based software system was developed using 3D CT volumes to detect COVID-19. For each patient, the lung region was segmented using a pre-trained UNet; then the segmented 3D lung region was fed into a 3D deep neural network to predict the probability of COVID-19 infectious. 499 CT volumes collected from Dec. 13, 2019, to Jan. 23, 2020, were used for training and 131 CT volumes collected from Jan 24, 2020, to Feb 6, 2020, were used for testing. The deep learning algorithm obtained 0.959 ROC AUC and 0.976 PR AUC. There was an operating point with 0.907 sensitivity and 0.911 specificity in the ROC curve. When using a probability threshold of 0.5 to classify COVID-positive and COVID-negative, the algorithm obtained an accuracy of 0.901, a positive predictive value of 0.840 and a very high negative predictive value of 0.982. The algorithm took only 1.93 seconds to process a single patient's CT volume using a dedicated GPU. Our weakly-supervised deep learning model can accurately predict the COVID-19 infectious probability in chest CT volumes without the need for annotating the lesions for training. The easily-trained and high-performance deep learning algorithm provides a fast way to identify COVID-19 patients, which is beneficial to control the outbreak of SARS-CoV-2. The developed deep learning software is available at \url{https://github.com/sydney0zq/covid-19-detection}.
ll4rxd9p
ll4rxd9p
2020-03-17
10.1101/2020.03.12.20027185
1.5
SARS Coronavirus Pathogenesis and Therapeutic Treatment Design
Emerging pathogens are either new or newly recognized or those that are increasing in incidence and spread. Since the identity of emerging pathogens from animal reservoirs is difficult to predict, the development for pathogen-specific therapeutics and vaccines is problematic. The highly pathogenic SARS coronavirus (SARS-CoV) emerged from zoonotic pools in 2002 to cause a global epidemic of severe acute respiratory syndrome (SARS). Many patients with SARS-CoV experienced an exacerbated form of disease called acute respiratory distress syndrome (ARDS) requiring mechanical ventilation and supplemental oxygen and half of these patients died. Similar to other viral pathogens like influenza and West Nile Virus, the severity of SARS-CoV disease increased with age. Unfortunately, successful vaccination in the most vulnerable populations is a difficult task because of immunological deficiencies associated with aging (immune senescence). Due to the rapidity of virus emergence, technologies like synthetic biology can be harnessed to facilitate rapid recombinant virus construction for studying the novel virus biology, pathogenesis and the evaluation of therapeutic interventions. Since predicting the antigenic identity of future emergence is difficult, candidate vaccines and therapeutics should have a maximal breadth of cross-protection, and panels of antigenically divergent synthetically reconstructed viruses can be used as tools for this evaluation. We discuss how synthetic reconstruction of many animal and human SARS-CoV has provided a model to study the molecular mechanisms governing emergence and pathogenesis of viral diseases. In addition, we review the evolution, epidemiology, and pathogenesis of epidemic and zoonotic SARS-CoV with focus on the development of broadly reactive therapeutics and vaccines that protect aged populations from the zoonotic pool.
llvu16ms
llvu16ms
2009-07-22
10.1007/978-3-642-03683-5_13
2
COVID-19 Guideline Modifications as CMS Announces “Opening Up America Again”: Comments from the Society of Surgical Oncology
lmgn3626
lmgn3626
2020-05-06
10.1245/s10434-020-08565-9
3
Understanding the present status and forecasting of COVID―19 in Wuhan
The present status of COVID―19 is analyzed and the end of the disease is forecasted. The peak of the epidemic is different in three regions, Wuhan, Hubei province except Wuhan, and mainland China except Hubei. In two regions except Wuhan, the peak of the epidemic passed ten days ago. If the trend until February 11 does not change, the disease may end by the end of February. In Wuhan, the epidemic reached a peak but the reported number of newly infected patients fluctuates largely. We need to know the reason for the big fluctuation to forecast the end of the disease.
lmoekp1m
lmoekp1m
2020-02-14
10.1101/2020.02.13.20022251
1
Coronavirus: just imagine…
loa5lrhg
loa5lrhg
2020-03-16
10.1186/s13054-020-2824-8
1.5
Antibody detection of SARS-CoV spike and nucleocapsid protein
Abstract Early detection and identification of SARS-CoV-infected patients and actions to prevent transmission are absolutely critical to prevent another SARS outbreak. Antibodies that specifically recognize the SARS-CoV spike and nucleocapsid proteins may provide a rapid screening method to allow accurate identification and isolation of patients with the virus early in their infection. For this reason, we raised peptide-induced polyclonal antibodies against SARS-CoV spike protein and polyclonal antibodies against SARS-CoV nucleocapsid protein using 6× His nucleocapsid recombinant protein. Western blot analysis and immunofluorescent staining showed that these antibodies specifically recognized SARS-CoV.
lob26ih1
lob26ih1
2004-02-20
10.1016/j.bbrc.2003.12.195
1.5
Biophysical characterization of the SARS-CoV-2 spike protein binding with the ACE2 receptor and implications for infectivity
SARS-CoV-2 is a novel highly virulent pathogen which gains entry to human cells by binding with the cell surface receptor – angiotensin converting enzyme (ACE2). We computationally contrasted the binding interactions between human ACE2 and coronavirus spike protein receptor binding domain (RBD) of the 2002 epidemic-causing SARS-CoV-1, SARS-CoV-2, and bat coronavirus RaTG13 using the Rosetta energy function. We find that the RBD of the spike protein of SARS-CoV-2 is highly optimized to achieve very strong binding with human ACE2 (hACE2) which is consistent with its enhanced infectivity. SARS-CoV-2 forms the most stable complex with hACE2 compared to SARS-CoV-1 (23% less stable) or RaTG13 (11% less stable) while occupying the greatest number of residues in the ATR1 binding site. Notably, the SARS-CoV-2 RBD out-competes the angiotensin 2 receptor type I (ATR1) which is the native binding partner of ACE2 by 35% in terms of the calculated binding affinity. Strong binding is mediated through strong electrostatic attachments with every fourth residue on the N-terminus alpha-helix (starting from Ser19 to Asn53) as the turn of the helix makes these residues solvent accessible. By contrasting the spike protein SARS-CoV-2 Rosetta binding energy with ACE2 of different livestock and pet species we find strongest binding with bat ACE2 followed by human, feline, equine, canine and finally chicken. This is consistent with the hypothesis that bats are the viral origin and reservoir species. These results offer a computational explanation for the increased infectivity of SARS-CoV-2 and allude to therapeutic modalities by identifying and rank-ordering the ACE2 residues involved in binding with the virus.
lotyldfd
lotyldfd
2020-05-11
10.1101/2020.03.30.015891
1.5
Focus on Receptors for Coronaviruses with Special Reference to Angiotensin-converting Enzyme 2 as a Potential Drug Target - A Perspective
Coronaviruses (CoVs) possess an enveloped, single, positive-stranded RNA genome which encodes for four membrane proteins, namely spike (S), envelope (E), membrane (M) and nucleocapsid (N) proteins 3-5 [1]. With regard to pathogenicity, S proteins are essential for viral entry into host cells [2, 3]. SARS-CoV binds to the angiotensin-converting enzyme (ACE)2 which is present on nonimmune cells, such as respiratory and intestinal epithelial cells, endothelial cells, kidney cells (renal tubules) and cerebral neurons and immune cells, such as alveolar monocytes/macrophages [4-6]. Of note, CD209L or liver/lymph node special intercellular adhesion molecule-3-grabbing non-integrin (SIGN) and dendritic cell (DC)-SIGN are alternative receptors for SARS-CoV but with lower affinity [7]. In the case of MERS-CoV, S proteins bind to the host cell receptor dipeptidyl peptidase 4 (DPP4 or CD26) which is broadly expressed on intestinal, alveolar, renal, hepatic and prostate cells as well as on activated leukocytes [8]. Then, viruses replicate in target cells with release of mature virions, which, in turn, invade new target cells [9]. Evidence has been provided that SARSCoV proteins are cleaved into two subunits, S1 and S2, respectively, and the amino acids 318-510 of the S1 represent the receptor-binding domain (RBD) which binds to ACE2 [10, 11]. Quite importantly, in the context of RBD there is the receptor-binding motif (RBM) (amino acids 424- 494), which accounts for complete binding to ACE2 [11]. Moreover, by means of two residues at positions 479 and 487 RBD allows virus progression and tropism [10, 11]. In the case of MERSCoV, its RBM binds to DPP4 with residues 484-567, thus, suggesting that its RBD differs from that of SARS-CoV [12, 13]. In a very recent paper, Wan and associates [14] have investigated the receptor recognition by COVID-19 (a new term to indicate the 2019-nCoV in Wuhan) on the bases of structural studies. In this respect, the sequence of COVID-19 RBM is similar to that of SARSCoV, thus, implicating that ACE2 may represent the binding receptors for COVID-19. Furthermore, gln493 residue of COVID-19 RBM seems to allow interaction with human ACE2, thus, suggesting the ability of this virus to infect human cells. According, to Wan and associates structural analysis [14], COVID-19 binds to human ACE2 with a lesser efficiency than human SARS-CoV (2002) but with higher affinity than human SARS-CoV (2003). Furthermore, same authors predicted that a single mutation at the 501 position may enhance the COVID-19 RBD binding capacity to human ACE2 and this evolution should be monitored in infected patients [14]. These predictive findings by Wan and associates [14] are confirmed by two contemporary studies by Letko and Muster [15] and Peng and associates [16]. In particular, the report by Peng and associates [16], points out the possible origin of COVID-19 from bats [16]. From a pathogenic point of view, evidence has been provided that binding of S2 to ACE2 receptor leads to its down-regulation with subsequent lung damage in the course of SARS-CoV infection [17]. Down-regulation of ACE2 causes excessive production of angiotensin (ANG) II by the related enzyme ACE with stimulation of ANG type 1a receptor (AT1R) and enhanced lung vascular permeability [18]. In particular, same authors have reported that recombinant ACE2 could attenuate severe acute lung injury in mice [18]. Moreover, Battle and associates [19] also proposed to use already available recombinant ACE2 for intercepting COVID-19 and attenuating infection. In the previous paragraphs, the presence of ACE2 on immune cells has been pointed out and, by analogy to epithelial cells, this receptor may also be down-regulated following viral entry. Therefore, in CoV-infected animal models and in infected humans further investigations are required to clarify a possible reduced expression of ACE2 on immune cells. In fact, in the course of SARS-CoV infection, a number of immune disorders have been detected. Three reports have demonstrated the ability of CoV to inhibit interferon (IFN)-ï¢ production in the course of SARS acting as IFN antagonist [20-22]. In senescent Balb/c mice, depletion of T lymphocytes is associated to more severe interstitial pneumonitis and delayed clearance of SARS-CoV, thus, suggesting a protective role played by these cells [23]. In this connection, both SARS-CoV and MERS-CoV have been shown to induce T cell apoptosis, thus, aggravating the clinical course of disease [24, 25]. Quite interestingly, memory CD8+ T cells specific for SARS-CoV M and N proteins have been detected up to 11 years post-infection [26]. As far as humoral immune responsiveness is concerned, evidence has been provided that S1 subunit from MERS-CoV is highly immunogenic in mice [27]. Moreover, monoclonal antibodies have been shown to be highly neutralizing against MERS-CoV replication and endowed with post exposure effectiveness in susceptible mice [28, 29]. Human neutralizing antibodies have also been isolated from a recovered patient, thus, suggesting the role of humoral immunity in the control of the persistence of CoV in the host [30]. In particular, IgG response occurs early in infection and its prolonged production may serve for virus clearance during recovery also in view of the absence of viremia in convalescent sera from SARS patients [31]. According to current literature, severity of COVID-19 infection correlates with lymphopenia and patients who died from COVID-19 had lower lymphocyte counts when compared to survivors [32, 33]. These data suggest that lymphocyte-mediated anti-viral activity is poorly effective against COVID-19. Despite lymphopenia, evidence for an exaggerate release of proinflammatory cytokines [interleukin (IL)-1 and IL-6] has been reported in the course acute respiratory syndrome in COVID19 infected patients, thus, aggravating the clinical course of disease [34]. As recently reported, during COVID-19 pandemic in both Italy and China higher frequency of fatalities have been observed in the frail elderly population with previous comorbidities [35]. It is well known that decline of immunity occurs in ageing and, therefore, COVID-19 may gain easier access to the respiratory tract in frail elderly patients [36]. There is evidence that ACE2 protects from severe acute lung failure and operates as a negative regulator of the renin-angiotensin system (RAS) [18, 37]. It is well known that ANG II via activation of the AT1R promotes detrimental effects on the host, such as, vasoconstriction, reactive oxygen species generation, inflammation and matrix remodelling [38]. ACE2 counterbalances the noxious effects exhibited by ANG II and AT1R via activation of AT2R which arrests cell growth, inflammation and fibrosis [39]. In this framework, Gurwitz [40] proposed to use AT1R blockers, such as losartan, as a potential treatment of COVID-19 infection. In fact, losartan as well as olmesartan, used for treating hypertension in patients, were able to increase ACE2 expression after 28 days treatment of rats with myocardial infarction [41]. Then, Gurwitz suggests to evaluate severity of symptoms in COVID-19 infected patients under previous chronic treatment with AT1R blockers in comparison to COVID-19 infected patients who did not take AT1R blockers [40]. Quite interestingly, 75% of aged COVID-19 infected patients admitted to Italian hospitals had hypertension [unpublished data]. However, the putative effects of ACE-2 down-regulation on the cardiovascular system in the course of COVID-19 pandemic need more intensive studies. Taken together, these evidences suggest that CoV-induced down-regulation of ACE2 activates RAS with collateral damage to organs, such as lungs, in the course of SARS-related pneumonia. Then, putative therapeutic measures aimed at increasing ACE2 levels on respiratory epithelial cells should be taken into serious consideration. Quite interestingly, over the past few years, three key papers have demonstrated the ability of a polyphenol, resveratrol (RES), to experimentally deactivate the RAS system in maternal and post-weaning high fat diet, arterial ageing and high fat diet, respectively [42-44]. In all these experimental models, RES led to an increase of ACE2 with reduction of organ damage, such as liver steatosis and aorta media thickness and decrease of adipose tissue mass, respectively. As far as the mechanism of action of RES is concerned, this polyphenol is able to activate sirtuin (Sirt)1 [45-47]. In turn, Sirt1 down-regulates AT1R expression via ACE2 up-regulation [43, 48]. Of importance, Lin and associates [48] have demonstrated the ability of RES to in vitro inhibit MERS-CoV infection of Vero E6 cells, thus, prolonging cell survival in virtue of an anti-apoptotic mechanism. These findings suggest a direct antiviral effect exerted by RES. It would be very interestingly to evaluate the direct effects of RES on COVID-19, in vitro. The data above discussed strongly suggest, that RES, as an activators of ACE2, should be investigated in animal models of CoV-induced severe pneumonia, also taking into account the antioxidant, anti-inflammatory and immunomodulating effects exerted by polyphenols [49]. Then, successful animal studies may pave the way for RES-based human trials in COVID-infected patients. Note added in proof During the reviewing process of this perspective other related papers have been published. Hanff and associates [50] have discussed the possible association between COVID-19-associated cardiovascular mortality and dysregulation of the Renin Angiotensin System (RAS). From a pharmacologic point of view, RAS inhibition leads to upregulation of ACE2, thus, attenuating acute respiratory syndrome and myocarditis in COVID-19-infected patients. Conversely, increase in ACE2 expression may facilitate the access into the host of COVID-19, thus, aggravating the clinical picture. Such a dilemma would be solved byclinical trials based on RAS blockade or initiation and monitoring related effects. Contemporarily, Danser and associates [51] claim that there is no evidence to stop RAS blockers in the course of COVID-19 infection. In fact, there are no available data which support that ACE inhibitors or ANG II type I receptor blockers increase COVID-19 infection via its binding to ACE2. Finally, Kuster and associates [52] write that there are no data on the strict relationship between ACE2 activity and SARS-CoV2 mortality. Moreover, in the SARSCoV2, cells expressing ACE2 were not attacked by the virus, while cells lacking ACE2 were bound by the SARS-CoV2 virus [53]. These findings suggest that also in the case of RES effects on COVID-19 infection, the dual role of ACE2 should be taken into serious consideration.
lqdgvsaq
lqdgvsaq
2020
3
Recombinant SARS-CoV-2 spike S1-Fc fusion protein induced high levels of neutralizing responses in nonhuman primates
The COVID-19 outbreak has become a global pandemic responsible for over 2,000,000 confirmed cases and over 126,000 deaths worldwide. In this study, we examined the immunogenicity of CHO-expressed recombinant SARS-CoV-2 S1-Fc fusion protein in mice, rabbits, and monkeys as a potential candidate for a COVID-19 vaccine. We demonstrate that the S1-Fc fusion protein is extremely immunogenic, as evidenced by strong antibody titers observed by day 7. Strong virus neutralizing activity was observed on day 14 in rabbits immunized with the S1-Fc fusion protein using a pseudovirus neutralization assay. Most importantly, in less than 20 days and three injections of the S1-Fc fusion protein, two monkeys developed higher virus neutralizing titers than a recovered COVID-19 patient in a live SARS-CoV-2 infection assay. Our data strongly suggests that the CHO-expressed SARS-CoV-2 S1-Fc recombinant protein could be a strong candidate for vaccine development against COVID-19. Highlights CHO-expressed S1-Fc protein is very immunogenic in various animals and can rapidly induce strong antibody production S1-Fc protein solicits strong neutralizing activities against live virus Stable CHO cell line expressing 50 mg/L of S1-Fc and a 3,000 L Bioreactor can produce 3 million doses of human COVID-19 vaccine every 10 days, making it an accessible and affordable option for worldwide vaccination
lr8haho9
lr8haho9
2020-04-23
10.1101/2020.04.21.052209
5
Midwives in a pandemic: A call for solidarity and compassion
ls3toeo4
ls3toeo4
2020-03-30
10.1016/j.wombi.2020.03.008
1
On‐Chip Screening of a Glycomimetic Library with C‐Type Lectins Reveals Structural Features Responsible for Preferential Binding of Dectin‐2 over DC‐SIGN/R and Langerin
A library of mannose‐ and fucose‐based glycomimetics was synthesized and screened in a microarray format against a set of C‐type lectin receptors (CLRs) that included DC‐SIGN, DC‐SIGNR, langerin, and dectin‐2. Glycomimetic ligands able to interact with dectin‐2 were identified for the first time. Comparative analysis of binding profiles allowed their selectivity against other CLRs to be probed.
lt039ueb
lt039ueb
2018-09-03
10.1002/chem.201802577
1
SARS‐CoV‐2 infection‐induced immune responses: friends or foes?
Severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) is an emerging coronavirus that belongs to the β genus, causing the outbreak of coronavirus disease 19 (COVID‐19). SARS‐CoV‐2 infection can stimulate a pronounced immune response in the host, which embodies in the decrease of lymphocytes and aberrant increase of cytokines in COVID‐19 patients. SARS‐CoV‐2 RNA and proteins interact with various pattern recognition receptors that switch on antiviral immune responses to regulate viral replication and spreading within the host in vivo. However, overactive and impaired immune responses also cause immune damage and subsequent tissue inflammation. This article focuses on the dual roles of immune system during SARS‐CoV‐2 infection, providing a theoretical basic for identifying therapeutic targets in a situation with an unfavorable immune reaction.
ltmuw6f8
ltmuw6f8
2020-05-23
10.1111/sji.12895
4
How a SARS antibody binds to SARS-CoV-2
esearchers at Scripps Research and the University of Hong Kong have shown how a human antibody for the virus that causes severe acute respiratory syndrome (SARS) can also bind the new COVID-19-causing coronavirus (Science 2020, DOI: 10 1126/science abb7269) The structural insights from might help in COVID-19 vaccine and drug design, the researchers say During a SARS epidemic in 2006, researchers isolated antibodies for the virus, SARS-CoV, from infected patients Earlier this year, researchers in China showed that one of those antibodies, CR3022, also binds to the spike protein of the virus that causes COVID-19, SARS-CoV-2 (Emerging Microbes Infect 2020, DOI: 10 1080/22221751 2020 1729069) To see how exactly the antibody binds to the spike protein, a group led by Ian A Wilson ordered a sample of CR3022 and produced sections of SARS-CoV-2’s spike protein called the receptor-binding domain (RBD) The group used X-ray crystallography to find that, as predicted by the Chinese researchers, the View: PDF ;Full Text HTML
lwaweuym
lwaweuym
2020
10.1021/cen-09814-scicon1
4
Etiologic Framework for the Study of Neurodegenerative Disorders as Well as Vascular and Metabolic Comorbidities on the Grounds of Shared Epidemiologic and Biologic Features
Background: During the last two decades, protein aggregation at all organismal levels, from viruses to humans, has emerged from a neglected area of protein science to become a central issue in biology and biomedicine. This article constitutes a risk-based review aimed at supporting an etiologic scenario of selected, sporadic, protein-associated, i.e., conformational, neurodegenerative disorders (NDDs), and their vascular- and metabolic-associated ailments. Methods: A rationale is adopted, to incorporate selected clinical data and results from animal-model research, complementing epidemiologic evidences reported in two prior articles. Findings: Theory is formulated assuming an underlying conformational transmission mechanism, mediated either by horizontal transfer of mammalian genes coding for specific aggregation-prone proteins, or by xeno-templating between bacterial and host proteins. We build a few population-based and experimentally-testable hypotheses focusing on: (1) non-disposable surgical instruments for sporadic Creutzfeldt-Jakob disease (sCJD) and other rapid progressive neurodegenerative dementia (sRPNDd), multiple system atrophy (MSA), and motor neuron disease (MND); and (2) specific bacterial infections such as B. pertussis and E. coli for all forms, but particularly for late-life sporadic conformational, NDDs, type 2 diabetes mellitus (T2DM), and atherosclerosis where natural protein fibrils present in such organisms as a result of adaptation to the human host induce prion-like mechanisms. Conclusion: Implications for cohort alignment and experimental animal research are discussed and research lines proposed.
lx2v5co7
lx2v5co7
2016-06-13
10.3389/fnagi.2016.00138
1
Forecasting the dynamics of COVID-19 Pandemic in Top 15 countries in April 2020: ARIMA Model with Machine Learning Approach
We here predicted some trajectories of COVID-19 in the coming days (until April 30, 2020) using the most advanced Auto-Regressive Integrated Moving Average Model (ARIMA). Our analysis predicted very frightening outcomes, which defines to worsen the conditions in Iran, entire Europe, especially Italy, Spain, and France. While South Korea, after the initial blast, has come to stability, the same goes for the COVID-19 origin country China with more positive recovery cases and confirm to remain stable. The United States of America (USA) will come as a surprise and going to become the epicenter for new cases during the mid-April 2020. Based on our predictions, public health officials should tailor aggressive interventions to grasp the power exponential growth, and rapid infection control measures at hospital levels are urgently needed to curtail the COVID-19 pandemic.
lxakf79k
lxakf79k
2020-03-31
10.1101/2020.03.30.20046227
1.5
Open Data Resources for Fighting COVID-19
We provide an insight into the open data resources pertinent to the study of the spread of Covid-19 pandemic and its control. We identify the variables required to analyze fundamental aspects like seasonal behaviour, regional mortality rates, and effectiveness of government measures. Open data resources, along with data-driven methodologies, provide many opportunities to improve the response of the different administrations to the virus. We describe the present limitations and difficulties encountered in most of the open-data resources. To facilitate the access to the main open-data portals and resources, we identify the most relevant institutions, at a world scale, providing Covid-19 information and/or auxiliary variables (demographics, mobility, etc.). We also describe several open resources to access Covid-19 data-sets at a country-wide level (i.e. China, Italy, Spain, France, Germany, U.S., etc.). In an attempt to facilitate the rapid response to the study of the seasonal behaviour of Covid-19, we enumerate the main open resources in terms of weather and climate variables. CONCO-Team: The authors of this paper belong to the CONtrol COvid-19 Team, which is composed of different researches from universities of Spain, Italy, France, Germany, United Kingdom and Argentina. The main goal of CONCO-Team is to develop data-driven methods for the better understanding and control of the pandemic.
lysvg3vw
lysvg3vw
2020-04-13
2.5
Combination of Biodata Mining and Computational Modelling in Identification and Characterization of ORF1ab Polyprotein of SARS-CoV-2 Isolated from Oronasopharynx of an Iranian Patient
BACKGROUND: Coronavirus disease 2019 (COVID-19) is an emerging zoonotic viral infection, which was started in Wuhan, China, in December 2019 and transmitted to other countries worldwide as a pandemic outbreak. Iran is one of the top ranked countries in the tables of COVID-19-infected and -mortality cases that make the Iranian patients as the potential targets for diversity of studies including epidemiology, biomedical, biodata, and viral proteins computational modelling studies. RESULTS: In this study, we applied bioinformatic biodata mining methods to detect CDS and protein sequences of ORF1ab polyprotein of SARS-CoV-2 isolated from oronasopharynx of an Iranian patient. Then through the computational modelling and antigenicity prediction approaches, the identified polyprotein sequence was analyzed. The results revealed that the identified ORF1ab polyprotein belongs to a part of nonstructural protein 1 (nsp1) with the high antigenicity residues in a glycine-proline or hydrophobic amino acid rich domain. CONCLUSIONS: The results revealed that nsp1 as a virulence factor and crucial agent in spreading of the COVID-19 among the society can be a potential target for the future epidemiology, drug, and vaccine studies.
lzdwpaki
lzdwpaki
2020-04-21
10.1186/s12575-020-00121-9
2.5
The anti-HIV drug nelfinavir mesylate (Viracept) is a potent inhibitor of cell fusion caused by the SARSCoV-2 spike (S) glycoprotein warranting further evaluation as an antiviral against COVID-19 infections
Severe acute respiratory syndrome coronavirus-2 (SARS CoV-2) is the causative agent of the coronavirus disease-2019 (COVID-19) pandemic. Coronaviruses enter cells via fusion of the viral envelope with the plasma membrane and/or via fusion of the viral envelope with endosomal membranes after virion endocytosis. The spike (S) glycoprotein is a major determinant of virus infectivity. Herein, we show that the transient expression of the SARS CoV-2 S glycoprotein in Vero cells caused extensive cell fusion (formation of syncytia) in comparison to limited cell fusion caused by the SARS S glycoprotein. Both S glycoproteins were detected intracellularly and on transfected Vero cell surfaces. These results are in agreement with published pathology observations of extensive syncytia formation in lung tissues of patients with COVID-19. These results suggest that SARS CoV-2 is able to spread from cell-to-cell much more efficiently than SARS effectively avoiding extracellular neutralizing antibodies. A systematic screening of several drugs including cardiac glycosides and kinase inhibitors and inhibitors of human immunodeficiency virus (HIV) entry revealed that only the FDA-approved HIV protease inhibitor, nelfinavir mesylate (Viracept) drastically inhibited S-n- and S-o-mediated cell fusion with complete inhibition at a 10-µM concentration. In-silico docking experiments suggested the possibility that nelfinavir may bind inside the S trimer structure, proximal to the S2 amino terminus directly inhibiting S-n- and S-o-mediated membrane fusion. Also, it is possible that nelfinavir may act to inhibit S proteolytic processing within cells. These results warrant further investigations of the potential of nelfinavir mesylate to inhibit virus spread at early times after SARS CoV-2 symptoms appear.
lzocumhd
lzocumhd
2020
4
SARS-CoV-2 pandemic and research gaps: Understanding SARS-CoV-2 interaction with the ACE2 receptor and implications for therapy
The COVID-19 pandemic is an emerging threat to global public health. While our current understanding of COVID-19 pathogenesis is limited, a better understanding will help us develop efficacious treatment and prevention strategies for COVID-19. One potential therapeutic target is angiotensin converting enzyme 2 (ACE2). ACE2 primarily catalyzes the conversion of angiotensin I (Ang I) to a nonapeptide angiotensin or the conversion of angiotensin II (Ang II) to angiotensin 1-7 (Ang 1-7) and has direct effects on cardiac function and multiple organs via counter-regulation of the renin-angiotensin system (RAS). Significant to COVID-19, ACE2 is postulated to serve as a major entry receptor for SARS-CoV-2 in human cells, as it does for SARS-CoV. Many infected individuals develop COVID-19 with fever, cough, and shortness of breath that can progress to pneumonia. Disease progression promotes the activation of immune cells, platelets, and coagulation pathways that can lead to multiple organ failure and death. ACE2 is expressed by epithelial cells of the lungs at high level, a major target of the disease, as seen in post-mortem lung tissue of patients who died with COVID-19, which reveals diffuse alveolar damage with cellular fibromyxoid exudates bilaterally. Comparatively, ACE2 is expressed at low level by vascular endothelial cells of the heart and kidney but may also be targeted by the virus in severe COVID-19 cases. Interestingly, SARS-CoV-2 infection downregulates ACE2 expression, which may also play a critical pathogenic role in COVID-19. Importantly, targeting ACE2/Ang 1-7 axis and blocking ACE2 interaction with the S protein of SARS-CoV-2 to curtail SARS-CoV-2 infection are becoming very attractive therapeutics potential for treatment and prevention of COVID-19. Here, we will discuss the following subtopics: 1) ACE2 as a receptor of SARS-CoV-2; 2) clinical and pathological features of COVID-19; 3) role of ACE2 in the infection and pathogenesis of SARS; 4) potential pathogenic role of ACE2 in COVID-19; 5) animal models for pathological studies and therapeutics; and 6) therapeutics development for COVID-19.
m0b2jlax
m0b2jlax
2020-06-12
10.7150/thno.48076
5
Relations of parameters for describing the epidemic of COVID―19 by the Kermack―McKendrick model
In order to quantitatively characterize the epidemic of COVID―19, useful relations among parameters describing an epidemic in general are derived based on the Kermack-McKendrick model. The first relation is 1/τgrow=1/τtrans−1/τinf, where τgrow is the time constant of the exponential growth of an epidemic, τtrans is the time for a pathogen to be transmitted from one patient to uninfected person, and the infectious time τinf is the time during which the pathogen keeps its power of transmission. The second relation p(∞) ≈1−exp(−(R0−1)/0.60) is the relation between p(∞), the final size of the disaster defined by the ratio of the total infected people to the population of the society,and the basic reproduction number, R0, which is the number of persons infected by the transmission of the pathogen from one infected person during the infectious time. The third relation 1/τend=1/τinf−(1−p(∞))/τtrans gives the decay time constant τend at the ending stage of the epidemic. Derived relations are applied to influenza in Japan in 2019 for characterizing the epidemic.
m0d72ntg
m0d72ntg
2020-03-03
10.1101/2020.02.26.20027797
1
Insight Derived from Molecular Docking and Molecular Dynamics Simulations into the Binding Interactions Between HIV-1 Protease Inhibitors and SARS-CoV-2 3CLpro
A novel severe acute respiratory syndrome coronavirus (SARS-CoV-2) was identified from respiratory illness patients in Wuhan, Hubei Province, China, which has recently emerged as a serious threat to the world public health Hower, no approved drugs have been found to effectively inhibit the virus Since it has been reported that the HIV-1 protease inhibitors can be used as anti-SARS drugs by tegarting SARS-CoV 3CLpro, we choose six approved anti-HIV-1 drugs to investigate their binding interactions between 3CLpro, and to evaluate their potential to become clinical drugs for the new coronavirus pneumonia (COVID19) caused by SARS-CoV-2 infection The molecular docking results indicate that, the 3CLpro of SARS-CoV-2 has a higher binding affinity for all the studied inhibitors than its SARS homologue Two docking complexes (indinavir and darunavir) with high docking scores were futher subjected to MM-PBSA binding free energy calculations to detail the molecular interactions between these two proteinase inhibitors and the 3CLpro Our results show that darunavir has the best binding affinity with SARS-CoV-2 and SARS-CoV 3CLpro among all inhibitors, indicating it has the potential to become an anti-COVID-19 clinical drug The likely reason behind the increased binding affinity of HIV-1 protease inhibitors toward SARS-CoV2 3CLpro than that of SARS-CoV were investigated by MD simulations Our study provides insight into the possible role of structural flexibility during interactions between 3CLpro and inhibitors, and sheds light on the structure-based design of anti-COVID-19 drugs targeting the SARS-CoV-2 3CLpro
m0hivi0u
m0hivi0u
2020
10.26434/chemrxiv.11932995.v1
0.5
Repurposing Therapeutics for COVID-19: Rapid Prediction of Commercially available drugs through Machine Learning and Docking
Background The outbreak of the novel coronavirus disease COVID 19, caused by the SARS-CoV-2 virus has spread rapidly around the globe during the past 3 months. As the virus infected cases and mortality rate of this disease is increasing exponentially, scientists and researchers all over the world are relentlessly working to understand this new virus along with possible treatment regimens by discovering active therapeutic agents and vaccines. So, there is an urgent requirement of new and effective medications that can treat the disease caused by SARS CoV 2. Methods and findings We perform the study of drugs that are already available in the market and being used for other diseases to accelerate clinical recovery, in other words repurposing of existing drugs. The vast complexity in drug design and protocols regarding clinical trials often prohibit developing various new drug combinations for this epidemic disease in a limited time. Recently, remarkable improvements in computational power coupled with advancements in Machine Learning (ML) technology have been utilized to revolutionize the drug development process. Consequently, a detailed study using ML for the repurposing of therapeutic agents is urgently required. Here, we report the ML model based on the Naive Bayes algorithm, which has an accuracy of around 73% to predict the drugs that could be used for the treatment of COVID-19. Our study predicts around ten FDA approved commercial drugs that can be used for repurposing. Among all, we suggest that the antiretroviral drug Atazanavir (DrugBank ID DB01072) would probably be one of the most effective drugs based on the selected criterions. Conclusions Our study can help clinical scientists in being more selective in identifying and testing the therapeutic agents for COVID 19 treatment. The ML based approach for drug discovery as reported here can be a futuristic smart drug designing strategy for community applications.
m0q7rm6z
m0q7rm6z
2020-04-07
10.1101/2020.04.05.20054254
1
Structural variations in human ACE2 may influence its binding with SARS‐CoV‐2 spike protein
The recent pandemic of COVID‐19, caused by SARS‐CoV‐2, is unarguably the most fearsome compared with the earlier outbreaks caused by other coronaviruses, SARS‐CoV and MERS‐CoV. Human ACE2 is now established as a receptor for the SARS‐CoV‐2 spike protein. Where variations in the viral spike protein, in turn, lead to the cross‐species transmission of the virus, genetic variations in the host receptor ACE2 may also contribute to the susceptibility and/or resistance against the viral infection. This study aims to explore the binding of the proteins encoded by different human ACE2 allelic variants with SARS‐CoV‐2 spike protein. Briefly, coding variants of ACE2 corresponding to the reported binding sites for its attachment with coronavirus spike protein were selected and molecular models of these variants were constructed by homology modeling. The models were then superimposed over the native ACE2 and ACE2‐spike protein complex, to observe structural changes in the ACE2 variants and their intermolecular interactions with SARS‐CoV‐2 spike protein, respectively. Despite strong overall structural similarities, the spatial orientation of the key interacting residues varies in the ACE2 variants compared with the wild‐type molecule. Most ACE2 variants showed a similar binding affinity for SARS‐CoV‐2 spike protein as observed in the complex structure of wild‐type ACE2 and SARS‐CoV‐2 spike protein. However, ACE2 alleles, rs73635825 (S19P) and rs143936283 (E329G) showed noticeable variations in their intermolecular interactions with the viral spike protein. In summary, our data provide a structural basis of potential resistance against SARS‐CoV‐2 infection driven by ACE2 allelic variants.
m0w0fl2u
m0w0fl2u
2020-04-15
10.1002/jmv.25832
3
Insights into the Recent 2019 Novel Coronavirus (SARS-CoV-2) in Light of Past Human Coronavirus Outbreaks
Coronaviruses (CoVs) are RNA viruses that have become a major public health concern since the Severe Acute Respiratory Syndrome-CoV (SARS-CoV) outbreak in 2002. The continuous evolution of coronaviruses was further highlighted with the emergence of the Middle East Respiratory Syndrome-CoV (MERS-CoV) outbreak in 2012. Currently, the world is concerned about the 2019 novel CoV (SARS-CoV-2) that was initially identified in the city of Wuhan, China in December 2019. Patients presented with severe viral pneumonia and respiratory illness. The number of cases has been mounting since then. As of late February 2020, tens of thousands of cases and several thousand deaths have been reported in China alone, in addition to thousands of cases in other countries. Although the fatality rate of SARS-CoV-2 is currently lower than SARS-CoV, the virus seems to be highly contagious based on the number of infected cases to date. In this review, we discuss structure, genome organization, entry of CoVs into target cells, and provide insights into past and present outbreaks. The future of human CoV outbreaks will not only depend on how the viruses will evolve, but will also depend on how we develop efficient prevention and treatment strategies to deal with this continuous threat.
m2c5bvuj
m2c5bvuj
2020-03-04
10.3390/pathogens9030186
4.5
Molecular Mechanism of Evolution and Human Infection with SARS-CoV-2
The outbreak of a novel coronavirus, which was later formally named the severe acute respiratory coronavirus 2 (SARS-CoV-2), has caused a worldwide public health crisis. Previous studies showed that SARS-CoV-2 is highly homologous to SARS-CoV and infects humans through the binding of the spike protein to ACE2. Here, we have systematically studied the molecular mechanisms of human infection with SARS-CoV-2 and SARS-CoV by protein-protein docking and MD simulations. It was found that SARS-CoV-2 binds ACE2 with a higher affinity than SARS-CoV, which may partly explain that SARS-CoV-2 is much more infectious than SARS-CoV. In addition, the spike protein of SARS-CoV-2 has a significantly lower free energy than that of SARS-CoV, suggesting that SARS-CoV-2 is more stable and may survive a higher temperature than SARS-CoV. This provides insights into the evolution of SARS-CoV-2 because SARS-like coronaviruses have originated in bats. Our computation also suggested that the RBD-ACE2 binding for SARS-CoV-2 is much more temperature-sensitive than that for SARS-CoV. Thus, it is expected that SARS-CoV-2 would decrease its infection ability much faster than SARS-CoV when the temperature rises. These findings would be beneficial for the disease prevention and drug/vaccine development of SARS-CoV-2.
m2cu5iof
m2cu5iof
2020
4.5
Neutralizing Antibodies against SARS-CoV-2 and Other Human Coronaviruses
Coronavirus (CoV) disease 2019 (COVID-19) caused by severe acute respiratory syndrome (SARS)-CoV-2 (also known as 2019-nCoV) is threatening global public health, social stability, and economic development. To meet this challenge, this article discusses advances in the research and development of neutralizing antibodies (nAbs) for the prevention and treatment of infection by SARS-CoV-2 and other human CoVs.
m3go4tun
m3go4tun
2020-04-02
10.1016/j.it.2020.03.007
1
Host resilience to emerging coronaviruses
Recently, two coronaviruses, severe acute respiratory syndrome coronavirus and Middle East respiratory syndrome coronavirus, have emerged to cause unusually severe respiratory disease in humans. Currently, there is a lack of effective antiviral treatment options or vaccine available. Given the severity of these outbreaks, and the possibility of additional zoonotic coronaviruses emerging in the near future, the exploration of different treatment strategies is necessary. Disease resilience is the ability of a given host to tolerate an infection, and to return to a state of health. This review focuses on exploring various host resilience mechanisms that could be exploited for treatment of severe acute respiratory syndrome coronavirus, Middle East respiratory syndrome coronavirus and other respiratory viruses that cause acute lung injury and acute respiratory distress syndrome.
m45lbfub
m45lbfub
2016-07-01
10.2217/fvl-2016-0060
0.5
Identification of Chymotrypsin-like Protease Inhibitors of SARS-CoV-2 Via Integrated Computational Approach.
Recently, the world has witnessed outbreak of a novel Coronavirus (SARS-CoV-2), the virus which initially emerged in Wuhan, China has now made its way to a large part of the world, resulting in a public emergency of international concern. The functional importance of Chymotrypsin-like protease (3CLpro) in viral replication and maturation turns it into an attractive target for the development of effective antiviral drugs against SARS and other coronaviruses. At present, there is no standard drug regime nor any vaccine available against the infection. The rapid development and identification of efficient interventions against SARS-CoV-2 remains a major challenge. Based on the available knowledge of closely related coronavirus and their safety profiles, repurposing of existing antiviral drugs and screening of available databases is considered a near term strategic and economic way to contain the SARS-CoV-2 pandemic. Herein, we applied computational drug design methods to identify Chymotrypsin-like protease inhibitors from FDA approved antiviral drugs and our in-house database of natural and drug-like compounds of synthetic origin. As a result three FDA approved drugs ( Remdesivir, Saquinavir and Darunavir) and two natural compounds (. flavone and coumarine derivatives) were identified as promising hits. Further, MD simulation and binding free energy calculations were performed to evaluate the dynamic behavior, stability of protein-ligand contact, and binding affinity of the hit compounds. Our results indicate that the identified compounds can inhibit the function of Chymotrypsin-like protease (3CLpro) of Coronavirus. Considering the severity of the spread of coronavirus, the current study is in-line with the concept of finding the new inhibitors against the vital pathway of the corona virus to expedite the process of drug discovery.
m55mro2m
m55mro2m
2020-04-02
10.1080/07391102.2020.1751298
3.5
SARS-CoV-2 Vaccines: Status Report
SARS-CoV-2, the causal agent of COVID-19, first emerged in late 2019 in China. It has since infected more than 870,000 individuals and caused more than 43,000 deaths globally. Here, we discuss therapeutic and prophylactic interventions for SARS-CoV-2 with a focus on vaccine development and its challenges. Vaccines are being rapidly developed but will likely come too late to affect the first wave of a potential pandemic. Nevertheless, critical lessons can be learned for the development of vaccines against rapidly emerging viruses. Importantly, SARS-CoV-2 vaccines will be essential to reducing morbidity and mortality if the virus establishes itself in the population.
m5ho8jqp
m5ho8jqp
2020-04-06
10.1016/j.immuni.2020.03.007
1
STAT2 signaling as double-edged sword restricting viral dissemination but driving severe pneumonia in SARS-CoV-2 infected hamsters
Since the emergence of SARS-CoV-2 causing COVID-19, the world is being shaken to its core with numerous hospitalizations and hundreds of thousands of deaths. In search for key targets of effective therapeutics, robust animal models mimicking COVID-19 in humans are urgently needed. Here, we show that productive SARS-CoV-2 infection in the lungs of mice is limited and restricted by early type I interferon responses. In contrast, we show that Syrian hamsters are highly permissive to SARS- CoV-2 and develop bronchopneumonia and a strong inflammatory response in the lungs with neutrophil infiltration and edema. Moreover, we identify an exuberant innate immune response as a key player in pathogenesis, in which STAT2 signaling plays a dual role, driving severe lung injury on the one hand, yet restricting systemic virus dissemination on the other. Finally, we assess SARS-CoV- 2-induced lung pathology in hamsters by micro-CT alike used in clinical practice. Our results reveal the importance of STAT2-dependent interferon responses in the pathogenesis and virus control during SARS-CoV-2 infection and may help rationalizing new strategies for the treatment of COVID-19 patients.
m5u6ryy9
m5u6ryy9
2020-07-02
10.1101/2020.04.23.056838
2
Genomic characterisation and epidemiology of 2019 novel coronavirus: implications for virus origins and receptor binding
BACKGROUND: In late December, 2019, patients presenting with viral pneumonia due to an unidentified microbial agent were reported in Wuhan, China. A novel coronavirus was subsequently identified as the causative pathogen, provisionally named 2019 novel coronavirus (2019-nCoV). As of Jan 26, 2020, more than 2000 cases of 2019-nCoV infection have been confirmed, most of which involved people living in or visiting Wuhan, and human-to-human transmission has been confirmed. METHODS: We did next-generation sequencing of samples from bronchoalveolar lavage fluid and cultured isolates from nine inpatients, eight of whom had visited the Huanan seafood market in Wuhan. Complete and partial 2019-nCoV genome sequences were obtained from these individuals. Viral contigs were connected using Sanger sequencing to obtain the full-length genomes, with the terminal regions determined by rapid amplification of cDNA ends. Phylogenetic analysis of these 2019-nCoV genomes and those of other coronaviruses was used to determine the evolutionary history of the virus and help infer its likely origin. Homology modelling was done to explore the likely receptor-binding properties of the virus. FINDINGS: The ten genome sequences of 2019-nCoV obtained from the nine patients were extremely similar, exhibiting more than 99·98% sequence identity. Notably, 2019-nCoV was closely related (with 88% identity) to two bat-derived severe acute respiratory syndrome (SARS)-like coronaviruses, bat-SL-CoVZC45 and bat-SL-CoVZXC21, collected in 2018 in Zhoushan, eastern China, but were more distant from SARS-CoV (about 79%) and MERS-CoV (about 50%). Phylogenetic analysis revealed that 2019-nCoV fell within the subgenus Sarbecovirus of the genus Betacoronavirus, with a relatively long branch length to its closest relatives bat-SL-CoVZC45 and bat-SL-CoVZXC21, and was genetically distinct from SARS-CoV. Notably, homology modelling revealed that 2019-nCoV had a similar receptor-binding domain structure to that of SARS-CoV, despite amino acid variation at some key residues. INTERPRETATION: 2019-nCoV is sufficiently divergent from SARS-CoV to be considered a new human-infecting betacoronavirus. Although our phylogenetic analysis suggests that bats might be the original host of this virus, an animal sold at the seafood market in Wuhan might represent an intermediate host facilitating the emergence of the virus in humans. Importantly, structural analysis suggests that 2019-nCoV might be able to bind to the angiotensin-converting enzyme 2 receptor in humans. The future evolution, adaptation, and spread of this virus warrant urgent investigation. FUNDING: National Key Research and Development Program of China, National Major Project for Control and Prevention of Infectious Disease in China, Chinese Academy of Sciences, Shandong First Medical University.
m6akijzn
m6akijzn
2020-01-30
10.1016/s0140-6736(20)30251-8
1.5
In vitro screening of a FDA approved chemical library reveals potential inhibitors of SARS-CoV-2 replication
A novel coronavirus, named SARS-CoV-2, emerged in 2019 from Hubei region in China and rapidly spread worldwide. As no approved therapeutics exists to treat Covid-19, the disease associated to SARS-Cov-2, there is an urgent need to propose molecules that could quickly enter into clinics. Repurposing of approved drugs is a strategy that can bypass the time consuming stages of drug development. In this study, we screened the Prestwick Chemical Library® composed of 1,520 approved drugs in an infected cell-based assay. 90 compounds were identified. The robustness of the screen was assessed by the identification of drugs, such as Chloroquine derivatives and protease inhibitors, already in clinical trials. The hits were sorted according to their chemical composition and their known therapeutic effect, then EC50 and CC50 were determined for a subset of compounds. Several drugs, such as Azithromycine, Opipramol, Quinidine or Omeprazol present antiviral potency with 2<EC50<20µM. By providing new information on molecules inhibiting SARS-CoV-2 replication in vitro, this study could contribute to the short-term repurposing of drugs against Covid-19.
m7dwbheg
m7dwbheg
2020-04-05
10.1101/2020.04.03.023846
1.5
ISAR News
m8p8msgt
m8p8msgt
2016-06-30
10.1016/s0166-3542(16)30236-4
0.5
Andrographolide as a potential inhibitor of SARS-CoV-2 main protease: an in silico approach
SARS-CoV-2 virus which caused the global pandemic the Coronavirus Disease- 2019 (COVID-2019) has infected about 1,203,959 patients and brought forth death rate about 64,788 among 206 countries as mentioned by WHO in the month of April 2020. The clinical trials are underway for Remdesivir, an investigational anti-viral drug from Gilead Sciences. Antimalarial drugs such as Chloroquine and Hydroxychloroquine derivatives are being used in emergency cases; however, they are not suitable for patients with conditions like diabetes, hypertension and cardiac issues. The lack of availability of approved treatment for this disease calls forth the scientific community to find novel compounds with the ability to treat it. This paper evaluates the compound Andrographolide from Andrographis paniculata as a potential inhibitor of the main protease of SARS-COV-2 (Mpro) through in silico studies such as molecular docking, target analysis, toxicity prediction and ADME prediction. Andrographolide was docked successfully in the binding site of SARS-CoV-2 Mpro. Computational approaches also predicts this molecule to have good solubility, pharmacodynamics property and target accuracy. This molecule also obeys Lipinski’s rule, which makes it a promising compound to pursue further biochemical and cell based assays to explore its potential for use against COVID-19. Communicated by Ramaswamy H. Sarma
m8utyd1m
m8utyd1m
2020-05-05
10.1080/07391102.2020.1760136
3
Missing clinical trial data: the knowledge gap in the safety of potential COVID-19 drugs
Abstract (290/300 words) Objectives: Several drugs are being repurposed for the treatment of the coronavirus disease 2019 (COVID-19) pandemic based on in vitro or early clinical findings. As these drugs are being used in varied regimens and dosages, it is important to enable synthesis of existing safety data from clinical trials. However, availability of safety information is limited by a lack of timely reporting of clinical trial results on public registries or through academic publication. We aimed to analyse the knowledge gap in safety data by quantifying the number of missing clinical trial results for drugs potentially being repurposed for COVID-19. Design: ClinicalTrials.gov was searched for 19 drugs that have been identified as potential treatments for COVID-19. Relevant clinical trials for any prior indication were listed by identifier (NCT number) and checked for timely result reporting (within 395 days of the primary completion date). Additionally, PubMed and Google Scholar were searched using the NCT number to identify publications of results not listed on the registry. A second, blinded search of 10% of trials was conducted to assess reviewer concordance. Results: Of 3754 completed trials, 1516 (40.4%) did not post results on ClinicalTrials.gov or in the academic literature. 1172 (31.2%) completed trials had tabular results on ClinicalTrials.gov. A further 1066 (28.4%) completed trials had results from the literature search, but did not report results on ClinicalTrials.gov. Key drugs missing clinical trial results include hydroxychloroquine (37.0% completed trials unreported), favipiravir (77.8%) and lopinavir (40.5%). Conclusion: There is an important evidence gap for the safety of drugs being repurposed for COVID-19. This uncertainty could cause a large burden of additional morbidity and mortality during the pandemic. We recommend caution in experimental drug use for non-severe disease and urge clinical trial sponsors to report missing results retrospectively.
m938suxh
m938suxh
2020-06-03
10.1101/2020.05.30.20117523
4
Evidence of the COVID-19 Virus Targeting the CNS: Tissue Distribution, Host–Virus Interaction, and Proposed Neurotropic Mechanisms
[Image: see text] The recent outbreak of coronavirus infectious disease 2019 (COVID-19) has gripped the world with apprehension and has evoked a scare of epic proportion regarding its potential to spread and infect humans worldwide. As we are in the midst of an ongoing pandemic of COVID-19, scientists are struggling to understand how it resembles and differs from the severe acute respiratory syndrome coronavirus (SARS-CoV) at the genomic and transcriptomic level. In a short time following the outbreak, it has been shown that, similar to SARS-CoV, COVID-19 virus exploits the angiotensin-converting enzyme 2 (ACE2) receptor to gain entry inside the cells. This finding raises the curiosity of investigating the expression of ACE2 in neurological tissue and determining the possible contribution of neurological tissue damage to the morbidity and mortality caused by COIVD-19. Here, we investigate the density of the expression levels of ACE2 in the CNS, the host–virus interaction and relate it to the pathogenesis and complications seen in the recent cases resulting from the COVID-19 outbreak. Also, we debate the need for a model for staging COVID-19 based on neurological tissue involvement.
m9i9gu5g
m9i9gu5g
2020-03-13
10.1021/acschemneuro.0c00122
1
The Outbreak of COVID-19 in Italy: Fighting the Pandemic
mcru4j6g
mcru4j6g
2020-04-01
10.1016/j.jaccas.2020.03.012
1.5
Conformational Reorganization of the SARS Coronavirus Spike Following Receptor Binding: Implications for Membrane Fusion
The SARS coronavirus (SARS-CoV) spike is the largest known viral spike molecule, and shares a similar function with all class 1 viral fusion proteins. Previous structural studies of membrane fusion proteins have largely used crystallography of static molecular fragments, in isolation of their transmembrane domains. In this study we have produced purified, irradiated SARS-CoV virions that retain their morphology, and are fusogenic in cell culture. We used cryo-electron microscopy and image processing to investigate conformational changes that occur in the entire spike of intact virions when they bind to the viral receptor, angiotensin-converting enzyme 2 (ACE2). We have shown that ACE2 binding results in structural changes that appear to be the initial step in viral membrane fusion, and precisely localized the receptor-binding and fusion core domains within the entire spike. Furthermore, our results show that receptor binding and subsequent membrane fusion are distinct steps, and that each spike can bind up to three ACE2 molecules. The SARS-CoV spike provides an ideal model system to study receptor binding and membrane fusion in the native state, employing cryo-electron microscopy and single-particle image analysis.
mcsdem7y
mcsdem7y
2007-10-24
10.1371/journal.pone.0001082
3.5
Identification of single-chain antibody fragments specific against SARS-associated coronavirus from phage-displayed antibody library
Abstract To develop early diagnostic reagents, effective vaccines, and even drugs against SARS-associated coronavirus (SARS-CoV), the human single fold single-chain antibody fragments, (scFv) libraries I+J (Tomlinson I+J) were used to identify novel scFvs, which can specifically bind to SARS-CoV. Interestingly, two scFvs (B5 and B9) exhibited higher binding specificity to SARS-CoV with the OD450 value 0.608 and 0.545, respectively, and their coding sequences shared the identical sequence composed of VH gene (351bp) and VL gene (327bp), so the two scFvs were uniformly named as SA59B and chosen for further analysis. SA59B scFv was expressed in soluble form in Escherichia coli HB2151 and purified by immobilized metal affinity chromatography. The soluble 30kDa SA59B scFv-antibody was verified in SDS–PAGE and Western-blot. The purified SA59B scFv-antibody was labeled with HRP by the glutaraldehyde method, and the concentration of HRP and SA59B scFv-antibody in the SA59B-HRP solution reached 2.4 and 2.28mg/ml, respectively. Then, the binding ability of SA59B-HRP to SARS-CoV was evaluated by ELISA with S/N of 11.6, indicating higher binding specificity between them. Finally, both the SA59B sequence specificity and its application for diagnosis, prophylaxis or therapy of SARS were discussed.
mehwd0dk
mehwd0dk
2005-04-08
10.1016/j.bbrc.2005.02.003
1.5
Clinical, molecular and epidemiological characterization of the SARS-CoV2 virus and the Coronavirus disease 2019 (COVID-19), a comprehensive literature review
Abstract Coronaviruses are an extensive family of viruses that can cause disease in both animals and humans. The current classification of coronaviruses recognizes 39 species in 27 subgenera that belong to the family Coronaviridae. From those, at least seven coronaviruses are known to cause respiratory infections in humans. Four of these viruses can cause common cold-like symptoms. Those that infect animals can evolve and become infectious to humans. Three recent examples of these viral jumps include SARS CoV, MERS-CoV and SARS CoV-2 virus. They are responsible for causing severe acute respiratory syndrome (SARS), Middle East respiratory syndrome (MERS) and the most recently discovered coronavirus disease during 2019 (COVID-19). COVID-19, a respiratory disease caused by the SARS-CoV-2 virus, was declared a pandemic by the World Health Organization (WHO) on 11 March 2020. The rapid spread of the disease has taken the scientific and medical community by surprise. Latest figures from 20th May 2020 show more than 5 million people had been infected with the virus, causing more than 330,000 deaths in over 210 countries worldwide. The large amount of information received daily relating to COVID-19 is so abundant and dynamic that medical staff, health authorities, academics and the media are not able to keep up with this new pandemic. In order to offer a clear insight of the extensive literature available, we have conducted a comprehensive literature review of the SARS CoV-2 Virus and the Coronavirus Diseases 2019 (COVID-19).
mettlmhz
mettlmhz
2020-05-30
10.1016/j.diagmicrobio.2020.115094
4.5
The missing pieces in the jigsaw and need for cohesive research amidst COVID 19 global response
mfiaubqb
mfiaubqb
2020-04-07
10.1016/j.mjafi.2020.04.001
1
Chapter 5 Respiratory infections of the human bocavirus
Abstract The human bocavirus is one of the most common respiratory viruses and occurs in all age groups. It is associated with upper and lower respiratory tract infections, and causes clinical symptoms from the mild common cold to life threatening respiratory diseases. Besides its ability to persist the virus appears to trigger chronic lung disease and increase the clinical symptoms, while being a putative trigger for fibrotic lung diseases. Laboratory diagnostics should include serological diagnostics in order to rule out a viremia because due to prolonged viral shedding acute and chronic infections cannot be differentiated on the detection of viral nucleic acids in respiratory specimen alone. Although Koch’s postulates cannot be formally fulfilled due to the lack of an animal model and the chance for clinical trials with volunteers are limited due to the long term effects of HBoV infections, there is no doubt that the virus is a serious pathogen and requires attention. The aim of the chapter is to present an overview of our current knowledge on respiratory infections with the human bocavirus, and to provide basic and essential information on clinical features, molecular diagnostics, and epidemiologic challenges arising with this pathogen.
mg7k1pt8
mg7k1pt8
2016-12-31
10.1016/b978-0-12-804543-5.00005-1
1
Adenoviral expression of a truncated S1 subunit of SARS-CoV spike protein results in specific humoral immune responses against SARS-CoV in rats
Abstract The causative agent of severe acute respiratory syndrome (SARS) has been identified as SARS-associated coronavirus (SARS-CoV), but the prophylactic treatment of SARS-CoV is still under investigation. We constructed a recombinant adenovirus containing a truncated N-terminal fragment of the SARS-CoV Spike (S) gene (from −45 to 1469, designated Ad-SN), which encoded a truncated S protein (490 amino-acid residues, a part of 672 amino-acid S1 subunit), and investigated whether this construct could induce effective immunity against SARS-CoV in Wistar rats. Rats were immunized either subcutaneously or intranasally with Ad-SN once a week for three consecutive weeks. Our results showed that all of the immunized animals generated humoral immunity against the SARS-CoV spike protein, and the sera of immunized rats showed strong capable of protecting from SARS-CoV infection in vitro. Histopathological examination did not find evident side effects in the immunized animals. These results indicate that an adenoviral-based vaccine carrying an N-terminal fragment of the Spike gene is able to elicit strong SARS-CoV-specific humoral immune responses in rats, and may be useful for the development of a protective vaccine against SARS-CoV infection.
mghgvr76
mghgvr76
2005-09-30
10.1016/j.virusres.2005.02.009
2.5
Dangers of ACE inhibitor and ARB usage in COVID-19: evaluating the evidence
Background: Concerns have been raised regarding the safety of Angiotensin Converting Enzyme Inhibitors (ACEIs) and Angiotensin Receptor Blockers (ARBs) in patients with COVID-19, based on the hypothesis that such medications may raise expression of ACE2, the receptor for SARS-CoV-2. Methods: We conducted a literature review of studies (n=12) in experimental animals and human subjects (n=11) and evaluated the evidence regarding the impact of administration of ACEIs and ARBs on ACE2 expression. We prioritized studies that assessed ACE2 protein expression data, measured directly or inferred from ACE2 activity assays. Results: The findings in animals are inconsistent with respect to an increase in ACE2 expression in response to treatment with ACEIs or ARBs. Control/sham animals show little to no effect in the plurality of studies. Those studies that report increases in ACE2 expression tend to involve acute injury models and/or higher doses than typically administered to patients. Data from human studies overwhelmingly imply that administration of ACEIs/ARBs does not increase ACE2 expression. Conclusion: Available evidence, in particular, data from human studies, does not support the hypothesis that ACEI/ARB use increases ACE2 expression and the risk of complications from COVID-19. We conclude that patients being treated with ACEIs and ARBs should continue their use for approved indications.
mgp38mdz
mgp38mdz
2020-03-30
10.1101/2020.03.25.20043927
1
Computational screening of antagonist against the SARS-CoV-2 (COVID-19) coronavirus by molecular docking
Abstract In the current episode of novel coronavirus (SARS-CoV-2) spreads, antiviral drug discovery is of great importance. Auto dock vina was used to screen potential drugs by molecular docking with the structure protein and non-structure protein sites of new coronavirus. Ribavirin, a common antiviral drug, as well as remdesivir, chloroquine and luteolin, were all studied. Honeysuckle is generally believed to have antiviral effect in traditional Chinese medicine, the main flavonoid in which is Luteolin. In the study, it was found luteolin could bind to the same sites of main protease of SARS-CoV-2 as the control molecular with a high affinity. Chloroquine, was proved clinically effective, can bind to the main protease, which may be the possible antiviral mechanism. And the study was restricted to molecular docking without validation by MD simulations. Interactions with the main protease may play a key role in in fighting against viruses. Luteolin is a potential antiviral molecule worthy of attention.
mh95ueih
mh95ueih
2020-05-08
10.1016/j.ijantimicag.2020.106012
3
DECLARACIÓN DE CONSENSO EN MEDICINA CRÍTICA PARA LA ATENCIÓN MULTIDISCIPLINARIA DEL PACIENTE CON SOSPECHA O CONFIRMACIÓN DIAGNÓSTICA DE COVID-19
Resumen El comportamiento de la infección por SARS-CoV-2 obligó a la Organización Mundial de la Salud a emitir una convocatoria global de activación de mecanismos de emergencia para atender la crisis de salud pública latente. Las Unidades de Cuidados Intensivos son uno de los principales recursos de los sistemas sanitarios dada la tasa de neumonías complicadas que presentan los pacientes infectados. En respuesta a los distintos lineamientos y diferentes niveles de evidencia de la información disponible, la Asociación Colombiana de Medicina crítica y Cuidados Intensivos (AMCI), convocó un equipo multidisciplinario de expertos en medicina crítica para establecer una declaratoria de consenso de buena práctica clínica para la atención de pacientes con COVID-19. Su objetivo es facilitar y estandarizar la toma de decisiones en los aspectos más relevantes desde la organización administrativa de las áreas de atención hasta el abordaje clínico del paciente, teniendo en cuenta la seguridad del personal sanitario, la infraestructura y recursos con los que cuenta el país para responder a la emergencia. Este documento está sujeto a la evolución del conocimiento y a los resultados de investigaciones en curso. Abstract The behaviour of the SARS-CoV-2 infection has forced World Health Organisation to call for the global activation of emergency and contingency mechanisms to respond to the world-wide public health crisis. Intensive Care Units are one of the main health care resources in this situation due to the number of expected cases of severe pneumonia from infected patients. Different guidelines and different levels of evidence from the available information have motivated Asociación Colombiana de Medicina crítica y Cuidados Intensivos (AMCI) to assemble a multidisciplinary team of experts in critical care medicine to prepare a consensus statement of good clinical practice for the care of patients with COVID-19. Its aim is to simplify and standardise decision-making in the most relevant aspects: from the administrative organisation of the care facilities, to the clinical approach of patients, taking into account the safety of health care professionals, and the infrastructure and resources available in Colombia to respond to the emergency. This document will be adapted to any new knowledge and results of on-going research.
mhdmy8kq
mhdmy8kq
2020-04-17
10.1016/j.acci.2020.04.003
2
Sofosbuvir as Repurposed Antiviral Drug Against COVID-19: Why Were we Convinced to Evaluate the Drug in a Registered/Approved Clinical Trial?
COVID-19 is a devastating global pandemic around the world. While the majority of infected cases appear mild, in some cases individuals present respiratory complications with possible serious lung damage. There are no specific treatments for COVID-19 as yet, though a number are under evaluation, including experimental antivirals. Sofosbuvir, the clinically approved anti-hepatitis C virus (HCV) drug, is also capable of suppressing other families of positive-strand RNA viruses; Flaviviridae and Togaviridae. Coronaviruses are a family of positive-strand RNA viruses with conserved polymerase, so SARS-CoV-2 RdRp is very likely to be effectively inhibited by sofosbuvir. More importantly, sofosbuvir is safe and well tolerated at 400 mg daily in a 24 week therapeutic regimen. Sofosbuvir active metabolite, however, shows an extremely high intracellular stability So, it is hypothesized that SARS-CoV-2 infection could also be susceptible to sofosbuvir and we were convinced to design and run a clinical trial to evaluate the effect of sofosbuvir 400 mg (in combination with velpatasvir 100 mg, as add-on treatment, in addition to standard of care) on the COVID-19. However, we believe that this manuscript/correspondence should be made available to the international scientific community as soon as possible, with the help of this esteemed journal.
mhfncx8h
mhfncx8h
2020-04-29
10.1016/j.arcmed.2020.04.018
3.5
COVID-19 Clinical Trials: A Primer for the Cardiovascular and Cardio-Oncology Communities
Abstract The COVID-19 pandemic has resulted in a proliferation of clinical trials that are designed to slow the spread of SARS-CoV-2, the virus that causes COVID-19. The overwhelming majority of cardiovascular and cancer patients are at increased risk for SARS-CoV-2 infection; accordingly, the cardiovascular and cardio-oncology communities are playing a major role in caring for COVID-19 patients. Many of the therapeutic agents that are being used to treat patients with COVID-19 are repurposed treatments for influenza, drugs that were not effective in Ebola patients, or treatments for malaria that were developed decades ago, and are unlikely to be familiar to the cardiovascular and cardio-oncology communities. Here we have provided a foundation for cardiovascular and cardio-oncology physicians who are on the frontline providing care to COVID-19 patients, so that they can better understand the emerging cardiovascular epidemiology of COVID-19, as well as the biological rationale for the clinical trials that are ongoing for the treatment of COVID-19 patients.
mhqiqgr7
mhqiqgr7
2020-04-17
10.1016/j.jaccao.2020.04.002
2
ACE-inibitori, sartani e sindrome respiratoria acuta da coronavirus 2./ [ACE-inhibitors, angiotensin receptor blockers and severe acute respiratory syndrome caused by coronavirus]
Some Authors recently suggested that angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs) should be discontinued, even temporarily, given the current pandemic of SARS-CoV-2 virus. The suggestion is based on the hypothesis that ACE-inhibitors and ARBs may favor the entry and diffusion of SARS-CoV-2 virus into the human cells. ACE-inhibitors and ARBs may increase the expression of ACE2 receptors, which are the sites of viral entry into the human organism. ACE2 receptors are ubiquitous, although they are extremely abundant on the cell surface of type 2 pneumocytes. Type 2 pneumocytes are small cylindrical alveolar cells located in close vicinity to pulmonary capillaries and responsible for the synthesis of alveolar surfactant, which is known to facilitate gas exchanges. The increased expression of ACE2 for effect of ACE-inhibitors and ARBs can be detected by increased production of angiotensin1-7 and mRNA related to ACE2. There is the fear that the increased expression of ACE2 induced by ACE-inhibitors and ARBs may ultimately facilitate the entry and diffusion of the SARS-CoV-2 virus. However, there is no clinical evidence to support this hypothesis. Furthermore, available data are conflicting and some counter-intuitive findings suggest that ARBs may be beneficial, not harmful. Indeed, studies conducted in different laboratories demonstrated that ACE2 receptors show a down-regulation (i.e. the opposite of what would happen with ACE-inhibitors and ARBs) for effect of their interaction with the virus. In animal studies, down-regulation of ACE2 has been found as prevalent in the pulmonary areas infected by virus, but not in the surrounding areas. In these studies, virus-induced ACE2 down-regulation would lead to a reduced formation of angiotensin1-7 (because ACE2 degrades angiotensin II into angiotensin1-7) with consequent accumulation of angiotensin II. The excess angiotensin II would favor pulmonary edema and inflammation, a phenomenon directly associated with angiotensin II levels, along with worsening in pulmonary function. Such detrimental effects have been blocked by ARBs in experimental models. In the light of the above considerations, it is reasonable to conclude that the suggestion to discontinue ACE-inhibitors or ARBs in all patients with the aim of preventing or limiting the diffusion of SARS-CoV-2 virus is not based on clinical evidence. Conversely, experimental studies suggest that ARBs might be useful in these patients to limit pulmonary damage through the inhibition of type 1 angiotensin II receptors. Controlled clinical studies in this area are eagerly awaited. This review discusses facts and theories on the potential impact of ACE-inhibitors and ARBs in the setting of the SARS-CoV-2 pandemic.
mi0pmyo4
mi0pmyo4
2020
3
Treatment and vaccines for severe acute respiratory syndrome
Summary The causative agent of severe acute respiratory syndrome (SARS), which affected over 8000 individuals worldwide and was responsible for over 700 deaths in the 2002–2003 outbreak, is a coronavirus that was unknown before the outbreak. Although many different treatments were used during the outbreak, none were implemented in a controlled fashion. Thus, the optimal treatment for SARS is unknown. Since the outbreak, much work has been done testing new agents against SARS using in-vitro methods and animal models. In addition, global research efforts have focused on the development of vaccines against SARS. Efforts should be made to evaluate the most promising treatments and vaccines in controlled clinical trials, should another SARS outbreak occur.
mivxm8oh
mivxm8oh
2005-03-31
10.1016/s1473-3099(05)01307-1
1
Lianhuaqingwen exerts anti-viral and anti-inflammatory activity against novel coronavirus (SARS-CoV-2)
Abstract Purpose Lianhuaqingwen (LH) as traditional Chinese medicine (TCM) formula has been used to treat influenza and exerted broad-spectrum antiviral effects on a series of influenza viruses and immune regulatory effects Ding et al. (2017). The goal of this study is to demonstrate the antiviral activity of LH against the novel SARS-CoV-2 virus and its potential effect in regulating host immune response. Methods The antiviral activity of LH against SARS-CoV-2 was assessed in Vero E6 cells using CPE and plaque reduction assay. The effect of LH on virion morphology was visualized under transmission electron microscope. Pro-inflammatory cytokine expression levels upon SARS-CoV-2 infection in Huh-7 cells were measured by real-time quantitative PCR assays. Results LH significantly inhibited SARS-CoV-2 replication in Vero E6 cells and markedly reduced pro-inflammatory cytokines (TNF-α, IL-6, CCL-2/MCP-1 and CXCL-10/IP-10) production at the mRNA levels. Furthermore, LH treatment resulted in abnormal particle morphology of virion in cells. Conclusions LH significantly inhibits the SARS-COV-2 replication, affects virus morphology and exerts anti-inflammatory activity in vitro. These findings indicate that LH protects against the virus attack, making its use a novel strategy for controlling the COVID-19 disease.
mk62bybt
mk62bybt
2020-06-30
10.1016/j.phrs.2020.104761
0.5
A new mouse-adapted strain of SARS-CoV as a lethal model for evaluating antiviral agents in vitro and in vivo
Severe acute respiratory syndrome (SARS) is a highly lethal emerging disease caused by coronavirus SARS-CoV. New lethal animal models for SARS were needed to facilitate antiviral research. We adapted and characterized a new strain of SARS-CoV (strain v2163) that was highly lethal in 5–6 week old BALB/c mice. It had nine mutations affecting 10 amino acid residues. Strain v2163 increased IL-1α, IL-6, MIP-1α, MCP-1, and RANTES in mice, and high IL-6 expression correlated with mortality. The infection largely mimicked human disease, but lung pathology lacked hyaline membrane formation. In vitro efficacy against v2163 was shown with known inhihibitors of SARS-CoV replication. In v2163-infected mice, Ampligen™ was fully protective, stinging nettle lectin (UDA) was partially protective, ribavirin was disputable and possibly exacerbated disease, and EP128533 was inactive. Ribavirin, UDA and Ampligen™ decreased IL-6 expression. Strain v2163 provided a valuable model for anti-SARS research.
mkfwhv6v
mkfwhv6v
2009-12-01
10.1016/j.virol.2009.09.023
2.5
Transcriptomics of In Vitro Immune-Stimulated Hemocytes from the Manila Clam Ruditapes philippinarum Using High-Throughput Sequencing
BACKGROUND: The Manila clam (Ruditapes philippinarum) is a worldwide cultured bivalve species with important commercial value. Diseases affecting this species can result in large economic losses. Because knowledge of the molecular mechanisms of the immune response in bivalves, especially clams, is scarce and fragmentary, we sequenced RNA from immune-stimulated R. philippinarum hemocytes by 454-pyrosequencing to identify genes involved in their immune defense against infectious diseases. METHODOLOGY AND PRINCIPAL FINDINGS: High-throughput deep sequencing of R. philippinarum using 454 pyrosequencing technology yielded 974,976 high-quality reads with an average read length of 250 bp. The reads were assembled into 51,265 contigs and the 44.7% of the translated nucleotide sequences into protein were annotated successfully. The 35 most frequently found contigs included a large number of immune-related genes, and a more detailed analysis showed the presence of putative members of several immune pathways and processes like the apoptosis, the toll like signaling pathway and the complement cascade. We have found sequences from molecules never described in bivalves before, especially in the complement pathway where almost all the components are present. CONCLUSIONS: This study represents the first transcriptome analysis using 454-pyrosequencing conducted on R. philippinarum focused on its immune system. Our results will provide a rich source of data to discover and identify new genes, which will serve as a basis for microarray construction and the study of gene expression as well as for the identification of genetic markers. The discovery of new immune sequences was very productive and resulted in a large variety of contigs that may play a role in the defense mechanisms of Ruditapes philippinarum.
mkwpuav6
mkwpuav6
2012-04-19
10.1371/journal.pone.0035009
1.5
Transmission and epidemiological characteristics of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infected Pneumonia (COVID-19): preliminary evidence obtained in comparison with 2003-SARS
Objectives: Latest epidemic data of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infected Pneumonia (COVID-19) was collected and a detailed statistical analysis was carried out to make comparison with 2003-SARS in order to provide scientific reference for the prevention and control of COVID-19. Methods: The information of COVID-19 and 2003-SARS from websites of NHCPRC and the World Health Organization was collected, and then the transmission dynamics of the two kinds of infectious diseases were analyzed. The information of 853 confirmed COVID-19 patients obtained from the website of health committees of 18 provinces. A descriptive epidemiological analysis method was employed to carefully analyze the epidemic characteristics. Subsequently, the COVID-19 epidemic data in Wuhan and other inland regions of China was analyzed separately and compared. A multivariate function model was constructed based on the confirmed COVID-19 case data. Results: The growth rate of new cases and deaths of COVID-19 were significantly faster than those of 2003-SARS. The number of confirmed cases in Wuhan and other inland areas both showed increasing trends. 853 confirmed COVID-19 cases aged 1 months to 94 years and the average age was (45.05 ± 17.22) years. The gender ratio (M: F) was 1.12: 1. Conclusions: The fatality rate of COVID-19 is lower than that of 2003-SARS and the cure rate is higher. The age of COVID-19 patients is mainly concentrated in the 30-50 years old (60.61%). The harm of the first-generation COVID-19 patients is higher than that of secondary cases.
mm4ngrla
mm4ngrla
2020-02-02
10.1101/2020.01.30.20019836
1
Structure-based design, synthesis, and biological evaluation of a series of novel and reversible inhibitors for the severe acute respiratory syndrome-coronavirus papain-like protease.
We describe here the design, synthesis, molecular modeling, and biological evaluation of a series of small molecule, nonpeptide inhibitors of SARS-CoV PLpro. Our initial lead compound was identified via high-throughput screening of a diverse chemical library. We subsequently carried out structure-activity relationship studies and optimized the lead structure to potent inhibitors that have shown antiviral activity against SARS-CoV infected Vero E6 cells. Upon the basis of the X-ray crystal structure of inhibitor 24-bound to SARS-CoV PLpro, a drug design template was created. Our structure-based modification led to the design of a more potent inhibitor, 2 (enzyme IC(50) = 0.46 microM; antiviral EC(50) = 6 microM). Interestingly, its methylamine derivative, 49, displayed good enzyme inhibitory potency (IC(50) = 1.3 microM) and the most potent SARS antiviral activity (EC(50) = 5.2 microM) in the series. We have carried out computational docking studies and generated a predictive 3D-QSAR model for SARS-CoV PLpro inhibitors.
mmqlwsye
mmqlwsye
2009
10.1021/jm900611t
0.5
Genomic characterization of the 2019 novel human-pathogenic coronavirus isolated from a patient with atypical pneumonia after visiting Wuhan
A mysterious outbreak of atypical pneumonia in late 2019 was traced to a seafood wholesale market in Wuhan of China. Within a few weeks, a novel coronavirus tentatively named as 2019 novel coronavirus (2019-nCoV) was announced by the World Health Organization. We performed bioinformatics analysis on a virus genome from a patient with 2019-nCoV infection and compared it with other related coronavirus genomes. Overall, the genome of 2019-nCoV has 89% nucleotide identity with bat SARS-like-CoVZXC21 and 82% with that of human SARS-CoV. The phylogenetic trees of their orf1a/b, Spike, Envelope, Membrane and Nucleoprotein also clustered closely with those of the bat, civet and human SARS coronaviruses. However, the external subdomain of Spike’s receptor binding domain of 2019-nCoV shares only 40% amino acid identity with other SARS-related coronaviruses. Remarkably, its orf3b encodes a completely novel short protein. Furthermore, its new orf8 likely encodes a secreted protein with an alpha-helix, following with a beta-sheet(s) containing six strands. Learning from the roles of civet in SARS and camel in MERS, hunting for the animal source of 2019-nCoV and its more ancestral virus would be important for understanding the origin and evolution of this novel lineage B betacoronavirus. These findings provide the basis for starting further studies on the pathogenesis, and optimizing the design of diagnostic, antiviral and vaccination strategies for this emerging infection.
mn0l7nar
mn0l7nar
2020-01-28
10.1080/22221751.2020.1719902
1.5
Recent highlights in the development of new antiviral drugs
Twenty antiviral drugs, that is about half of those that are currently approved, are formally licensed for clinical use in the treatment of human immunodeficiency virus infections (acquired immune deficiency syndrome). The others are used in the treatment of herpesvirus (e.g. herpes simplex virus, varicella zoster virus and cytomegalo virus), hepatitis B virus, hepatitis C virus or influenza virus infections. Recent endeavours have focussed on the development of improved antiviral therapies for virus infections that have already proved amenable to antiviral drug treatment, as well as for virus infections for which, at present, no antiviral drugs have been formally approved (i.e. human papilloma viruses, adenoviruses, human herpesvirus type 6, poxviruses, severe acute respiratory syndrome coronavirus and hemorrhagic fever viruses).
mnhm7jdo
mnhm7jdo
2005-10-31
10.1016/j.mib.2005.08.010
0.5
Susceptibility of ferrets, cats, dogs, and different domestic animals to SARS-coronavirus-2
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes the infectious disease COVID-19, which was first reported in Wuhan, China in December, 2019. Despite the tremendous efforts to control the disease, COVID-19 has now spread to over 100 countries and caused a global pandemic. SARS-CoV-2 is thought to have originated in bats; however, the intermediate animal sources of the virus are completely unknown. Here, we investigated the susceptibility of ferrets and animals in close contact with humans to SARS-CoV-2. We found that SARS-CoV-2 replicates poorly in dogs, pigs, chickens, and ducks, but efficiently in ferrets and cats. We found that the virus transmits in cats via respiratory droplets. Our study provides important insights into the animal reservoirs of SARS-CoV-2 and animal management for COVID-19 control.
mo4luyx6
mo4luyx6
2020-03-31
10.1101/2020.03.30.015347
1
Chapter 19 Advances in structure-assisted antiviral discovery for animal viral diseases
Abstract The latest advancements in drug development are structure-assisted and computer-aided identification, design, and synthesis of target-specific antiviral. Structural virology of animal viruses has made valuable contribution to our understanding of viruses in general, replication, evolution, and interaction with the host. Structure–function relation studies are definitely the need of the hour for rational design of drugs and vaccines to effectively treat animal viral diseases. These studies are important for economical, veterinary, and human medical perspectives. X-ray crystallography, nuclear magnetic resonance and cryo-electron microscopy techniques elaborate the structure–function relation studies by utilizing various computational approaches for structure-assisted designing of drug molecules and antiviral against viruses. Availability of protein three-dimensional structures, high-performance computing, data management software, and internet are enhancing the modern day drug discovery process. Computational tools offer the advantage of delivering new drug candidates more quickly and at a lower cost. Various viral proteins that are necessary for the survival of the virus inside the host are discussed in this chapter such as viral polymerase, helicase, protease, etc. Various antiviral drug molecules identified and designed on the basis of the structure of viral proteins which are highlighted, and disclosed details of the available inhibitors and potential antiviral are discussed. Further improvement in identified inhibitors, the need of novel structure-based drugs and their clinical testing is emphasized. This chapter describes briefly the structural techniques and advances made in animal virology toward structure-based identification and development of antiviral for treatment of animal viruses. In the future, the studies discussed may serve as the basis for development of potential antiviral against animal viral diseases.
mog52dn8
mog52dn8
2020-12-31
10.1016/b978-0-12-816352-8.00019-9
1
Structural and Evolutionary Analysis Indicate that the SARS-CoV-2 Mpro is an Inconvenient Target for Small-Molecule Inhibitors Design
The novel coronavirus whose outbreak took place in December 2019 continues to spread at a rapid rate worldwide. In the absence of an effective vaccine, inhibitor repurposing or de novo drug design may offer a longer-term strategy to combat this and future infections due to similar viruses. Here, we report on detailed classical and mix-solvent molecular dynamics simulations of the main protease (Mpro) enriched by evolutionary and stability analysis of the protein. The results were compared with those for a highly similar SARS Mpro protein. In spite of a high level of sequence similarity, the active sites in both proteins show major differences in both shape and size indicating that repurposing SARS drugs for COVID-19 may be futile. Furthermore, analysis of the binding site’s conformational changes during the simulation time indicates its flexibility and plasticity, which dashes hopes for rapid and reliable drug design. Conversely, structural stability of the protein with respect to flexible loop mutations indicates that the virus’ mutability will pose a further challenge to the rational design of small-molecule inhibitors. However, few residues contribute significantly to the protein stability and thus can be considered as key anchoring residues for Mpro inhibitor design.
mp3a9c9u
mp3a9c9u
2020-04-06
10.1101/2020.02.27.968008
1.5
Pressure-Regulated Ventilator Splitting (PReVentS): A COVID-19 Response Paradigm from Yale University
In the current COVID-19 crisis, the US and many countries in the world are suffering acute shortages of modern ventilators to care for desperately ill patients. Since modern ICU ventilators are powerful devices that can deliver very high gas flow rates and pressures, multiple physicians have attempted to ventilate more than one patient on a single ventilator -- so-called 'vent splitting'. Early applications of this approach have utilized simple concatenations of ventilator tubing and T-pieces, to provide flow to more than one patient. Additional approaches using custom flow splitters -- sometimes made using 3D printing technologies -- have also advanced into the clinic with FDA approval. However, heretofore there has been less progress made on controlling individual ventilatory pressures for patients with severe lung disease. Given the inherent variability and instability of lung compliance amongst patients with COVID-19, there remains an important need to provide a means of extending ventilator usefulness to more than one patient, but in a way that provides more tailored pressures that can be titrated over time. In this descriptive report, we provide the basis for a ventilator circuit that can support two patients with individualized peak inspiratory and end-expiratory pressures. The circuit is comprised of exclusively 'off the shelf' materials and is inexpensive to produce. The circuit can be used with typical ICU ventilators, and with anesthesia ventilators used in operating rooms. Inspiratory and end-expiratory pressures for each patient can be titrated over time, without changes for one patient affecting the ventilation parameters of the other patient. Using in-line spirometry, individual tidal volumes can be measured for each patient. This Pressure-Regulated Ventilator Splitting (PReVentS) Yale University protocol operates under a pressure-control ventilatory mode, and may function optimally when patients are not triggering breaths from the ventilator. This method has been tested thus far only in the laboratory with mock lungs, and has not yet been deployed in animals or in patients. However, given the novelty and potential utility of this approach, we deemed it appropriate to provide this information to the broader critical care community at the present time. In coming days and weeks, we will continue to characterize and refine this approach, using large animal models and proof-of-principle human studies.
mqj071gp
mqj071gp
2020-04-06
10.1101/2020.04.03.20052217
1
A Mouse-Adapted SARS-Coronavirus Causes Disease and Mortality in BALB/c Mice
No single animal model for severe acute respiratory syndrome (SARS) reproduces all aspects of the human disease. Young inbred mice support SARS-coronavirus (SARS-CoV) replication in the respiratory tract and are available in sufficient numbers for statistical evaluation. They are relatively inexpensive and easily accessible, but their use in SARS research is limited because they do not develop illness following infection. Older (12- to 14-mo-old) BALB/c mice develop clinical illness and pneumonitis, but they can be hard to procure, and immune senescence complicates pathogenesis studies. We adapted the SARS-CoV (Urbani strain) by serial passage in the respiratory tract of young BALB/c mice. Fifteen passages resulted in a virus (MA15) that is lethal for mice following intranasal inoculation. Lethality is preceded by rapid and high titer viral replication in lungs, viremia, and dissemination of virus to extrapulmonary sites accompanied by lymphopenia, neutrophilia, and pathological changes in the lungs. Abundant viral antigen is extensively distributed in bronchial epithelial cells and alveolar pneumocytes, and necrotic cellular debris is present in airways and alveoli, with only mild and focal pneumonitis. These observations suggest that mice infected with MA15 die from an overwhelming viral infection with extensive, virally mediated destruction of pneumocytes and ciliated epithelial cells. The MA15 virus has six coding mutations associated with adaptation and increased virulence; when introduced into a recombinant SARS-CoV, these mutations result in a highly virulent and lethal virus (rMA15), duplicating the phenotype of the biologically derived MA15 virus. Intranasal inoculation with MA15 reproduces many aspects of disease seen in severe human cases of SARS. The availability of the MA15 virus will enhance the use of the mouse model for SARS because infection with MA15 causes morbidity, mortality, and pulmonary pathology. This virus will be of value as a stringent challenge in evaluation of the efficacy of vaccines and antivirals.
mqnqjn0c
mqnqjn0c
2007-01-12
10.1371/journal.ppat.0030005
4
Antibodies against trimeric S glycoprotein protect hamsters against SARS-CoV challenge despite their capacity to mediate FcγRII-dependent entry into B cells in vitro
Vaccine-induced antibodies can prevent or, in the case of feline infectious peritonitis virus, aggravate infections by coronaviruses. We investigated whether a recombinant native full-length S-protein trimer (triSpike) of severe acute respiratory syndrome coronavirus (SARS-CoV) was able to elicit a neutralizing and protective immune response in animals and analyzed the capacity of anti-S antibodies to mediate antibody-dependent enhancement (ADE) of virus entry in vitro and enhancement of replication in vivo. SARS-CoV-specific serum and mucosal immunoglobulins were readily detected in immunized animals. Serum IgG blocked binding of the S-protein to the ACE2 receptor and neutralized SARS-CoV infection in vitro. Entry into human B cell lines occurred in a FcγRII-dependent and ACE2-independent fashion indicating that ADE of virus entry is a novel cell entry mechanism of SARS-CoV. Vaccinated animals showed no signs of enhanced lung pathology or hepatitis and viral load was undetectable or greatly reduced in lungs following challenge with SARS-CoV. Altogether our results indicate that a recombinant trimeric S protein was able to elicit an efficacious protective immune response in vivo and warrant concern in the safety evaluation of a human vaccine against SARS-CoV.
mqnz9gts
mqnz9gts
2007-01-08
10.1016/j.vaccine.2006.08.011
1.5
Human organs-on-chips as tools for repurposing approved drugs as potential influenza and COVID19 therapeutics in viral pandemics
Rapidly spreading viral pandemics, such as those caused by influenza and SAR-CoV-2 (COVID19), require rapid action and the fastest way to combat this challenge is by repurposing existing drugs as anti-viral therapeutics. Here we first show that human organ-on-a-chip (Organ Chip) microfluidic culture devices lined by a highly differentiated, primary, human lung airway epithelium cultured under an air-liquid interface and fed by continuous medium flow can be used to model virus entry, replication, strain-dependent virulence, host cytokine production, and recruitment of circulating immune cells in response to infection by influenza, as well as effects of existing and novel therapeutics. These Airway Chips, which contain human lung epithelial cells that express high levels of ACE2 and TMPRSS2, were then used to assess the inhibitory activities of 7 clinically approved drugs (chloroquine, arbidol, toremifene, clomiphene, amodiaquine, verapamil, and amiodarone) that we found inhibit infection by viral pseudoparticles expressing SARS-CoV-2 spike protein in human Huh-7 cells, and others recently showed suppress infection by native SARS-CoV-2 in Vero cells. However, when these drugs were administered under flow at the maximal concentration in blood reported in clinical studies in human Airway Chips, only two of these drugs — amodiaquine and toremifene — significantly inhibited entry of the pseudotyped SARS-CoV-2 virus. This work suggests that human Organ Chip technology may be used in conjunction with existing rapid cell-based screening assays to study human disease pathogenesis and expedite drug repurposing in biothreat crises caused by pandemic viruses.
mrgw2mnx
mrgw2mnx
2020-04-15
10.1101/2020.04.13.039917
2
Molecular Mechanism of Evolution and Human Infection with SARS-CoV-2
The outbreak of a novel coronavirus, which was later formally named the severe acute respiratory coronavirus 2 (SARS-CoV-2), has caused a worldwide public health crisis. Previous studies showed that SARS-CoV-2 is highly homologous to SARS-CoV and infects humans through the binding of the spike protein to ACE2. Here, we have systematically studied the molecular mechanisms of human infection with SARS-CoV-2 and SARS-CoV by protein-protein docking and MD simulations. It was found that SARS-CoV-2 binds ACE2 with a higher affinity than SARS-CoV, which may partly explain that SARS-CoV-2 is much more infectious than SARS-CoV. In addition, the spike protein of SARS-CoV-2 has a significantly lower free energy than that of SARS-CoV, suggesting that SARS-CoV-2 is more stable and may survive a higher temperature than SARS-CoV. This provides insights into the evolution of SARS-CoV-2 because SARS-like coronaviruses have originated in bats. Our computation also suggested that the RBD-ACE2 binding for SARS-CoV-2 is much more temperature-sensitive than that for SARS-CoV. Thus, it is expected that SARS-CoV-2 would decrease its infection ability much faster than SARS-CoV when the temperature rises. These findings would be beneficial for the disease prevention and drug/vaccine development of SARS-CoV-2.
mrnid1i2
mrnid1i2
2020-04-10
10.3390/v12040428
4
SARS-CoV-2 and viral sepsis: observations and hypotheses
Summary Since the outbreak of coronavirus disease 2019 (COVID-19), clinicians have tried every effort to understand the disease, and a brief portrait of its clinical features have been identified. In clinical practice, we noticed that many severe or critically ill COVID-19 patients developed typical clinical manifestations of shock, including cold extremities and weak peripheral pulses, even in the absence of overt hypotension. Understanding the mechanism of viral sepsis in COVID-19 is warranted for exploring better clinical care for these patients. With evidence collected from autopsy studies on COVID-19 and basic science research on severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and SARS-CoV, we have put forward several hypotheses about SARS-CoV-2 pathogenesis after multiple rounds of discussion among basic science researchers, pathologists, and clinicians working on COVID-19. We hypothesise that a process called viral sepsis is crucial to the disease mechanism of COVID-19. Although these ideas might be proven imperfect or even wrong later, we believe they can provide inputs and guide directions for basic research at this moment.
mrvk9r4w
mrvk9r4w
2020-04-17
10.1016/s0140-6736(20)30920-x
3
In Vitro and In Vivo Pharmacological Models to Assess Demyelination and Remyelination
In making a selection of cellular tools and animal models for generating screening assays in the search for new drugs, one needs to take into consideration the practicality of their use in the drug discovery process. Conducting high-throughput primary screens using libraries of small molecules, close to 1 million members in size, requires the generation of large numbers of cells which are easily acquired, reliably enriched, and reproducibly responsive to standard positive controls. These cells need to be similar in form and function to their counterparts in human disease. In vitro assays that can be mechanized by using robots can therefore save time and costs. In selecting in vivo models, consideration must be given to the species and strain of animal chosen, the appropriateness of the model to human disease, the extent of animal husbandry required during the in-life pharmacological assessment, the technical aspects of generating the model and harvesting the tissues for analyses, the cost of research tools in terms of time and money (demyelinating and remyelinating agents, amount of compound to be generated), and the length of time required for drug testing in the model. A consideration of the translational aspects of the in vivo model compared to those used in the clinic is also important. These themes will be developed with examples for drug discovery in the field of CNS demyelination and repair, specifically as it pertains to multiple sclerosis. SUPPLEMENTARY INFORMATION: The online version of this article (doi:10.1038/npp.2008.145) contains supplementary material, which is available to authorized users.
mslm0auu
mslm0auu
2008-09-17
10.1038/npp.2008.145
2
The origin, transmission and clinical therapies on coronavirus disease 2019 (COVID-19) outbreak – an update on the status
An acute respiratory disease, caused by a novel coronavirus (SARS-CoV-2, previously known as 2019-nCoV), the coronavirus disease 2019 (COVID-19) has spread throughout China and received worldwide attention. On 30 January 2020, World Health Organization (WHO) officially declared the COVID-19 epidemic as a public health emergency of international concern. The emergence of SARS-CoV-2, since the severe acute respiratory syndrome coronavirus (SARS-CoV) in 2002 and Middle East respiratory syndrome coronavirus (MERS-CoV) in 2012, marked the third introduction of a highly pathogenic and large-scale epidemic coronavirus into the human population in the twenty-first century. As of 1 March 2020, a total of 87,137 confirmed cases globally, 79,968 confirmed in China and 7169 outside of China, with 2977 deaths (3.4%) had been reported by WHO. Meanwhile, several independent research groups have identified that SARS-CoV-2 belongs to β-coronavirus, with highly identical genome to bat coronavirus, pointing to bat as the natural host. The novel coronavirus uses the same receptor, angiotensin-converting enzyme 2 (ACE2) as that for SARS-CoV, and mainly spreads through the respiratory tract. Importantly, increasingly evidence showed sustained human-to-human transmission, along with many exported cases across the globe. The clinical symptoms of COVID-19 patients include fever, cough, fatigue and a small population of patients appeared gastrointestinal infection symptoms. The elderly and people with underlying diseases are susceptible to infection and prone to serious outcomes, which may be associated with acute respiratory distress syndrome (ARDS) and cytokine storm. Currently, there are few specific antiviral strategies, but several potent candidates of antivirals and repurposed drugs are under urgent investigation. In this review, we summarized the latest research progress of the epidemiology, pathogenesis, and clinical characteristics of COVID-19, and discussed the current treatment and scientific advancements to combat the epidemic novel coronavirus.
msohf5oa
msohf5oa
2020-03-13
10.1186/s40779-020-00240-0
1
Perspectives on therapeutic neutralizing antibodies against the Novel Coronavirus SARS-CoV-2
A newly identified novel coronavirus (SARS-CoV-2) is causing pneumonia-associated respiratory syndrome across the world. Epidemiology, genomics, and pathogenesis of the SARS-CoV-2 show high homology with that of SARS-CoV. Current efforts are focusing on development of specific antiviral drugs. Therapeutic neutralizing antibodies (NAbs) against SARS-CoV-2 will be greatly important therapeutic agents for the treatment of coronavirus disease 2019 (COVID-19). Herein, the host immune responses against SARS-CoV discussed in this review provide implications for developing NAbs and understanding clinical interventions against SARS-CoV-2. Further, we describe the benefits, challenges and considerations of NAbs against SARS-CoV-2. Although many challenges exist, NAbs still offer a therapeutic option to control the current pandemic and the possible re-emergence of the virus in the future, and their development therefore remains a high priority.
msvfq7z1
msvfq7z1
2020
3.5
Protein structure analysis of the interactions between SARS-CoV-2 spike protein and the human ACE2 receptor: from conformational changes to novel neutralizing antibodies
The recent severe acute respiratory syndrome, known as Corona Virus Disease 2019 (COVID-19) has spread so much rapidly and severely to induce World Health Organization (WHO) to declare state of emergency over the new coronavirus SARS-CoV-2 pandemic. While several countries have chosen the almost complete lock-down for slowing down SARS-CoV-2 spread, scientific community is called to respond to the devastating outbreak by identifying new tools for diagnosis and treatment of the dangerous COVID-19. With this aim we performed an in silico comparative modeling analysis, which allows to gain new insights about the main conformational changes occurring in the SARS-CoV-2 spike protein, at the level of the receptor binding domain (RBD), along interactions with human cells angiotensin converting enzyme 2 (ACE2) receptor, that favour human cell invasion. Furthermore, our analysis provides i) an ideal pipeline to identify already characterized antibodies that might target SARS-CoV-2 spike RBD, for preventing interactions with the human ACE2, and ii) instructions for building new possible neutralizing antibodies, according to chemical/physical space restraints and complementary determining regions (CDR) mutagenesis of the identified existing antibodies. The proposed antibodies show in silico a high affinity for SARS-CoV-2 spike RBD and can be used as reference antibodies also for building new high affinity antibodies against present and future coronavirus able to invade human cells through interactions of their spike proteins with the human ACE2. More in general, our analysis provides indications for the set-up of the right biological molecular context for investigating spike RBD-ACE2 interactions for the development of new vaccines, diagnosis kits and other treatments based on the usage or the targeting of SARS-CoV-2 spike protein.
mswmkgl4
mswmkgl4
2020-04-18
10.1101/2020.04.17.046185
2.5
Clinical management and infection control of SARS: Lessons learned
Abstract The outbreak of severe acute respiratory syndrome (SARS) in 2003 was the first emergence of an important human pathogen in the 21st century. Responding to the epidemic provided clinicians with extensive experience in diagnosing and treating a novel respiratory viral disease. In this article, we review the experience of the SARS epidemic, focusing on measures taken to identify and isolate patients, prevent the transmission of infection to healthcare workers and develop effective therapies. Lessons learned from the SARS epidemic will be especially important in responding to the current emergence of another highly pathogenic human coronavirus, the agent of Middle East respiratory syndrome (MERS), and to the recently emerging H7N9 influenza A virus in China. This paper forms part of a symposium in Antiviral Research on “From SARS to MERS: 10years of research on highly pathogenic human coronaviruses.”
mt5o8xn3
mt5o8xn3
2013-11-30
10.1016/j.antiviral.2013.08.016
1
Coronavirus Pandemic—Therapy and Vaccines
The current coronavirus COVID-19 pandemic, which originated in Wuhan, China, has raised significant social, psychological and economic concerns in addition to direct medical issues. The rapid spread of severe acute respiratory syndrome-coronavirus (SARS-CoV)-2 to almost every country on the globe and the failure to contain the infections have contributed to fear and panic worldwide. The lack of available and efficient antiviral drugs or vaccines has further worsened the situation. For these reasons, it cannot be overstated that an accelerated effort for the development of novel drugs and vaccines is needed. In this context, novel approaches in both gene therapy and vaccine development are essential. Previous experience from SARS- and MERS-coronavirus vaccine and drug development projects have targeted glycoprotein epitopes, monoclonal antibodies, angiotensin receptor blockers and gene silencing technologies, which may be useful for COVID-19 too. Moreover, existing antivirals used for other types of viral infections have been considered as urgent action is necessary. This review aims at providing a background of coronavirus genetics and biology, examples of therapeutic and vaccine strategies taken and potential innovative novel approaches in progress.
mt8zsbhb
mt8zsbhb
2020-05-03
10.3390/biomedicines8050109
4
Cell entry mechanisms of SARS-CoV-2
A novel severe acute respiratory syndrome (SARS)-like coronavirus (SARS-CoV-2) is causing the global coronavirus disease 2019 (COVID-19) pandemic. Understanding how SARS-CoV-2 enters human cells is a high priority for deciphering its mystery and curbing its spread. A virus surface spike protein mediates SARS-CoV-2 entry into cells. To fulfill its function, SARS-CoV-2 spike binds to its receptor human ACE2 (hACE2) through its receptor-binding domain (RBD) and is proteolytically activated by human proteases. Here we investigated receptor binding and protease activation of SARS-CoV-2 spike using biochemical and pseudovirus entry assays. Our findings have identified key cell entry mechanisms of SARS-CoV-2. First, SARS-CoV-2 RBD has higher hACE2 binding affinity than SARS-CoV RBD, supporting efficient cell entry. Second, paradoxically, the hACE2 binding affinity of the entire SARS-CoV-2 spike is comparable to or lower than that of SARS-CoV spike, suggesting that SARS-CoV-2 RBD, albeit more potent, is less exposed than SARS-CoV RBD. Third, unlike SARS-CoV, cell entry of SARS-CoV-2 is preactivated by proprotein convertase furin, reducing its dependence on target cell proteases for entry. The high hACE2 binding affinity of the RBD, furin preactivation of the spike, and hidden RBD in the spike potentially allow SARS-CoV-2 to maintain efficient cell entry while evading immune surveillance. These features may contribute to the wide spread of the virus. Successful intervention strategies must target both the potency of SARS-CoV-2 and its evasiveness.
mtgge7sw
mtgge7sw
2020
4.5
Insights on cross-species transmission of SARS-CoV-2 from structural modeling
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is responsible for the ongoing global pandemic that has infected more than 6 million people in more than 180 countries worldwide. Like other coronaviruses, SARS-CoV-2 is thought to have been transmitted to humans from wild animals. Given the scale and widespread geographical distribution of the current pandemic, the question emerges whether human-to-animal transmission is possible and if so, which animal species are most at risk. Here, we investigated the structural properties of several ACE2 orthologs bound to the SARS-CoV-2 spike protein. We found that species known not to be susceptible to SARS-CoV-2 infection have non-conservative mutations in several ACE2 amino acid residues that disrupt key polar and charged contacts with the viral spike protein. Our models also predict affinity-enhancing mutations that could be used to design ACE2 variants for therapeutic purposes. Finally, our study provides a blueprint for modeling viral-host protein interactions and highlights several important considerations when designing these computational studies and analyzing their results.
mtq6yh25
mtq6yh25
2020-06-05
10.1101/2020.06.05.136861
4
Prophylactic and therapeutic intranasal administration with an immunomodulator, Hiltonol® (Poly IC:LC), in a lethal SARS-CoV-infected BALB/c mouse model
Abstract Hiltonol®, (Poly IC:LC), a potent immunomodulator, is a synthetic, double-stranded polyriboinosinic-polyribocytidylic acid (poly IC) stabilized with Poly-L-lysine and carboxymethyl cellulose (LC). Hiltonol® was tested for efficacy in a lethal SARS-CoV-infected BALB/c mouse model. Hiltonol® at 5, 1, 0.5 or 0.25 mg/kg/day by intranasal (i.n.) route resulted in significant survival benefit when administered at selected times 24 h prior to challenge with a lethal dose of mouse-adapted severe acute respiratory syndrome coronavirus (SARS-CoV). The infected BALB/c mice receiving the Hiltonol® treatments were also significantly effective in protecting mice against weight loss due to infection (p < 0.001). Groups of 20 mice were dosed with Hiltonol® at 2.5 or 0.75 mg/kg by intranasal instillation 7, 14, and 21 days before virus exposure and a second dose was given 24 h later, prophylactic Hiltonol® treatments (2.5 mg/kg/day) were completely protective in preventing death, and in causing significant reduction in lung hemorrhage scores, lung weights and lung virus titers. Hiltonol® was also effective as a therapeutic when give up to 8 h post virus exposure; 100% of the-infected mice were protected against death when Hiltonol® was administered at 5 mg/kg/day 8 h after infection. Our data suggest that Hiltonol® treatment of SARS-CoV infection in mice leads to substantial prophylactic and therapeutic effects and could be used for treatment of other virus disease such as those caused by MERS-CoV a related coronavirus. These properties might be therapeutically advantageous if Hiltonol® is considered for possible clinical use.
mv7sk5aa
mv7sk5aa
2017-03-31
10.1016/j.antiviral.2016.12.007
4
Screening of drugs by FRET analysis identifies inhibitors of SARS-CoV 3CL protease
SARS-CoV 3CL protease is essential for viral protein processing and is regarded as a good drug target to prevent SARS-CoV replication. In the present study, we established a high-throughput FRET technique for screening for anti-SARS-CoV 3CL protease drugs. Of a thousand existing drugs examined, hexachlorophene was identified as the most potent in inhibiting SARS-CoV 3CL protease. Further characterization showed that it was effective at micromolar concentrations (K(i) = 4 μM). The binding mode was competitive, and the inhibitory effect was dependent on preincubation time. Two other drugs, triclosan and nelfinavir, were about 10 times less potent. The structure-based search and biological evaluation of various hexachlorophene analogues were described. These analogues gave optimal inhibitory activity against SARS-CoV 3CL protease with IC(50) values ranging from 7.6 to 84.5 μM. Optimization of hexachlorophene analogues was shown to provide several active 3CL protease inhibitors that function as potential anti-SARS agents.
mvkgqfkj
mvkgqfkj
2005-07-22
10.1016/j.bbrc.2005.05.095
1
Déjà vu: Stimulating open drug discovery for SARS-CoV-2
In the past decade we have seen two major Ebola virus outbreaks in Africa, the Zika virus in Brazil and the Americas and the current pandemic of coronavirus disease (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). There is a strong sense of déjà vu because there are still no effective treatments. In the COVID-19 pandemic, despite being a new virus, there are already drugs suggested as active in in vitro assays that are being repurposed in clinical trials. Promising SARS-CoV-2 viral targets and computational approaches are described and discussed. Here, we propose, based on open antiviral drug discovery approaches for previous outbreaks, that there could still be gaps in our approach to drug discovery.
mwf0fjua
mwf0fjua
2020-04-19
10.1016/j.drudis.2020.03.019
2
A study of non-prescription usage of antibiotics in the upper respiratory tract infections in the urban population
mwfr5tzf
mwfr5tzf
2013
10.4103/0976-500x.107687
4
An Effective CTL Peptide Vaccine for Ebola Zaire Based on Survivors’ CD8+ Targeting of a Particular Nucleocapsid Protein Epitope with Potential Implications for COVID-19 Vaccine Design
The 2013-2016 West Africa EBOV epidemic was the biggest EBOV outbreak to date. An analysis of virus-specific CD8+ T-cell immunity in 30 survivors showed that 26 of those individuals had a CD8+ response to at least one EBOV protein. The dominant response (25/26 subjects) was specific to the EBOV nucleocapsid protein (NP). It has been suggested that epitopes on the EBOV NP could form an important part of an effective T-cell vaccine for Ebola Zaire. We show that a 9-amino-acid peptide NP44-52 (YQVNNLEEI) located in a conserved region of EBOV NP provides protection against morbidity and mortality after mouse adapted EBOV challenge. A single vaccination in a C57BL/6 mouse using an adjuvanted microsphere peptide vaccine formulation containing NP44-52 is enough to confer immunity in mice. Our work suggests that a peptide vaccine based on CD8+ T-cell immunity in EBOV survivors is conceptually sound and feasible. Nucleocapsid proteins within SARS-CoV-2 contain multiple class I epitopes with predicted HLA restrictions consistent with broad population coverage. A similar approach to a CTL vaccine design may be possible for that virus.
mwnnmwnw
mwnnmwnw
2020-04-28
10.1016/j.vaccine.2020.04.034
3
Information Mining for COVID-19 Research From a Large Volume of Scientific Literature
The year 2020 has seen an unprecedented COVID-19 pandemic due to the outbreak of a novel strain of coronavirus in 180 countries. In a desperate effort to discover new drugs and vaccines for COVID-19, many scientists are working around the clock. Their valuable time and effort may benefit from computer-based mining of a large volume of health science literature that is a treasure trove of information. In this paper, we have developed a graph-based model using abstracts of 10,683 scientific articles to find key information on three topics: transmission, drug types, and genome research related to coronavirus. A subgraph is built for each of the three topics to extract more topic-focused information. Within each subgraph, we use a betweenness centrality measurement to rank order the importance of keywords related to drugs, diseases, pathogens, hosts of pathogens, and biomolecules. The results reveal intriguing information about antiviral drugs (Chloroquine, Amantadine, Dexamethasone), pathogen-hosts (pigs, bats, macaque, cynomolgus), viral pathogens (zika, dengue, malaria, and several viruses in the coronaviridae virus family), and proteins and therapeutic mechanisms (oligonucleotide, interferon, glycoprotein) in connection with the core topic of coronavirus. The categorical summary of these keywords and topics may be a useful reference to expedite and recommend new and alternative directions for COVID-19 research.
myu0e9vf
myu0e9vf
2020-04-05
2
Pre-existing and de novo humoral immunity to SARS-CoV-2 in humans
Several related human coronaviruses (HCoVs) are endemic in the human population, causing mild respiratory infections1. Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), the etiologic agent of Coronavirus disease 2019 (COVID-19), is a recent zoonotic infection that has quickly reached pandemic spread2,3. Zoonotic introduction of novel coronaviruses is thought to occur in the absence of pre-existing immunity in the target human population. Using diverse assays for detection of antibodies reactive with the SARS-CoV-2 Spike (S) glycoprotein, we demonstrate the presence of pre-existing immunity in uninfected and unexposed humans to the new coronavirus. SARS-CoV-2 S-reactive antibodies, exclusively of the IgG class, were readily detectable by a sensitive flow cytometry-based method in SARS-CoV-2-uninfected individuals with recent HCoV infection and targeted the S2 subunit. In contrast, SARS-CoV-2 infection induced higher titres of SARS-CoV-2 S-reactive IgG antibodies, as well as concomitant IgM and IgA antibodies throughout the observation period of 6 weeks since symptoms onset. HCoV patient sera also variably reacted with SARS-CoV-2 S and nucleocapsid (N), but not with the S1 subunit or the receptor binding domain (RBD) of S on standard enzyme immunoassays. Notably, HCoV patient sera exhibited specific neutralising activity against SARS-CoV-2 S pseudotypes, according to levels of SARS-CoV-2 S-binding IgG and with efficiencies comparable to those of COVID-19 patient sera. Distinguishing pre-existing and de novo antibody responses to SARS-CoV-2 will be critical for serology, seroprevalence and vaccine studies, as well as for our understanding of susceptibility to and natural course of SARS-CoV-2 infection.
n0actmsc
n0actmsc
2020-05-15
10.1101/2020.05.14.095414
4.5
Candidate drugs against SARS-CoV-2 and COVID-19
Abstract Outbreak and pandemic of coronavirus SARS-CoV-2 in 2019/2020 will challenge global health for the future. Because a vaccine against the virus will not be available in the near future, we herein try to offer a pharmacological strategy to combat the virus. There exists a number of candidate drugs that may inhibit infection with and replication of SARS-CoV-2. Such drugs comprise inhibitors of TMPRSS2 serine protease and inhibitors of angiotensin-converting enzyme 2 (ACE2). Blockade of ACE2, the host cell receptor for the S protein of SARS-CoV-2 and inhibition of TMPRSS2, which is required for S protein priming may prevent cell entry of SARS-CoV-2. Further, chloroquine and hydroxychloroquine, and off-label antiviral drugs, such as the nucleotide analogue remdesivir, HIV protease inhibitors lopinavir and ritonavir, broad-spectrum antiviral drugs arbidol and favipiravir as well as antiviral phytochemicals available to date may prevent spread of SARS-CoV-2 and morbidity and mortality of COVID-19 pandemic.
n0mz098o
n0mz098o
2020-04-29
10.1016/j.phrs.2020.104859
2
Induction of protective immunity against severe acute respiratory syndrome coronavirus (SARS-CoV) infection using highly attenuated recombinant vaccinia virus DIs
Abstract SARS-coronavirus (SARS-CoV) has recently been identified as the causative agent of SARS. We constructed a series of recombinant DIs (rDIs), a highly attenuated vaccinia strain, expressing a gene encoding four structural proteins (E, M, N and S) of SARS-CoV individually or simultaneously. These rDIs elicited SARS-CoV-specific serum IgG antibody and T-cell responses in vaccinated mice following intranasal or subcutaneous administration. Mice that were subcutaneously vaccinated with rDIs expressing S protein with or without other structural proteins induced a high level of serum neutralizing IgG antibodies and demonstrated marked protective immunity against SARS-CoV challenge in the absence of a mucosal IgA response. These results indicate that the potent immune response elicited by subcutaneous injection of rDIs containing S is able to control mucosal infection by SARS-CoV. Thus, replication-deficient DIs constructs hold promise for the development of a safe and potent SARS vaccine.
n1pkj68j
n1pkj68j
2006-08-01
10.1016/j.virol.2006.03.020
2
Potential inhibitors against papain-like protease of novel coronavirus (SARS-CoV-2) from FDA approved drugs
Licence: CC BY-NC-ND 4 0 Citation information: Arya, Rimanshee;Das, Amit;Prashar, Vishal;Kumar, Mukesh (2020): Potential inhibitors against papain-like protease of novel coronavirus (SARS-CoV-2) from FDA approved drugs ChemRxiv Preprint https://doi org/10 26434/chemrxiv 11860011 v2 The cases of 2019 novel coronavirus (SARS-CoV-2) infection have been continuously increasing ever since its outbreak in China last December Currently, there are no approved drugs to treat the infection In this scenario, there is a need to utilize the existing repertoire of FDA approved drugs to treat the disease The rational selection of these drugs could be made by testing their ability to inhibit any SARS-CoV-2 proteins essential for viral life-cycle We chose one such crucial viral protein, the papain-like protease (PLpro), to screen the FDA approved drugs in silico The homology model of the protease was built based on the SARS-coronavirus PLpro structure, and the drugs were docked in S3/S4 pockets of the active site of the enzyme In our docking studies, sixteen FDA approved drugs, including chloroquine and formoterol, was found to bind the target enzyme with significant affinity and good geometry, suggesting their potential to be utilized against the virus File list (1) download file view on ChemRxiv 2019-nCoV_final_draft2_ChemRxiv pdf (1 15 MiB) Abstract The cases of 2019 novel coronavirus (SARS-CoV-2) infection have been continuously increasing ever since its outbreak in China last December Currently, there are no approved drugs to treat the infection In this scenario, there is a need to utilize the existing repertoire of FDA approved drugs to treat the disease The rational selection of these drugs could be made by testing their ability to inhibit any SARS-CoV-2 proteins essential for viral life-cycle We chose one such crucial viral protein, the papain-like protease (PLpro), to screen the FDA approved drugs in silico The homology model of the protease was built based on the SARS-coronavirus PLpro structure, and the drugs were docked in S3/S4 pockets of the active site of the enzyme In our docking studies, sixteen FDA approved drugs, including chloroquine and formoterol, was found to bind the target enzyme with significant affinity and good geometry, suggesting their potential to be utilized against the virus
n2tckfjq
n2tckfjq
2020
10.26434/chemrxiv.11860011.v2
0.5
New Virus, New Challenge
The ongoing COVID-19 pandemic has made us to consider the emergence of potential viral diseases in the future. Animals can carry vast and diverse virus species, most of which we do not understand yet, and the spillover events of the viruses from the unknown pool in animals to human population always occurred in the past. To effectively prevent and control the emerging viral diseases, we should make efforts to explore the unknown virus species in nature and prepare in advance.
n4qh8vg4
n4qh8vg4
2020-05-21
10.1016/j.xinn.2020.04.005
4
siRNA targeting the Leader sequence of SARS-CoV inhibits virus replication
SARS-CoV (the SARS-Associated Coronavirus) was reported as a novel virus member in the coronavirus family, which was the cause of severe acute respiratory syndrome. Coronavirus replication occurs through a unique mechanism employing Leader sequence in the transcripts when initiating transcription from the genome. Therefore, we cloned the Leader sequence from SARS-CoV(BJ01), which is identical to that identified from SARS-CoV(HKU-39849), and constructed specific siRNA targeting the Leader sequence. Using EGFP and RFP reporter genes fused with the cloned SARS-CoV Leader sequence, we demonstrated that the siRNA targeting the Leader sequence decreased the mRNA abundance and protein expression levels of the reporter genes in 293T cells. By stably expressing the siRNA in Vero E6 cells, we provided data that the siRNA could effectively and specifically decrease the mRNA abundance of SARS-CoV genes as analyzed by RT-PCR and Northern blot. Our data indicated that the siRNA targeting the Leader sequence inhibited the replication of SARS-CoV in Vero E6 cells by silencing gene expression. We further demonstrated, via transient transfection experiments, that the siRNA targeting the Leader sequence had a much stronger inhibitory effect on SARS-CoV replication than the siRNAs targeting the Spike gene or the antisense oligodeoxynucleotides did. This report provides evidence that targeting Leader sequence using siRNA could be a powerful tool in inhibiting SARS-CoV replication.
n4r40yit
n4r40yit
2005-03-17
10.1038/sj.gt.3302479
2
Features, Evaluation and Treatment Coronavirus (COVID-19)
According to the World Health Organization (WHO), viral diseases continue to emerge and represent a serious issue to public health In the last twenty years, several viral epidemics such as the severe acute respiratory syndrome coronavirus (SARS-CoV) in 2002 to 2003, and H1N1 influenza in 2009, have been recorded Most recently, the Middle East respiratory syndrome coronavirus (MERS-CoV) was first identified in Saudi Arabia in 2012 In a timeline that reaches the present day, an epidemic of cases with unexplained low respiratory infections detected in Wuhan, the largest metropolitan area in China's Hubei province, was first reported to the WHO Country Office in China, on December 31, 2019 Published literature can trace the beginning of symptomatic individuals back to the beginning of December 2019 As they were unable to identify the causative agent, these first cases were classified as "pneumonia of unknown etiology " The Chinese Center for Disease Control and Prevention (CDC) and local CDCs organized an intensive outbreak investigation program The etiology of this illness is now attributed to a novel virus belonging to the coronavirus (CoV) family, COVID-19 On February 11, 2020, the WHO Director-General, Dr Tedros Adhanom Ghebreyesus, announced that the disease caused by this new CoV was a "COVID-19," which is the acronym of "coronavirus disease 2019" In the past twenty years, two additional coronavirus epidemics have occurred SARS-CoV provoked a large-scale epidemic beginning in China and involving two dozen countries with approximately 8000 cases and 800 deaths, and the MERS-CoV that began in Saudi Arabia and has approximately 2,500 cases and 800 deaths and still causes as sporadic cases This new virus seems to be very contagious and has quickly spread globally In a meeting on January 30, 2020, per the International Health Regulations (IHR, 2005), the outbreak was declared by the WHO a Public Health Emergency of International Concern (PHEIC) as it had spread to 18 countries with four countries reporting human-to-human transmission An additional landmark occurred on February 26, 2020, as the first case of the disease, not imported from China, was recorded in the United States Initially, the new virus was called 2019-nCoV Subsequently, the task of experts of the International Committee on Taxonomy of Viruses (ICTV) termed it the SARS-CoV-2 virus as it is very similar to the one that caused the SARS outbreak (SARS-CoVs) The CoVs have become the major pathogens of emerging respiratory disease outbreaks They are a large family of single-stranded RNA viruses (+ssRNA) that can be isolated in different animal species For reasons yet to be explained, these viruses can cross species barriers and can cause, in humans, illness ranging from the common cold to more severe diseases such as MERS and SARS Interestingly, these latter viruses have probably originated from bats and then moving into other mammalian hosts — the Himalayan palm civet for SARS-CoV, and the dromedary camel for MERS-CoV — before jumping to humans The dynamics of SARS-Cov-2 are currently unknown, but there is speculation that it also has an animal origin The potential for these viruses to grow to become a pandemic worldwide seems to be a serious public health risk Concerning COVID-19, the WHO raised the threat to the CoV epidemic to the "very high" level, on February 28, 2020 Probably, the effects of the epidemic caused by the new CoV has yet to emerge as the situation is quickly evolving World governments are at work to establish countermeasures to stem possible devastating effects Health organizations coordinate information flows and issues directives and guidelines to best mitigate the impact of the threat At the same time, scientists around the world work tirelessly, and information about the transmission mechanisms, the clinical spectrum of disease, new diagnostics, and prevention and therapeutic strategies are rapidly developing Many uncertainties remain with regard to both the virus-host interac ion and the evolution of the epidemic, with specific reference to the times when the epidemic will reach its peak At the moment, the therapeutic strategies to deal with the infection are only supportive, and prevention aimed at reducing transmission in the community is our best weapon Aggressive isolation measures in China have led to a progressive reduction of cases in the last few days In Italy, in geographic regions of the north of the peninsula, political and health authorities are making incredible efforts to contain a shock wave that is severely testing the health system In the midst of the crisis, the authors have chosen to use the "Statpearls" platform because, within the PubMed scenario, it represents a unique tool that may allow them to make updates in real-time The aim, therefore, is to collect information and scientific evidence and to provide an overview of the topic that will be continuously updated
n4v4n8d1
n4v4n8d1
2020
1.5
Conformational Flexibility of a Short Loop near the Active Site of the SARS-3CLpro is Essential to Maintain Catalytic Activity
The SARS 3C-like proteinase (SARS-3CLpro), which is the main proteinase of the SARS coronavirus, is essential to the virus life cycle. This enzyme has been shown to be active as a dimer in which only one protomer is active. However, it remains unknown how the dimer structure maintains an active monomer conformation. It has been observed that the Ser139-Leu141 loop forms a short 3(10)-helix that disrupts the catalytic machinery in the inactive monomer structure. We have tried to disrupt this helical conformation by mutating L141 to T in the stable inactive monomer G11A/R298A/Q299A. The resulting tetra-mutant G11A/L141T/R298A/Q299A is indeed enzymatically active as a monomer. Molecular dynamics simulations revealed that the L141T mutation disrupts the 3(10)-helix and helps to stabilize the active conformation. The coil-3(10)-helix conformational transition of the Ser139-Leu141 loop serves as an enzyme activity switch. Our study therefore indicates that the dimer structure can stabilize the active conformation but is not a required structure in the evolution of the active enzyme, which can also arise through simple mutations.
n69iewmx
n69iewmx
2016-02-16
10.1038/srep20918
2.5
Enisamium is a small molecule inhibitor of the influenza A virus and SARS-CoV-2 RNA polymerases
Influenza A virus and coronavirus strains cause a mild to severe respiratory disease that can result in death. Although vaccines exist against circulating influenza A viruses, such vaccines are ineffective against emerging pandemic influenza A viruses. Currently, no vaccine exists against coronavirus infections, including pandemic SARS-CoV-2, the causative agent of the Coronavirus Disease 2019 (COVID-19). To combat these RNA virus infections, alternative antiviral strategies are needed. A key drug target is the viral RNA polymerase, which is responsible for viral RNA synthesis. In January 2020, the World Health Organisation identified enisamium as a candidate therapeutic against SARS-CoV-2. Enisamium is an isonicotinic acid derivative that is an inhibitor of multiple influenza B and A virus strains in cell culture and clinically approved in 11 countries. Here we show using in vitro assays that enisamium and its putative metabolite, VR17-04, inhibit the activity of the influenza virus and the SARS-CoV-2 RNA polymerase. VR17-04 displays similar efficacy against the SARS-CoV-2 RNA polymerase as the nucleotide analogue remdesivir triphosphate. These results suggest that enisamium is a broad-spectrum small molecule inhibitor of RNA virus RNA synthesis, and implicate it as a possible therapeutic option for treating SARS-CoV-2 infection. Unlike remdesivir, enisamium does not require intravenous administration which may be advantageous for the development of COVID-19 treatments outside a hospital setting.
n7gfsyxs
n7gfsyxs
2020-01-06
10.1101/2020.04.21.053017
3
When Darkness Becomes a Ray of Light in the Dark Times: Understanding the COVID-19 via the Comparative Analysis of the Dark Proteomes of SARS-CoV-2, Human SARS and Bat SARS-Like Coronaviruses
Recently emerged coronavirus designated as SARS-CoV-2 (also known as 2019 novel coronavirus (2019-nCoV) or Wuhan coronavirus) is a causative agent of coronavirus disease 2019 (COVID-19), which is rapidly spreading throughout the world now. More than 9,00,000 cases of SARS-CoV-2 infection and more than 47,000 COVID-19-associated mortalities have been reported worldwide till the writing of this article, and these numbers are increasing every passing hour. World Health Organization (WHO) has declared the SARS-CoV-2 spread as a global public health emergency and admitted that the COVID-19 is a pandemic now. The multiple sequence alignment data correlated with the already published reports on the SARS-CoV-2 evolution and indicated that this virus is closely related to the bat Severe Acute Respiratory Syndrome-like coronavirus (bat SARS-like CoV) and the well-studied Human SARS coronavirus (SARS CoV). The disordered regions in viral proteins are associated with the viral infectivity and pathogenicity. Therefore, in this study, we have exploited a set of complementary computational approaches to examine the dark proteomes of SARS-CoV-2, bat SARS-like, and human SARS CoVs by analysing the prevalence of intrinsic disorder in their proteins. According to our findings, SARS-CoV-2 proteome contains very significant levels of structural order. In fact, except for Nucleocapsid, Nsp8, and ORF6, the vast majority of SARS-CoV-2 proteins are mostly ordered proteins containing less intrinsically disordered protein regions (IDPRs). However, IDPRs found in SARS-CoV-2 proteins are functionally important. For example, cleavage sites in its replicase 1ab polyprotein are found to be highly disordered, and almost all SARS-CoV-2 proteins were shown to contain molecular recognition features (MoRFs), which are intrinsic disorder-based protein-protein interaction sites that are commonly utilized by proteins for interaction with specific partners. The results of our extensive investigation of the dark side of the SARS-CoV-2 proteome will have important implications for the structural and non-structural biology of SARS or SARS-like coronaviruses. Significance The infection caused by a novel coronavirus (SARS-CoV-2) that causes severe respiratory disease with pneumonia-like symptoms in humans is responsible for the current COVID-19 pandemic. No in-depth information on structures and functions of SARS-CoV-2 proteins is currently available in the public domain, and no effective anti-viral drugs and/or vaccines are designed for the treatment of this infection. Our study provides the first comparative analysis of the order- and disorder-based features of the SARS-CoV-2 proteome relative to human SARS and bat CoV that may be useful for structure-based drug discovery.
n7ylgqfu
n7ylgqfu
2020-04-03
10.1101/2020.03.13.990598
1
Can the Coronavirus Disease 2019 (COVID-19) Affect the Eyes? A Review of Coronaviruses and Ocular Implications in Humans and Animals
In December 2019, a novel coronavirus (CoV) epidemic, caused by the severe acute respiratory syndrome coronavirus – 2 (SARS-CoV-2) emerged from China. This virus causes the coronavirus disease 2019 (COVID-19). Since then, there have been anecdotal reports of ocular infection. The ocular implications of human CoV infections have not been widely studied. However, CoVs have been known to cause various ocular infections in animals. Clinical entities such as conjunctivitis, anterior uveitis, retinitis, and optic neuritis have been documented in feline and murine models. In this article, the current evidence suggesting possible human CoV infection of ocular tissue is reviewed. The review article will also highlight animal CoVs and their associated ocular infections. We hope that this article will serve as a start for further research into the ocular implications of human CoV infections.
n8fwy791
n8fwy791
2020-03-16
10.1080/09273948.2020.1738501
1
Literature-related discovery: Potential treatments and preventatives for SARS
Abstract Literature-related discovery (LRD) is the linking of two or more previously disjoint concepts in order to produce novel, interesting, plausible, and intelligible connections (i.e., potential discovery). LRD has been used to identify potential treatments or preventative actions for challenging medical problems, among myriad other applications. Severe acute respiratory syndrome (SARS) was the first pandemic of the 21st century. SARS was eventually controlled through increased hygienic measures (e.g., face mask protection, frequent hand washing, living quarter disinfection), travel restrictions, and quarantine. According to recent reviews of SARS, none of the drugs that were used during the pandemic worked. For the present paper, SARS was selected as the first application of LRD to an infectious disease. The main goal of this research was to identify non-drug non-surgical treatments that would 1) prevent the occurrence, or 2) reduce the progression rate, or 3) stop/reverse the progression of SARS. The MeSH taxonomy of Medline was used to restrict potential discoveries to selected semantic classes, and to identify potential discoveries efficiently. To enhance the volume of potential discovery, databases were used in addition to Medline. These included the Science Citation Index (SCI) and, in contrast to previous work, a full text database. Because of the richness of the full text, ‘surgical’ queries were developed that targeted the exact types of potential discovery of interest while eliminating clutter more efficiently.
n8tvglif
n8tvglif
2011-09-30
10.1016/j.techfore.2011.03.022
0.5
COVID-19: an Immunopathological View
Since its emergence in December 2019, it took only a couple of months for an outbreak of the novel coronavirus disease 2019 (COVID-19) to be declared a pandemic by the World Health Organization (WHO). This along with the highly infectious nature of the disease and the associated mortality call for particular attention to the underlying (immuno)pathomechanism(s). The latter will inform case management and vaccine design. Unravelling these mechanisms can assist basic scientists, laboratory medicine practitioners, clinicians, public health practitioners, funding agencies, and health care policymakers in responding to the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic.
n92atcrx
n92atcrx
2020-04-22
10.1128/msphere.00344-20
2.5
Un nuevo coronavirus emerge
n9l86dln
n9l86dln
2020-03-31
10.1016/j.rce.2020.01.001
1.5
Might renin–angiotensin system blockers play a role in the COVID-19 pandemic?
Since December 2019, a new coronavirus, named SARS-CoV-2, has spread globally, affecting >200 000 people worldwide with the so-called COVID-19 disease. The scientific community is actively and constantly working to identify the mechanisms involved in the diffusion of this virus and the pathogenesis of the infection, with its most frequent and severe complication, namely interstitial pneumonia. To date, SARS-CoV-2 is known to enter the host cells via the angiotensin-converting enzyme 2 protein. For this reason, the hypothesis that drugs capable of increasing the expression of this protein may have a role in the spread of the virus and in the symptomatology of affected patients has taken hold. The purpose of this Editorial is to briefly show the evidence currently available in this regard and to provide ideas for future research.
naulq6q7
naulq6q7
2020-04-14
10.1093/ehjcvp/pvaa030
3
Immune responses in Balb/c mice induced by a candidate SARS-CoV inactivated vaccine prepared from F69 strain
The immunogenicity of a candidate-inactivated vaccine prepared from SARS-CoV F69 strain was evaluated in Balb/c mice. Potent humoral immune responses were induced under the elicitation of three times of immunizations at 2-week intervals with this vaccine, combined with three types of adjuvants (Freund's adjuvant, Al(OH)(3) adjuvant and CpG adjuvant). Titers of specific IgG antibodies in three test groups all peaked in the sixth week after first vaccination, but significant differences existed in the kinetics of specific IgG antibody levels. The strong neutralizing capacity exhibited in micro-cytopathic effect neutralization tests indicated the specific antibodies are protective. Western blot assay further demonstrated the specificity of the induced serum antibodies.
nb6miso7
nb6miso7
2005-05-02
10.1016/j.vaccine.2004.11.073
1.5
Saliva: potential diagnostic value and transmission of 2019-nCoV
2019-nCoV epidemic was firstly reported at late December of 2019 and has caused a global outbreak of COVID-19 now. Saliva, a biofluid largely generated from salivary glands in oral cavity, has been reported 2019-nCoV nucleic acid positive. Besides lungs, salivary glands and tongue are possibly another hosts of 2019-nCoV due to expression of ACE2. Close contact or short-range transmission of infectious saliva droplets is a primary mode for 2019-nCoV to disseminate as claimed by WHO, while long-distance saliva aerosol transmission is highly environment dependent within indoor space with aerosol-generating procedures such as dental practice. So far, no direct evidence has been found that 2019-nCoV is vital in air flow for long time. Therefore, to prevent formation of infectious saliva droplets, to thoroughly disinfect indoor air and to block acquisition of saliva droplets could slow down 2019-nCoV dissemination. This review summarizes diagnostic value of saliva for 2019-nCoV, possibly direct invasion into oral tissues, and close contact transmission of 2019-nCoV by saliva droplets, expecting to contribute to 2019-nCoV epidemic control.
nbzi0bvc
nbzi0bvc
2020-04-17
10.1038/s41368-020-0080-z
2.5
A mouse-adapted SARS-CoV-2 model for the evaluation of COVID-19 medical countermeasures
Coronaviruses are prone to emergence into new host species most recently evidenced by SARS-CoV-2, the causative agent of the COVID-19 pandemic. Small animal models that recapitulate SARS-CoV-2 disease are desperately needed to rapidly evaluate medical countermeasures (MCMs). SARS-CoV-2 cannot infect wildtype laboratory mice due to inefficient interactions between the viral spike (S) protein and the murine ortholog of the human receptor, ACE2. We used reverse genetics to remodel the S and mACE2 binding interface resulting in a recombinant virus (SARS-CoV-2 MA) that could utilize mACE2 for entry. SARS-CoV-2 MA replicated in both the upper and lower airways of both young adult and aged BALB/c mice. Importantly, disease was more severe in aged mice, and showed more clinically relevant phenotypes than those seen in hACE2 transgenic mice. We then demonstrated the utility of this model through vaccine challenge studies in immune competent mice with native expression of mACE2. Lastly, we show that clinical candidate interferon (IFN) lambda-1a can potently inhibit SARS-CoV-2 replication in primary human airway epithelial cells in vitro, and both prophylactic and therapeutic administration diminished replication in mice. Our mouse-adapted SARS-CoV-2 model demonstrates age-related disease pathogenesis and supports the clinical use of IFN lambda-1a treatment in human COVID-19 infections.
nc0bsilq
nc0bsilq
2020-05-07
10.1101/2020.05.06.081497
3
Comparison of the COVID-2019 (SARS-CoV-2) pathogenesis with SARS-CoV and MERS-CoV infections
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), was first identified in several patients who traveled to Wuhan or went to a seafood wholesale market in Wuhan. The phylogenetic tree showed that SARS-CoV-2 was 96.2% identical to bat β-coronaviruses from lineage B. Also, several studies reported that SARS-CoV-2 uses the SARS-CoV receptor, angiotensin-converting enzyme 2, for entry to target cells. Lung alveolar and small intestine are potential targets for SARS-CoV-2 due to the high expression of the angiotensin-converting enzyme 2 receptor. In this review, we focused on the zoonotic β-coronaviruses and given there is no specific drug or vaccine for coronavirus disease 2019, we reviewed the literature on the therapy options for SARS and Middle East respiratory syndrome coronavirus infection, in order to discover their possible use in the treatment of SARS-CoV-2 infections.
ncl2p7kg
ncl2p7kg
2020-05-20
10.2217/fvl-2020-0050
4
Serology characteristics of SARS-CoV-2 infection since the exposure and post symptoms onset
Background Timely diagnosis of SARS-CoV-2 infection is the prerequisite for treatment and preventive quarantine. The serology characteristics and complement diagnosis value of antibody test to RNA test needs to be demonstrated. Method A patient cohort study was conducted at the first affiliated hospital of Zhejiang University, China. Serial sera of COVID-19 patients were collected and total antibody (Ab), IgM and IgG antibody against SARS-CoV-2 were detected. The antibody dynamics during the infection were described. Results The seroconversion rate for Ab, IgM and IgG in COVID-19 patients was 98.8% (79/80), 93.8% (75/80) and 93.8% (75/80), respectively. The first detectible serology marker is total antibody and followed by IgM and IgG, with a median seroconversion time of 15, 18 and 20 day post exposure (d.p.e) or 9, 10 and 12 days post onset, separately. The antibody levels increased rapidly since 6 d.p.o and accompanied with the decline of viral load. For patients in the early stage of illness (0-7d.p.o),Ab showed the highest sensitivity (64.1%) compared to the IgM and IgG (33.3% for both, p<0.001). The sensitivities of Ab, IgM and IgG detection increased to 100%, 96.7% and 93.3% two weeks later, respectively. Conclusions Typical acute antibody response is induced during the SARS-CoV-2 infection. The serology testing provides important complementation to RNA test for pathogenic specific diagnosis and helpful information to evaluate the adapted immunity status of patient. It should be strongly recommended to apply well-validated antibody tests in the clinical management and public health practice to improve the control of COVID-19 infection.
ndpuezpo
ndpuezpo
2020-03-27
10.1101/2020.03.23.20041707
1.5
In vitro screening antiviral activity of Thai medicinal plants against porcine reproductive and respiratory syndrome virus
BACKGROUND: Porcine reproductive and respiratory syndrome (PRRS) caused by PRRS virus (PRRSV) results in economic losses in the swine industry globally. Several studies have investigated the use of plant extracts in the prevention and control of PRRS outbreaks. Thai medicinal plants may be useful for treating PRRSV infection in pigs. Therefore, we investigated the in vitro anti-PRRSV and antioxidant properties of seven Thai medicinal plants: Caesalpinia sappan Linn., Garcinia mangostana Linn., Houttuynia cordata, Perilla frutescens, Clinacanthus nutans, Phyllanthus emblica, and Tiliacora triandra. RESULTS: Using antiviral screening, we observed that T. triandra extract strongly inhibited PRRSV infectivity in MARC-145 cells [virus titer 3.5 median tissue culture infective dose (TCID(50))/ml (log10)] at 24 h post-infection, whereas C. sappan extract strongly inhibited PRRSV replication [virus titer 2.5 TCID(50)/ml (log10)] at 72 h post-infection. C. sappan extract had the highest total phenolic content [220.52 mM gallic acid equivalent/g] and lowest half-maximal inhibitory concentration [1.17 mg/ml in 2,2-diphenyl-1-picrylhydrazyl and 2.58 mg/ml in 2,2-azino-bis (3-ethylbenzothiazo-line-6-sulfonic acid) diammonium salt]. CONCLUSION: T. triandra extract could inhibit PRRSV infectivity, whereas C. sappan extract was the most effective in inhibiting PRRSV replication in MARC-145 cells. This study elucidates the antiviral activities of Thai medicinal plant extracts in vivo. The results promise that Thai medicinal plant extracts, particularly T. triandra and C. sappan extracts, can be developed into pharmaceutical drugs for the prevention of PRRS in pigs.
ndrja7os
ndrja7os
2020-03-30
10.1186/s12917-020-02320-8
4.5
Origin and evolution of pathogenic coronaviruses
Severe acute respiratory syndrome coronavirus (SARS-CoV) and Middle East respiratory syndrome coronavirus (MERS-CoV) are two highly transmissible and pathogenic viruses that emerged in humans at the beginning of the 21st century. Both viruses likely originated in bats, and genetically diverse coronaviruses that are related to SARS-CoV and MERS-CoV were discovered in bats worldwide. In this Review, we summarize the current knowledge on the origin and evolution of these two pathogenic coronaviruses and discuss their receptor usage; we also highlight the diversity and potential of spillover of bat-borne coronaviruses, as evidenced by the recent spillover of swine acute diarrhoea syndrome coronavirus (SADS-CoV) to pigs.
ne5r4d4b
ne5r4d4b
2018-12-10
10.1038/s41579-018-0118-9
3
Development of human neutralizing monoclonal antibodies for prevention and therapy of MERS-CoV infections
The recent Middle East respiratory syndrome coronavirus (MERS-CoV) outbreak poses a serious threat to public health. Here, we summarize recent advances in identifying human neutralizing monoclonal antibodies (mAbs) against MERS-CoV, describe their mechanisms of action, and analyze their potential for treatment of MERS-CoV infections.
nf085z53
nf085z53
2015-02-01
10.1016/j.micinf.2014.11.008
2.5
Eosinopenia and elevated C-reactive protein facilitate triage of COVID-19 patients in fever clinic: a retrospective case-control study
Abstract Background Coronavirus disease (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is currently a pandemic affecting over 200 countries. Many cities have established designated fever clinics to triage suspected COVID-19 patients from other patients with similar symptoms. However, given the limited availability of the nucleic acid test as well as long waiting time for both the test and radiographic examination, the quarantine or therapeutic decisions for a large number of mixed patients were often not made in time. We aimed to identify simple and quickly available laboratory biomarkers to facilitate effective triage at the fever clinics for sorting suspected COVID-19 patients from those with COVID-19-like symptoms. Methods We collected clinical, etiological, and laboratory data of 989 patients who visited the Fever Clinic at Wuhan Union Hospital, Wuhan, China, from Jan 31 to Feb 21. Based on polymerase chain reaction (PCR) nucleic acid testing for SARS-CoV-2 infection, they were divided into two groups: SARS-CoV-2-positive patients as cases and SARS-CoV-2-negative patients as controls. We compared the clinical features and laboratory findings of the two groups, and analyzed the diagnostic performance of several laboratory parameters in predicting SARS-CoV-2 infection and made relevant comparisons to the China diagnosis guideline of having a normal or decreased number of leukocytes (≤9•5 109/L) or lymphopenia (<1•1 109/L). Findings Normal or decreased number of leukocytes (≤9•5 109/L), lymphopenia (<1•1 109/L), eosinopenia (<0•02 109/L), and elevated hs-CRP (≥4 mg/L) were presented in 95•0%, 52•2%, 74•7% and 86•7% of COVID-19 patients, much higher than 87•2%, 28•8%, 31•3% and 45•2% of the controls, respectively. The eosinopenia produced a sensitivity of 74•7% and specificity of 68•7% for separating the two groups with the area under the curve (AUC) of 0•717. The combination of eosinopenia and elevated hs-CRP yielded a sensitivity of 67•9% and specificity of 78•2% (AUC=0•730). The addition of eosinopenia alone or the combination of eosinopenia and elevated hs-CRP into the guideline-recommended diagnostic parameters for COVID-19 improved the predictive capacity with higher than zero of both net reclassification improvement (NRI) and integrated discrimination improvement (IDI). Interpretation The combination of eosinopenia and elevated hs-CRP can effectively triage suspected COVID-19 patients from other patients attending the fever clinic with COVID-19-like initial symptoms. This finding would be particularly useful for designing triage strategies in an epidemic region having a large number of patients with COVID-19 and other respiratory diseases while limited medical resources for nucleic acid tests and radiographic examination. Funding This work was supported by the National Natural Science Foundation of China (NSFC) and the Major Scientific and Technological Innovation Projects of Hubei Province (MSTIP).
nf2vd6o1
nf2vd6o1
2020-05-03
10.1016/j.eclinm.2020.100375
3
Propagation analysis and prediction of the COVID-19
Based on the official data modeling, this paper studies the transmission process of the Corona Virus Disease 2019 (COVID-19). The error between the model and the official data curve is within 3%. At the same time, it realized forward prediction and backward inference of the epidemic situation, and the relevant analysis help relevant countries to make decisions.
nf51yjmj
nf51yjmj
2020-03-18
10.1101/2020.03.14.20036202
1.5
Occupational Animal Contact in Southern and Central Vietnam
Despite the global zoonotic disease burden, the underlying exposures that drive zoonotic disease emergence are not understood. Here, we aimed to assess exposures to potential sources of zoonotic disease and investigate the demographics, attitudes, and behavior of individuals with sustained occupational animal contact in Vietnam. We recruited 581 animal workers (animal-raising farmers, slaughterers, animal health workers, and rat traders) and their families in southern and central Vietnam into a cohort. Cohort members were followed for 3 years and interviewed annually regarding (1) demography and attitudes regarding zoonotic disease, (2) medical history, (3) specific exposures to potential zoonotic infection sources, and (4) socioeconomic status. Interview information over the 3 years was combined and analyzed as cross-sectional data. Of the 297 cohort members interviewed, the majority (79.8%; 237/297) reported raising livestock; almost all (99.6%; 236/237) reported being routinely exposed to domestic animals, and more than a quarter (28.7%; 68/237) were exposed to exotic animals. Overall, 70% (208/297) reported slaughtering exotic animals; almost all (99.5%; 207/208) reported consuming such animals. The consumption of raw blood and meat was common (24.6%; 73/297 and 37%; 110/297, respectively). Over half (58.6%; 174/297) reported recent occupational animal-induced injuries that caused bleeding; the use of personal protective equipment (PPE) was limited. Our work demonstrates that individuals working with animals in Vietnam are exposed to a wide range of species, and there are limited procedures for reducing potential zoonotic disease exposures. We advocate better education, improved animal security, and enforced legislation of PPE for those with occupational animal exposure in Vietnam.
ngby52hd
ngby52hd
2019-11-13
10.1007/s10393-019-01444-0
5
Dynamic Modeling to Identify Mitigation Strategies for Covid-19 Pandemic
Relevant pandemic-spread scenario simulations provide guiding principles for containment and mitigation policy developments. Here we devise a simple model to predict the effectiveness of different mitigation strategies. The model consists of a set of simple differential equations considering the population size, reported and unreported infections, reported and unreported recoveries and the number of Covid-19-inflicted deaths. For simplification, we assume that Covid-19 survivors are immune (e.g. mutations are not considered) and that the virus can only be passed on by persons with undetected infections. While the latter assumption is a simplification (it is neglected that e.g. hospital staff may be infected by detected patients with symptoms), it was introduced here to keep the model as simple as possible. Moreover, the current version of the model does not account for age-dependent differences in the death rates, but considers higher mortality rates due to temporary shortage of intensive care units. Some of the model parameters have been fitted to the reported cases outside of China1 from January 22 to March 12 of the 2020 Covid-19 pandemic. The other parameters were chosen in a plausible range to the best of our knowledge. We compared infection rates, the total number of people getting infected and the number of deaths in six different scenarios. Social distancing or increased testing can contain or drastically reduce the infections and the predicted number of deaths when compared to a situation without mitigation. We find that mass-testing alone and subsequent isolation of detected cases can be an effective mitigation strategy, alone and in combination with social distancing. However, unless one assumes that the virus can be globally defeated by reducing the number of infected persons to zero, testing must be upheld, albeit at reduced intensity, to prevent subsequent waves of infection. The model suggests that testing strategies can be equally effective as social distancing, though at much lower economical costs. We discuss how our mathematical model may help to devise an optimal mix of mitigation strategies against the Covid-19 pandemic. The website corona-lab.ch provides an interactive simulation tool based on the presented model.
ngsstnpr
ngsstnpr
2020-03-30
10.1101/2020.03.27.20045237
1.5
Nosocomial Transmission of Emerging Viruses via Aerosol-Generating Medical Procedures
Recent nosocomial transmission events of emerging and re-emerging viruses, including Ebola virus, Middle East respiratory syndrome coronavirus, Nipah virus, and Crimean–Congo hemorrhagic fever orthonairovirus, have highlighted the risk of nosocomial transmission of emerging viruses in health-care settings. In particular, concerns and precautions have increased regarding the use of aerosol-generating medical procedures when treating patients with such viral infections. In spite of increasing associations between aerosol-generating medical procedures and the nosocomial transmission of viruses, we still have a poor understanding of the risks of specific procedures and viruses. In order to identify which aerosol-generating medical procedures and emerging viruses pose a high risk to health-care workers, we explore the mechanisms of aerosol-generating medical procedures, as well as the transmission pathways and characteristics of highly pathogenic viruses associated with nosocomial transmission. We then propose how research, both in clinical and experimental settings, could advance current infection control guidelines.
nhg4jesr
nhg4jesr
2019-10-12
10.3390/v11100940
1
SARS-CoV-2 and SARS-CoV Spike-RBD Structure and Receptor Binding Comparison and Potential Implications on Neutralizing Antibody and Vaccine Development
SARS-CoV-2 and SARS-CoV share a common human receptor ACE2. Protein-protein interaction structure modeling indicates that spike-RBD of the two viruses also has similar overall binding conformation and binding free energy to ACE2. In vitro assays using recombinant ACE2 proteins and ACE2 expressing cells confirmed the two coronaviruses’ similar binding affinities to ACE2. The above studies provide experimental supporting evidences and possible explanation for the high transmissibility observed in the SARS-CoV-2 outbreak. Potent ACE2-blocking SARS-CoV neutralizing antibodies showed limited cross-binding and neutralizing activities to SARS-CoV-2. ACE2-non-blocking SARS-CoV RBD antibodies, though with weaker neutralizing activities against SARS-CoV, showed positive cross-neutralizing activities to SARS-CoV-2 with an unknown mechanism. These findings suggest a trade-off between the efficacy and spectrum for therapeutic antibodies to different coronaviruses, and hence highlight the possibilities and challenges in developing broadly protecting antibodies and vaccines against SARS-CoV-2 and its future mutants.
nhq0oq8y
nhq0oq8y
2020-02-20
10.1101/2020.02.16.951723
2.5
Covid-19 and the angiotensin-converting enzyme (ACE2): Areas for research
nhvho1iw
nhvho1iw
2020-04-20
10.1016/j.hrtlng.2020.04.012
3
Improved Molecular Diagnosis of COVID-19 by the Novel, Highly Sensitive and Specific COVID-19-RdRp/Hel Real-Time Reverse Transcription-PCR Assay Validated In Vitro and with Clinical Specimens
On 31 December 2019, the World Health Organization was informed of a cluster of cases of pneumonia of unknown etiology in Wuhan, China. Subsequent investigations identified a novel coronavirus, now named severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), from the affected patients. Highly sensitive and specific laboratory diagnostics are important for controlling the rapidly evolving SARS-CoV-2-associated coronavirus disease 2019 (COVID-19) epidemic. In this study, we developed and compared the performance of three novel real-time reverse transcription-PCR (RT-PCR) assays targeting the RNA-dependent RNA polymerase (RdRp)/helicase (Hel), spike (S), and nucleocapsid (N) genes of SARS-CoV-2 with that of the reported RdRp-P2 assay, which is used in >30 European laboratories. Among the three novel assays, the COVID-19-RdRp/Hel assay had the lowest limit of detection in vitro (1.8 50% tissue culture infective doses [TCID(50)]/ml with genomic RNA and 11.2 RNA copies/reaction with in vitro RNA transcripts). Among 273 specimens from 15 patients with laboratory-confirmed COVID-19 in Hong Kong, 77 (28.2%) were positive by both the COVID-19-RdRp/Hel and RdRp-P2 assays. The COVID-19-RdRp/Hel assay was positive for an additional 42 RdRp-P2-negative specimens (119/273 [43.6%] versus 77/273 [28.2%]; P < 0.001), including 29/120 (24.2%) respiratory tract specimens and 13/153 (8.5%) non-respiratory tract specimens. The mean viral load of these specimens was 3.21 × 10(4) RNA copies/ml (range, 2.21 × 10(2) to 4.71 × 10(5) RNA copies/ml). The COVID-19-RdRp/Hel assay did not cross-react with other human-pathogenic coronaviruses and respiratory pathogens in cell culture and clinical specimens, whereas the RdRp-P2 assay cross-reacted with SARS-CoV in cell culture. The highly sensitive and specific COVID-19-RdRp/Hel assay may help to improve the laboratory diagnosis of COVID-19.
njne526i
njne526i
2020-04-23
10.1128/jcm.00310-20
3.5
Age-dependent progression of SARS-CoV-2 infection in Syrian hamsters
In late 2019, an outbreak of a severe respiratory disease caused by an emerging coronavirus, SARS-CoV-2, resulted in high morbidity and mortality in infected humans1. Complete understanding of COVID-19, the multi-faceted disease caused by SARS-CoV-2, requires suitable small animal models, as does the development and evaluation of vaccines and antivirals2. Because age-dependent differences of COVID-19 were identified in humans3, we compared the course of SARS-CoV-2 infection in young and aged Syrian hamsters. We show that virus replication in the upper and lower respiratory tract was independent of the age of the animals. However, older hamsters exhibited more pronounced and consistent weight loss. In situ hybridization in the lungs identified viral RNA in bronchial epithelium, alveolar epithelial cells type I and II, and macrophages. Histopathology revealed clear age-dependent differences, with young hamsters launching earlier and stronger immune cell influx than aged hamsters. The latter developed conspicuous alveolar and perivascular edema, indicating vascular leakage. In contrast, we observed rapid lung recovery at day 14 after infection only in young hamsters. We propose that comparative assessment in young versus aged hamsters of SARS-CoV-2 vaccines and treatments may yield valuable information as this small-animal model appears to mirror age-dependent differences in human patients.
nk0qqofq
nk0qqofq
2020-06-10
10.1101/2020.06.10.144188
4
Currently prescribed drugs in the UK that could up or downregulate ACE2 in COVID-19 disease: A systematic review
Objective: To review evidence on routinely prescribed drugs in the UK that could up or downregulate Angiotensin Converting Enzyme 2 (ACE2) and potentially affect COVID-19 disease Design: Systematic review Data source: MEDLINE, EMBASE, CINAHL, the Cochrane Library and Web of Science Study selection: Any design with animal or human models examining a currently prescribed UK drug compared to a control, placebo or sham group, and reporting an effect on ACE2 level, activity or gene expression. Data extraction and synthesis: MEDLINE, EMBASE, CINAHL, the Cochrane Library, Web of Science and OpenGrey from inception to 1st April 2020. Methodological quality was assessed using the SYRCLE's risk of bias tool for animal studies and Cochrane risk of bias tool for human studies. Results: We screened 3,360 titles and included 112 studies with 21 different drug classes identified as influencing ACE2 activity. Ten studies were in humans and 102 were in animal models None examined ACE2 in human lungs. The most frequently examined drugs were Angiotensin Receptor Blockers (ARBs) (n= 55) and Angiotensin-Converting Enzyme- Inhibitors (ACE-I) (n= 22). More studies reported upregulation than downregulation with ACE-I (n=22), ARBs (n=55), insulin (n=8), thiazolidinedione (n=7) aldosterone agonists (n=3), statins (n=5), oestrogens (n=5) calcium channel-blockers (n=3) GLP-1 agonists (n=2) and NSAIDs (n=2). Conclusions: There is an abundance of academic literature and media reports on the potential of drugs that could attenuate or exacerbate COVID-19 disease. This is leading to trials of repurposed drugs and uncertainty amongst patients and clinicians concerning continuation or cessation of prescribed medications. Our review indicates that the impact of currently prescribed drugs on ACE2 has been poorly studied in-vivo, particularly in human lungs where the SARS-CoV-2 virus appears to enact its pathogenic effects. We found no convincing evidence to justify starting or stopping currently prescribed drugs to influence outcomes of COVID-19 disease.
nkc5dxw5
nkc5dxw5
2020-05-26
10.1101/2020.05.19.20106856
4
Susceptibility of ferrets, cats, dogs, and other domesticated animals to SARS-coronavirus 2
Severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) causes the infectious disease COVID-19 (coronavirus disease 2019), which was first reported in Wuhan, China, in December 2019. Despite extensive efforts to control the disease, COVID-19 has now spread to more than 100 countries and caused a global pandemic. SARS-CoV-2 is thought to have originated in bats; however, the intermediate animal sources of the virus are unknown. In this study, we investigated the susceptibility of ferrets and animals in close contact with humans to SARS-CoV-2. We found that SARS-CoV-2 replicates poorly in dogs, pigs, chickens, and ducks, but ferrets and cats are permissive to infection. Additionally, cats are susceptible to airborne transmission. Our study provides insights into the animal models for SARS-CoV-2 and animal management for COVID-19 control.
nm2ubi13
nm2ubi13
2020
3
The hallmarks of COVID-19 disease
Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is a novel coronavirus that has caused a worldwide pandemic of the human respiratory illness COVID-19, resulting in a severe threat to public health and safety. Analysis of the genetic tree suggests that SARS-CoV-2 belongs to the same Betacoronavirus group as severe acute respiratory syndrome coronavirus (SARS-CoV) and Middle East respiratory syndrome coronavirus (MERS-CoV). Although the route for viral transmission remains a mystery, SARS-CoV-2 may have originated in an animal reservoir, likely that of bat. The clinical features of COVID-19, such as fever, cough, shortness of breath, and fatigue, are similar to those of many acute respiratory infections. There is currently no specific treatment for COVID-19, but antiviral therapy combined with supportive care is the main strategy. Here, we summarize recent progress in understanding the epidemiological, virological, and clinical characteristics of COVID-19 and discuss potential targets with existing drugs for the treatment of this emerging zoonotic disease.
nm6nu8pj
nm6nu8pj
2020-05-22
10.1371/journal.ppat.1008536
4
Recommendations for coronavirus infection in rheumatic diseases treated with biologic therapy
Abstract The Coronavirus-associated disease, that was first identified in 2019 in China (CoViD-19), is a pandemic caused by a bat-derived beta-coronavirus, named SARS-CoV2. It shares homology with SARS and MERS-CoV, responsible for past outbreaks in China and in Middle East. SARS-CoV2 spread from China where the first infections were described in December 2019 and is responsible for the respiratory symptoms that can lead to acute respiratory distress syndrome. A cytokine storm has been shown in patients who develop fatal complications, as observed in past coronavirus infections. The management includes ventilatory support and broad-spectrum antiviral drugs, empirically utilized, as a targeted therapy and vaccines have not been developed. Based upon our limited knowledge on the pathogenesis of CoViD-19, a potential role of some anti-rheumatic drugs may be hypothesized, acting as direct antivirals or targeting host immune response. Antimalarial drugs, commonly used in rheumatology, may alter the lysosomal proteases that mediates the viral entry into the cell and have demonstrated efficacy in improving the infection. Anti-IL-1 and anti-IL-6 may interfere with the cytokine storm in severe cases and use of tocilizumab has shown good outcomes in a small cohort. Baricitinib has both antiviral and anti-inflammatory properties. Checkpoints inhibitors such as anti-CD200 and anti-PD1 could have a role in the treatment of CoViD-19. Rheumatic disease patients taking immunosuppressive drugs should be recommended to maintain the chronic therapy, prevent infection by avoiding social contacts and pausing immunosuppressants in case of infection. National and international registries are being created to collect data on rheumatic patients with CoViD-19.
nn15iyqd
nn15iyqd
2020-05-31
10.1016/j.jaut.2020.102442
1
Are We Ready for the New Coronavirus?
nnftb092
nnftb092
2020-03-11
10.1016/j.arbres.2020.02.009
1
Effect of continuous renal replacement therapy on all-cause mortality in COVID-19 patients undergoing invasive mechanical ventilation: a retrospective cohort study
Background: Since December 2019, when coronavirus disease 2019 (COVID 19) emerged in Wuhan and rapidly spread throughout the world, critically ill patients have a high mortality rate. We aimed to assess the effect of continuous renal replacement therapy (CRRT) on all cause mortality in patients with COVID 19 undergoing invasive mechanical ventilation. Methods: In this retrospective cohort study, we included all patients with COVID 19 undergoing invasive mechanical ventilation at Optical Valley Branch of Tongji Hospital Affiliated with Tongji Medical College, Huazhong University of Science and Technology, Wuhan from February 12th to March 2nd, 2020. Demographic, clinical, laboratory, and treatment data were collected and analyzed. All patients were followed until death or end of follow up (March 9th), and all survivors were followed for at least one week. Findings: Of 36 hospitalized COVID-19 patients with invasive mechanical ventilation, the mean age was 69.4 (SD 1.8) years and 30 (83.3%) were men. 22 (61.1%) patients received CRRT (CRRT group) and 14 cases (38.9%) were managed in conventional strategy (non CRRT group). There was no difference in age, sex, comorbidities, complications, treatments and most of the laboratory findings, except for patients in the CRRT group with higher levels of aspartate aminotransferase and serum creatinine. During the average follow-up period of 10.4 days, 12 of 22 (54.5%) patients in CRRT group and 11 of 14 (78.6%) patients in non CRRT group died. Kaplan Meier analysis demonstrated a prolonged survival in patients in CRRT group than non CRRT group (P=0.032). The association between CRRT treatment and a reduced risk of mortality remained significant after adjusting for confounding factors in seven different models, with an adjusted hazard ratio (aHR) varying between 0.283 and 0.424. Older age, higher levels of IL1b, IL2 receptor, hs cTnI and NT proBNP were independently associated with increased risk of mortality in patients with CRRT treatment. Interpretation: CRRT may be beneficial for the treatment of COVID 19 patients with invasive mechanical ventilation. Further prospective multicenter studies with larger sample sizes are required.
nnlynjoy
nnlynjoy
2020-03-20
10.1101/2020.03.16.20036780
1.5
Bcr-Abl tyrosine kinase inhibitor imatinib as a potential drug for COVID-19
The rapid geographic expansion of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the infectious agent of Coronavirus Disease 2019 (COVID-19) pandemic, poses an immediate need for potent drugs that can help contain the outbreak. Enveloped viruses infect the host cell by cellular membrane fusion, a crucial mechanism required for virus replication. The SARS-CoV-2 spike glycoprotein, due to its primary interaction with the human angiotensin-converting enzyme 2 (ACE2) cell-surface receptor, is considered as a potential target for drug development. Based on in silico screening followed by in vitro studies, here we report that the existing FDA-approved Bcr-Abl tyrosine kinase inhibitor, imatinib, inhibits SARS-CoV-2 with an IC50 of 130 nM. We provide initial evidence that inhibition of virus fusion may explain the antiviral action of imatinib. This finding is significant since pinpointing the mode of action allows evaluating the drug’s affinity to the SARS-CoV-2-specific target protein, and in turn, helps make inferences on the potency of the drug and evidence-based recommendations on its dosage. To this end, we provide evidence that imatinib binds to the receptor-binding domain (RBD) of SARS-CoV-2 spike protein with an affinity at micromolar, i.e., 2.32 ± 0.9 µM, levels. We also show that imatinib inhibits other coronaviruses, SARS-CoV and MERS-CoV, possibly via fusion inhibition. Based on promising in vitro results, we propose the Abl kinase inhibitor (ATKI), imatinib, to be a viable repurposable drug candidate for further clinical validation against COVID-19.
nnv2e7gr
nnv2e7gr
2020-06-18
10.1101/2020.06.18.158196
5
Viral Pneumonia Screening on Chest X-ray Images Using Confidence-Aware Anomaly Detection
Cluster of viral pneumonia occurrences during a short period of time may be a harbinger of an outbreak or pandemic, like SARS, MERS, and recent COVID-19. Rapid and accurate detection of viral pneumonia using chest X-ray can be significantly useful in large-scale screening and epidemic prevention, particularly when other chest imaging modalities are less available. Viral pneumonia often have diverse causes and exhibit notably different visual appearances on X-ray images. The evolution of viruses and the emergence of novel mutated viruses further result in substantial dataset shift, which greatly limits the performance of classification approaches. In this paper, we formulate the task of differentiating viral pneumonia from non-viral pneumonia and healthy controls into an one-class classification-based anomaly detection problem, and thus propose the confidence-aware anomaly detection (CAAD) model, which consists of a shared feature extractor, an anomaly detection module, and a confidence prediction module. If the anomaly score produced by the anomaly detection module is large enough or the confidence score estimated by the confidence prediction module is small enough, we accept the input as an anomaly case (i.e., viral pneumonia). The major advantage of our approach over binary classification is that we avoid modeling individual viral pneumonia classes explicitly and treat all known viral pneumonia cases as anomalies to reinforce the one-class model. The proposed model outperforms binary classification models on the clinical X-VIRAL dataset that contains 5,977 viral pneumonia (no COVID-19) cases, 18,619 non-viral pneumonia cases, and 18,774 healthy controls.
np4pujk8
np4pujk8
2020-03-27
2
Protease Inhibitors: Candidate Drugs to Inhibit Severe Acute Respiratory Syndrome Coronavirus 2 Replication
The number of patients infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has rapidly increased, although the WHO declared a pandemic. However, drugs that function against SARS-CoV-2 have not been established. SARS-CoV-2 has been suggested to bind angiotensin-converting enzyme 2, the receptor of the SARS coronavirus. SARS coronavirus and coronavirus 229E, the cause of the common cold, replicate through cell-surface and endosomal pathways using a protease, the type II transmembrane protease. To examine the effects of protease inhibitors on the replication of coronavirus 229E, we pretreated primary cultures of human nasal epithelial (HNE) cells with camostat or nafamostat, each of which has been used for the treatment of pancreatitis and/or disseminated intravascular coagulation. HNE cells were then infected with coronavirus 229E, and viral titers in the airway surface liquid of the cells were examined. Pretreatment with camostat (0.1-10 µg/mL) or nafamostat (0.01-1 µg/mL) reduced the titers of coronavirus 229E. Furthermore, a significant amount of type II transmembrane protease protein was detected in the airway surface liquid of HNE cells. Additionally, interferons have been reported to have antiviral effects against SARS coronavirus. The additive effects of interferons on the inhibitory effects of other candidate drugs to treat SARS-CoV-2 infection, such as lopinavir, ritonavir and favipiravir, have also been studied. These findings suggest that protease inhibitors of this type may inhibit coronavirus 229E replication in human airway epithelial cells at clinical concentrations. Protease inhibitors, interferons or the combination of these drugs may become candidate drugs to inhibit the replication of SARS-CoV-2.
npp1y2ay
npp1y2ay
2020
4
Disease-specific B cell epitopes for serum antibodies from patients with severe acute respiratory syndrome (SARS) and serologic detection of SARS antibodies by epitope-based peptide antigens
Severe acute respiratory syndrome (SARS) has emerged as a highly contagious, sometimes fatal disease. To find disease-specific B cell epitopes, phage-displayed random peptide libraries were panned on serum immunoglobulin (Ig) G antibodies from patients with SARS. Forty-nine immunopositive phage clones that bound specifically to serum from patients with SARS were selected. These phageborne peptides had 4 consensus motifs, of which 2 corresponded to amino acid sequences reported for SARS-associated coronavirus (SARSCoV). Synthetic peptide binding and competitive-inhibition assays further confirmed that patients with SARS generated antibodies against SARS-CoV. Immunopositive phage clones and epitope-based peptide antigens demonstrated clinical diagnostic potential by reacting with serum from patients with SARS. Antibody-response kinetics were evaluated in 4 patients with SARS, and production of IgM, IgG, and IgA were documented as part of the immune response. In conclusion, B cell epitopes of SARS corresponded to novel coronavirus. Our epitope-based serologic test may be useful in laboratory detection of the virus and in further study of the pathogenesis of SARS.
nqt9lhcc
nqt9lhcc
2004-08-15
10.1086/422753
1
Chapter 2 Prediction of Medicinal Properties Using Mathematical Models and Computation, and Selection of Plant Materials
Abstract In any phytochemical drug discovery programme, one of the major issues is the appropriate selection of target plant species that may provide lead for new drug discovery and development. Conducting research without any working hypotheses may produce serendipitous discoveries, but the chances of success are much slimmer than any information-based targeted approach. Therefore, the plant selection process is extremely important for ensuring success. In recent years, there have been significant amounts of work involving applications of various mathematical modelling and computational techniques to predict medicinal properties of plants, and thus to provide information-based selection of plant materials for further studies aiming at potential drug discovery and development. This chapter presents an overview of methods and processes involved in plant selection by utilizing various mathematical modelling and computational techniques.
nr1wl84k
nr1wl84k
2018-12-31
10.1016/b978-0-12-812364-5.00002-x
2.5
Chimeric severe acute respiratory syndrome coronavirus (SARS-CoV) S glycoprotein and influenza matrix 1 efficiently form virus-like particles (VLPs) that protect mice against challenge with SARS-CoV
SARS-CoV was the cause of the global pandemic in 2003 that infected over 8000 people in 8 months. Vaccines against SARS are still not available. We developed a novel method to produce high levels of a recombinant SARS virus-like particles (VLPs) vaccine containing the SARS spike (S) protein and the influenza M1 protein using the baculovirus insect cell expression system. These chimeric SARS VLPs have a similar size and morphology to the wild type SARS-CoV. We tested the immunogenicity and protective efficacy of purified chimeric SARS VLPs and full length SARS S protein vaccines in a mouse lethal challenge model. The SARS VLP vaccine, containing 0.8 μg of SARS S protein, completely protected mice from death when administered intramuscular (IM) or intranasal (IN) routes in the absence of an adjuvant. Likewise, the SARS VLP vaccine, containing 4 μg of S protein without adjuvant, reduced lung virus titer to below detectable level, protected mice from weight loss, and elicited a high level of neutralizing antibodies against SARS-CoV. Sf9 cell-produced full length purified SARS S protein was also an effective vaccine against SARS-CoV but only when co-administered IM with aluminum hydroxide. SARS-CoV VLPs are highly immunogenic and induce neutralizing antibodies and provide protection against lethal challenge. Sf9 cell-based VLP vaccines are a potential tool to provide protection against novel pandemic agents.
nr9485qf
nr9485qf
2011-09-01
10.1016/j.vaccine.2011.06.111
4.5
Cumulative biological source index: Volumes 1–20
nslfi9tp
nslfi9tp
2007-09-02
10.1016/s1572-5995(97)80048-8
1.5
Extracellular superoxide dismutase, a molecular transducer of health benefits of exercise
Extracellular superoxide dismutase (EcSOD) is the only extracellular scavenger of superoxide anion (O(2)(.-)) with unique binding capacity to cell surface and extracellular matrix through its heparin-binding domain. Enhanced EcSOD activity prevents oxidative stress and damage, which are fundamental in a variety of disease pathologies. In this review we will discuss the findings in humans and animal studies supporting the benefits of EcSOD induced by exercise training in reducing oxidative stress in various tissues. In particularly, we will highlight the importance of skeletal muscle EcSOD, which is induced by endurance exercise and redistributed through the circulation to the peripheral tissues, as a molecular transducer of exercise training to confer protection against oxidative stress and damage in various disease conditions.
nv2ebnly
nv2ebnly
2020-03-19
10.1016/j.redox.2020.101508
3
Activation of the SARS coronavirus spike protein via sequential proteolytic cleavage at two distinct sites.
The coronavirus spike protein (S) plays a key role in the early steps of viral infection, with the S1 domain responsible for receptor binding and the S2 domain mediating membrane fusion. In some cases, the S protein is proteolytically cleaved at the S1-S2 boundary. In the case of the severe acute respiratory syndrome coronavirus (SARS-CoV), it has been shown that virus entry requires the endosomal protease cathepsin L; however, it was also found that infection of SARS-CoV could be strongly induced by trypsin treatment. Overall, in terms of how cleavage might activate membrane fusion, proteolytic processing of the SARS-CoV S protein remains unclear. Here, we identify a proteolytic cleavage site within the SARS-CoV S2 domain (S2', R797). Mutation of R797 specifically inhibited trypsin-dependent fusion in both cell-cell fusion and pseudovirion entry assays. We also introduced a furin cleavage site at both the S2' cleavage site within S2 793-KPTKR-797 (S2'), as well as at the junction of S1 and S2. Introduction of a furin cleavage site at the S2' position allowed trypsin-independent cell-cell fusion, which was strongly increased by the presence of a second furin cleavage site at the S1-S2 position. Taken together, these data suggest a novel priming mechanism for a viral fusion protein, with a critical proteolytic cleavage event on the SARS-CoV S protein at position 797 (S2'), acting in concert with the S1-S2 cleavage site to mediate membrane fusion and virus infectivity.
nvpnfbds
nvpnfbds
2009
10.1073/pnas.0809524106
2.5
Identification of Antiviral Drug Candidates against SARS-CoV-2 from FDA-Approved Drugs
Drug repositioning is the only feasible option to immediately address the COVID-19 global challenge. We screened a panel of 48 FDA-approved drugs against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) which were preselected by an assay of SARS-CoV. We identified 24 potential antiviral drug candidates against SARS-CoV-2 infection. Some drug candidates showed very low 50% inhibitory concentrations (IC50s), and in particular, two FDA-approved drugs-niclosamide and ciclesonide-were notable in some respects.
nyd1fhta
nyd1fhta
2020
3
Compounds with Therapeutic Potential against Novel Respiratory 2019 Coronavirus
Currently, the expansion of the novel human respiratory coronavirus (known as SARS-CoV-2 [severe acute respiratory syndrome coronavirus 2], COVID-2019 [coronavirus disease 2019], or 2019-nCoV [2019 novel coronavirus]) has stressed the need for therapeutic alternatives to alleviate and stop this new epidemic. The previous epidemics of infections by high-morbidity human coronaviruses, such as SARS-CoV in 2003 and the Middle East respiratory syndrome coronavirus (MERS-CoV) in 2012, prompted the characterization of compounds that could be potentially active against the currently emerging novel coronavirus, SARS-CoV-2. The most promising compound is remdesivir (GS-5734), a nucleotide analog prodrug currently in clinical trials for treating Ebola virus infections. Remdesivir inhibited the replication of SARS-CoV and MERS-CoV in tissue cultures, and it displayed efficacy in nonhuman animal models. In addition, a combination of the human immunodeficiency virus type 1 (HIV-1) protease inhibitors lopinavir/ritonavir and interferon beta (LPV/RTV–IFN-β) was shown to be effective in patients infected with SARS-CoV. LPV/RTV–IFN-β also improved clinical parameters in marmosets and mice infected with MERS-CoV. Remarkably, the therapeutic efficacy of remdesivir appeared to be superior to that of LPV/RTV–IFN-β against MERS-CoV in a transgenic humanized mouse model. The relatively high mortality rates associated with these three novel human coronavirus infections, SARS-CoV, MERS-CoV, and SARS-CoV-2, have suggested that proinflammatory responses might play a role in the pathogenesis. It remains unknown whether the generated inflammatory state should be targeted. Therapeutics that target the coronavirus alone might not be able to reverse highly pathogenic infections. This minireview aims to provide a summary of therapeutic compounds that have shown potential in fighting SARS-CoV-2 infections.
nz8qvuw6
nz8qvuw6
2020-04-21
10.1128/aac.00399-20
2
Puzzle of highly pathogenic human coronaviruses (2019-nCoV)
nzvuugls
nzvuugls
2020-02-22
10.1007/s13238-020-00693-y
1
Molecular Detection of SARS-CoV-2 in Formalin Fixed Paraffin Embedded Specimens
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the cause of human coronavirus disease 2019 (COVID-19), emerged in Wuhan, China in December 2019. The virus rapidly spread globally, resulting in a public-health crisis including more than one million cases and tens of thousands of deaths. Here, we describe the identification and evaluation of commercially available reagents and assays for the molecular detection of SARS-CoV-2 in infected formalin fixed paraffin embedded (FFPE) cell pellets. We identified a suitable rabbit polyclonal anti-SARS-CoV spike protein antibody and a mouse monoclonal anti-SARS-CoV nucleocapsid protein (NP) antibody for cross detection of the respective SARS-CoV-2 proteins by immunohistochemistry (IHC) and immunofluorescence assay (IFA). Next, we established RNAscope in situ hybridization (ISH) to detect SARS-CoV-2 RNA. Furthermore, we established a multiplex fluorescence ISH (mFISH) to detect positive-sense SARS-CoV-2 RNA and negative-sense SARS-CoV-2 RNA (a replicative intermediate indicating viral replication). Finally, we developed a dual staining assay using IHC and ISH to detect SARS-CoV-2 antigen and RNA in the same FFPE section. These reagents and assays will accelerate COVID-19 pathogenesis studies in humans and in COVID-19 animal models.
nzwe7hpg
nzwe7hpg
2020-04-21
10.1101/2020.04.21.042911
2
Home Medical Nutrition during SARS-CoV-2 pandemic – a position paper
Summary Background The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the cause of a worldwide rapidly spreading illness, Coronavirus Disease 2019 (COVID-19). Patients fed enterally and parenterally at home are exposed to the same risk of infection as the general population, but more prone to complications than others. Therefore the guidance for care-givers and care-takers of these patients is needed. Methods The literature search identified no relevant systematic reviews or studies on the subject. Therefore a panel of 21 experts from 13 home medical nutrition (HMN) centres in Poland was formed. Twenty-three key issues relevant to the management of SARS-CoV-2 infection or COVID-19 in the HMN settings were identified and discussed. Some statements diverge from the available nutrition, surgical or ICU guidelines, some are based on the best available experience. Each topic was discussed and assessed during two Delphi rounds subsequently. Statements were graded strong or weak based on the balance between benefit and harm, resource and cost implications, equity, and feasibility. Results the panel issued 23 statements, all of them were graded strong. Two scored 85.71% agreement, eleven 95.23%, and ten 100%. The topics were: infection control, enrolment to HMN, logistics and patient information. Conclusions the position paper present pragmatic statements for HMN to be implemented in places without existing protocols for SARS-CoV-2 pandemic. They represent the state of knowledge available at the moment and may change should new evidence occurs.
nzy2iphz
nzy2iphz
2020-05-11
10.1016/j.clnesp.2020.05.002
3.5
MERS-CoV spike nanoparticles protect mice from MERS-CoV infection
The Middle East respiratory syndrome coronavirus (MERS-CoV) was first discovered in late 2012 and has gone on to cause over 1800 infections and 650 deaths. There are currently no approved therapeutics or vaccinations for MERS-CoV. The MERS-CoV spike (S) protein is responsible for receptor binding and virion entry to cells, is immunodominant and induces neutralizing antibodies in vivo, all of which, make the S protein an ideal target for anti-MERS-CoV vaccines. In this study, we demonstrate protection induced by vaccination with a recombinant MERS-CoV S nanoparticle vaccine and Matrix-M1 adjuvant combination in mice. The MERS-CoV S nanoparticle vaccine produced high titer anti-S neutralizing antibody and protected mice from MERS-CoV infection in vivo.
o0o3djz9
o0o3djz9
2017-03-01
10.1016/j.vaccine.2017.02.012
4.5
Therapy with a Severe Acute Respiratory Syndrome–Associated Coronavirus–Neutralizing Human Monoclonal Antibody Reduces Disease Severity and Viral Burden in Golden Syrian Hamsters
BackgroundImmunotherapy with monoclonal antibodies (MAbs) offers safe interventions for the prevention of infection in patients after organ transplantation and for the treatment of cancers and autoimmune diseases. MAb 201 is a severe acute respiratory syndrome–associated coronavirus (SARS-CoV)–specific MAb that prevents establishment of viral replication in vitro and prevents viral replication in vivo when administered prophylactically. The efficacy of MAb 201 in the treatment of SARS was evaluated in golden Syrian hamsters, an animal model that supports SARS-CoV replication to high levels and displays severe pathological changes associated with infection, including pneumonitis and pulmonary consolidation MethodsGolden Syrian hamsters that were intranasally inoculated with SARS-CoV were treated with various doses of MAb 201 or an irrelevant MAb 24 h after inoculation. Two to 7 days after infection, the hamsters were killed, and their lungs were collected for evaluation of viral titers and pathological findings ResultsPostexposure treatment with MAb 201 can alleviate the viral burden and associated pathological findings in a golden Syrian hamster model of SARS-CoV infection. After a hamster is treated with MAb 201, its viral burden is reduced by 10(2.4)–10(3.9) 50% tissue-culture infectious doses per gram of tissue, and the severity of associated pathological findings, including interstitial pneumonitis and consolidation, is also remarkably reduced ConclusionsThe demonstration of successful postexposure MAb 201 therapy in an animal model that demonstrates viral replication and associated pulmonary pathological findings suggests that MAb 201 may be useful in the arsenal of tools to combat SARS
o0ou0r1c
o0ou0r1c
2006-03-01
10.1086/500143
1.5
Systematic Survey of Zoonotic and Sapronotic Microbial Agents
Viruses, bacteria, fungi, protozoa, and metazoa (parasitic worms and arthropods) are among the aetiological agents of zoonoses and sapronoses. Our survey only concerns the agents of microbial diseases (i.e., not the metazoan invasions and infestations), and is arranged according to systematic position. In addition, a new zoonotic disease caused by prions – variant of Creutzfeld-Jakob disease – is included.
o0vacxc2
o0vacxc2
2010-11-10
10.1007/978-90-481-9657-9_8
2
Crystal structure of Nsp15 endoribonuclease NendoU from SARS‐CoV‐2
Severe Acute Respiratory Syndrome coronavirus 2 (SARS‐CoV‐2) is rapidly spreading around the world. There is no existing vaccine or proven drug to prevent infections and stop virus proliferation. Although this virus is similar to human and animal SARS‐CoVs and Middle East Respiratory Syndrome coronavirus (MERS‐CoVs), the detailed information about SARS‐CoV‐2 proteins structures and functions is urgently needed to rapidly develop effective vaccines, antibodies, and antivirals. We applied high‐throughput protein production and structure determination pipeline at the Center for Structural Genomics of Infectious Diseases to produce SARS‐CoV‐2 proteins and structures. Here we report two high‐resolution crystal structures of endoribonuclease Nsp15/NendoU. We compare these structures with previously reported homologs from SARS and MERS coronaviruses.
o0x269k5
o0x269k5
2020-05-02
10.1002/pro.3873
3.5
EZH2-mediated H3K27me3 inhibits ACE2 expression
Abstract The outbreak of corona virus disease 2019 (COVID-19) caused by SARS-CoV-2 infection is spreading globally and quickly, leading to emerging health issues. SARS-CoV-2 enters into and infects host cells through its spike glycoprotein recognizing the cell receptor Angiotensin-converting enzyme II (ACE2). Here, we noticed that ACE2 was further enhanced by SARS-CoV-2 infection. Human germ cells and early embryos express high level of ACE2. Notably, RNA-seq result showed that reduction of H3K27me3, but not H3K4/9/36me3, led to upregulation of Ace2 expression in mouse germ cell line GC-2. In agreement with this result, we found in human embryonic stem cells that ACE2 expression was significantly increased in absence of EZH2, the major enzyme catalyzing H3K27me3. ChIP-seq analysis further confirmed decrease of H3K27me3 signal and increase of H3K27ac signal at ACE2 promoter upon EZH2 knockout. Therefore, we propose that EZH2-mediated H3K27me3 at ACE2 promoter region inhibits ACE2 expression in mammalian cells. This regulatory pattern may also exist in other human cells and tissues. Our discovery provides clues for pathogenesis and targeted drug therapy towards ACE2 expression for prevention and adjuvant therapy of COVID-19.
o12jqt5z
o12jqt5z
2020-04-08
10.1016/j.bbrc.2020.04.010
2.5
In silico studies on the comparative characterization of the interactions of SARS‐CoV‐2 spike glycoprotein with ACE‐2 receptor homologs and human TLRs
Coronavirus disease‐2019 (COVID‐19) outbreak due to novel coronavirus or severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) infection has come out as a major threat for mankind in recent times. It is continually taking an enormous toll on mankind by means of increasing number of deaths, associated comorbidities, and socioeconomic loss around the globe. Unavailability of chemotherapeutics/vaccine has posed tremendous challenges to scientists and doctors for developing an urgent therapeutic strategy. In this connection, the present in silico study aims to understand the sequence divergence of spike protein (the major infective protein of SARS‐CoV‐2), its mode of interaction with the angiotensin‐converting enzyme‐2 receptor (ACE2) receptor of human and related animal hosts/reservoir. Moreover, the involvement of the human Toll‐like receptors (TLRs) against the spike protein has also been demonstrated. Our data indicated that the spike glycoprotein of SARS‐CoV‐2 is phylogenetically close to bat coronavirus and strongly binds with ACE2 receptor protein from both human and bat origin. We have also found that cell surface TLRs, especially TLR4 is most likely to be involved in recognizing molecular patterns from SARS‐CoV‐2 to induce inflammatory responses. The present study supported the zoonotic origin of SARS‐CoV‐2 from a bat and also revealed that TLR4 may have a crucial role in the virus‐induced inflammatory consequences associated with COVID‐19. Therefore, selective targeting of TLR4‐spike protein interaction by designing competitive TLR4‐antagonists could pave a new way to treat COVID‐19. Finally, this study is expected to improve our understanding on the immunobiology of SARS‐CoV‐2 and could be useful in adopting spike protein, ACE2, or TLR‐guided intervention strategy against COVID‐19 shortly.
o1uol5u3
o1uol5u3
2020-05-17
10.1002/jmv.25987
3
Treatment of respiratory virus infections
Abstract Respiratory viral infections (RVIs) can be associated with a wide range of clinical manifestations ranging from self-limited upper respiratory tract infections to more devastating conditions, such as pneumonia. RVIs constitute the most frequent reason for medical consultations in the world and they have a considerable impact on quality of life and productivity. Therefore, the prevention and control of RVIs remain major clinical goals. Currently, there are approximately 200 known respiratory viruses that can be grouped into one family of DNA viruses (Adenoviridae) and four families of RNA viruses (Orthomyxoviridae, Paramyxoviridae, Picornaviridae and Coronaviridae). In this paper, we review the major respiratory viruses that cause disesases in humans, with an emphasis on current treatment options.
o35dkbof
o35dkbof
2006-06-30
10.1016/j.antiviral.2006.01.006
1.5
Dynamics of anti-SARS-Cov-2 IgM and IgG antibodies among COVID-19 patients
o3cfolip
o3cfolip
2020-04-23
10.1016/j.jinf.2020.04.019
3.5
COVID-19 pandemic and therapy with ibuprofen or renin-angiotensin system blockers: no need for interruptions or changes in ongoing chronic treatments
Scientists hypothesized that drugs such as ibuprofen or renin-angiotensin system (RAS) blockers could exacerbate the novel coronavirus disease COVID-19 by upregulating the angiotensin-converting enzyme 2 (ACE2), which serves as an entry receptor for the coronavirus SARS-CoV-2. This hypothesis was taken up by the lay press and led to concerns among doctors and patients whether the use of these drugs was still safe and justified against the background of the pandemic spread of SARS-CoV-2 with an increasing number of cases and deaths. In this article, we summarize what is known about the effect of RAS blockers or non-steroidal anti-inflammatory drugs (NSAIDs) on the course of COVID-19 disease. In the case of RAS inhibition, we also find evidence for the opposite hypothesis, namely, that RAS inhibition in COVID-19 could be protective. In view of the inconsistent and limited evidence and after weighing up the benefits and risks, we would not currently recommend discontinuing or switching an effective treatment with RAS blockers. NSAIDs should be used at the lowest effective dose for the shortest possible period. The choice of drug to treat COVID-19-associated fever or pain should be based on a benefit-risk assessment for known side effects (e.g., kidney damage, gastrointestinal ulceration).
o40ey199
o40ey199
2020-05-15
10.1007/s00210-020-01890-6
4.5
Identification of SARS-CoV RBD-targeting monoclonal antibodies with cross-reactive or neutralizing activity against SARS-CoV-2
SARS-CoV-2-caused COVID-19 cases are growing globally, calling for developing effective therapeutics to control the current pandemic. SARS-CoV-2 and SARS-CoV recognize angiotensin-converting enzyme 2 (ACE2) receptor via the receptor-binding domain (RBD). Here, we identified six SARS-CoV RBD-specific neutralizing monoclonal antibodies (nAbs) that cross-reacted with SARS-CoV-2 RBD, two of which, 18F3 and 7B11, neutralized SARS-CoV-2 infection. 18F3 recognized conserved epitopes on SARS-CoV and SARS-CoV-2 RBDs, whereas 7B11 recognized epitopes on SARS-CoV RBD not fully conserved in SARS-CoV-2 RBD. The 18F3-recognizing epitopes on RBD did not overlap with the ACE2-binding sites, whereas those recognized by 7B11 were close to the ACE2-binding sites, explaining why 7B11 could, but 18F3 could not, block SARS-CoV or SARS-CoV-2 RBD binding to ACE2 receptor. Our study provides an alternative approach to prevent SARS-CoV-2 infection using anti-SARS-CoV nAbs.
o5545c1x
o5545c1x
2020-05-13
10.1016/j.antiviral.2020.104820
3
Microarray analysis of long non-coding RNA expression profiles uncovers a Toxoplasma-induced negative regulation of host immune signaling
BACKGROUND: Toxoplasma gondii is an obligate intracellular protozoan parasite that can infect mammalian cells and thereby regulate host gene expression. The long non-coding RNAs (lncRNAs) have been demonstrated to be an important class of RNA molecules that regulate many biological processes, including host-pathogen interactions. However, the role of host lncRNAs in the response to T. gondii infection remains largely unknown. METHODS: We applied a microarray approach to determine the differential expression profiles of both lncRNAs and mRNAs in the human foreskin fibroblast (HFF) cells after T. gondii infection. The Gene Ontology and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were performed to reveal the potential functions of T. gondii-induced genes. Based on the co-expression networks of lncRNAs and immune-related genes, the role of NONSHAT022487 on the regulation of UNC93B1 related immune signaling was investigated by the knockdown and over-expression of lncRNA in human macrophage derived from the PMA-induced promonocytic cell line THP-1. RESULTS: Our data showed that 996 lncRNAs and 109 mRNAs in HFF cells were significantly and differentially expressed following T. gondii infection (fold change ≥ 5, P < 0.05). The results from the GO and KEGG pathway analyses indicated that the mRNAs with differential expression were mainly involved in the host immune response. Remarkably, we identified a novel lncRNA, NONSHAT022487, which suppresses the expression of the immune-related molecule UNC93B1. After T. gondii infection, NONSHAT022487 impaired the secretion of the cytokines IL-12, TNF-α, IL-1β and IFN-γ by downregulating UNC93B1 expression in human macrophage cells. CONCLUSIONS: Our study identified infection-induced lncRNA expression as a novel mechanism by which the Toxoplasma parasite regulates host immune signaling, which advances our understanding of the interaction of T. gondii parasites and host cells. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s13071-018-2697-8) contains supplementary material, which is available to authorized users.
o7f0q31t
o7f0q31t
2018-03-12
10.1186/s13071-018-2697-8
3
Potential Antiviral Drugs for SARS-Cov-2 Treatment: Preclinical Findings and Ongoing Clinical Research
Severe acute respiratory syndrome coronavirus 2 (SARS-Cov-2), initially termed 2019-new CoV (2019-nCoV), is a novel coronavirus responsible for the severe respiratory illness currently ongoing worldwide from the beginning of December 2019. This beta gene virus, very close to bat coronaviruses (bat-CoV-RaTG13) and bat-SL-CoVZC45, causes a severe disease, similar to those caused by Middle East respiratory syndrome (MERS)-CoV and SARS-CoV viruses, featured by low to moderate mortality rate. Unfortunately, the antiviral drugs commonly used in clinical practice to treat viral infections, are not applicable to SARS-Cov-2 and no vaccine is available. Thus, it is extremely necessary to identify new drugs suitable for the treatment of the 2019-nCoV outbreak. Different preclinical studies conducted on other coronaviruses suggested that promising clinical outcomes for 2019-nCoV should be obtained by using alpha-interferon, chloroquine phosphate, arabinol, remdesivir, lopinavir/ritonavir, and anti-inflammatory drugs. Moreover, clinical trials with these suitable drugs should be performed on patients affected by SARS-Cov-2 to prove their efficacy and safety. Finally, a very promising therapeutic drug, tocilizumab, is discussed; it is currently used to treat patients presenting COVID-19 pneumonia. Herein, we recapitulate these experimental studies to highlight the use of antiviral drugs for the treatment of SARS-Cov-2 disease.
o8vao91j
o8vao91j
2020
4.5
Interferon alfacon1 is an inhibitor of SARS-corona virus in cell-based models
Abstract Preliminary data examining interferon alfacon1 treatment of SARS-CoV (severe acute respiratory syndrome-corona virus)-infected patients suggests this therapy is well tolerated and of therapeutic benefit. We report herein that interferon alfacon1, has potent in vitro antiviral activity against SARS-CoV. In a cytopathic effect protection (CPE) assay, interferon alfacon1 inhibited the generation of CPE in a dose-dependent manner with an IC50 of 0.001μg/ml, a clinically achievable level. Furthermore, interferon alfacon1 also demonstrated significant antiviral activity in yield reduction and plaque reduction assays. The in vitro antiviral activity of interferon alfacon1 against SARS-CoV suggests continued evaluation of interferon alfacon1 as a therapeutic treatment for patients infected with SARS-CoV.
o8ygdd14
o8ygdd14
2005-06-30
10.1016/j.antiviral.2005.01.002
2
Novel antibody epitopes dominate the antigenicity of spike glycoprotein in SARS-CoV-2 compared to SARS-CoV
o9fvzwj5
o9fvzwj5
2020-03-04
10.1038/s41423-020-0385-z
3
Current global vaccine and drug efforts against COVID-19: Pros and cons of bypassing animal trials.
COVID-19 has become one of the biggest health concern, along with huge economic burden. With no clear remedies to treat the disease, doctors are repurposing drugs like chloroquine and remdesivir to treat COVID-19 patients. In parallel, research institutes in collaboration with biotech companies have identified strategies to use viral proteins as vaccine candidates for COVID-19. Although this looks promising, they still need to pass the test of challenge studies in animal models. As various models for SARS-CoV-2 are under testing phase, biotech companies have bypassed animal studies and moved to Phase I clinical trials. In view of the present outbreak, this looks a justified approach, but the problem is that in the absence of animal studies, we can never predict the outcomes in humans. Since animal models are critical for vaccine development and SARS-CoV-2 has different transmission dynamics, in this review we compare different animal models of SARS-CoV-2 with humans for their pathogenic, immune response and transmission dynamics that make them ideal models for vaccine testing for COVID-19. Another issue of using animal model is the ethics of using animals for research; thus, we also discuss the pros and cons of using animals for vaccine development studies.
oa8vzf02
oa8vzf02
2020
5
The Crisis and Aftermath-II: Society and Economics
This chapter mentions some other groundbreaking innovations and technological improvements that came along after the crisis. The recent attempts at creating digital currencies, famously known as cryptocurrencies, and their corresponding platform blockchain were some of these. How and why did they emerge? What do their inventions imply for our future? And why are they important? Sharing economy and memberships (as opposed to ownerships) are other examples of profound changes. Increasing use of shared goods, services like Uber and Airbnb, and the unstoppable trend of membership services like e-newspapers, e-libraries, and music streaming points to one conclusion: the end of the idea of ownership. On the governmental side, we have been observing an increasing inclination toward authoritarian states. Liberalism seems to have failed. People have been losing their trust in economic regimes. My argument in this chapter is that without the 2008 crisis, there would have never been these developments and innovations.
obrj0f17
obrj0f17
2020-04-05
10.1007/978-3-030-43343-7_5
1.5
Infection with MERS-CoV Causes Lethal Pneumonia in the Common Marmoset
The availability of a robust disease model is essential for the development of countermeasures for Middle East respiratory syndrome coronavirus (MERS-CoV). While a rhesus macaque model of MERS-CoV has been established, the lack of uniform, severe disease in this model complicates the analysis of countermeasure studies. Modeling of the interaction between the MERS-CoV spike glycoprotein and its receptor dipeptidyl peptidase 4 predicted comparable interaction energies in common marmosets and humans. The suitability of the marmoset as a MERS-CoV model was tested by inoculation via combined intratracheal, intranasal, oral and ocular routes. Most of the marmosets developed a progressive severe pneumonia leading to euthanasia of some animals. Extensive lesions were evident in the lungs of all animals necropsied at different time points post inoculation. Some animals were also viremic; high viral loads were detected in the lungs of all infected animals, and total RNAseq demonstrated the induction of immune and inflammatory pathways. This is the first description of a severe, partially lethal, disease model of MERS-CoV, and as such will have a major impact on the ability to assess the efficacy of vaccines and treatment strategies as well as allowing more detailed pathogenesis studies.
odc5yx7g
odc5yx7g
2014-08-21
10.1371/journal.ppat.1004250
4
Deep Transfer Learning based Classification Model for COVID-19 Disease
Abstract The COVID-19 infection is increasing at a rapid rate, with the availability of limited number of testing kits. Therefore, the development of COVID-19 testing kits is still an open area of research. Recently, many studies have shown that chest Computed Tomography(CT) images can be used for COVID-19 testing, as chest CT images show a bilateral change in COVID-19 infected patients. However, the classification of COVID-19 patients from chest CT images is not an easy task as predicting the bilateral change is defined as an ill-posed problem. Therefore, in this paper, a deep transfer learning technique is used to classify COVID-19 infected patients. Additionally, a top-2 smooth loss function with cost-sensitive attributes is also utilized to handle noisy and imbalanced COVID-19 dataset kind of problems. Experimental results reveal that the proposed deep transfer learning-based COVID-19 classification model provides efficient results as compared to the other supervised learning models.
oegn8m1k
oegn8m1k
2020-05-20
10.1016/j.irbm.2020.05.003
5
Eltrombopag is a potential target for drug intervention in SARS-CoV-2 spike protein
The COVID-19 pandemic, caused by the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), is a current global threat for which there is an urgent need to search for an effective therapy. The transmembrane spike (S) glycoprotein of SARS-CoV-2 directly binds to the host angiotensin-converting enzyme 2 (ACE2) and mediates viral entrance, which is therefore considered as a promising drug target. Considering that new drug development is a time-consuming process, drug repositioning may facilitate rapid drug discovery dealing with sudden infectious diseases. Here, we compared the differences between the virtual structural proteins of SARS-CoV-2 and SARS-CoV, and selected a pocket mainly localizing in the fusion cores of S2 domain for drug screening. A virtual drug design algorithm screened the Food and Drug Administration-approved drug library of 1234 compounds, and 13 top scored compounds were obtained through manual screening. Through in vitro molecular interaction experiments, eltrombopag was further verified to possess a high binding affinity to S protein plus human ACE2 and could potentially affect the stability of the ACE2-S protein complex. Hence, it is worth further exploring eltrombopag as a potential drug for the treatment of SARS-CoV-2 infection.
ogiicyik
ogiicyik
2020
5
A Social Network Model of the COVID-19 Pandemic
In the COVID-19 coronavirus pandemic, currently vaccines and specific anti-viral treatment are not yet available. Thus, preventing viral transmission by case isolation, quarantine, and social distancing is essential to slowing its spread. Here we model social networks using weighted graphs, where vertices represent individuals and edges represent contact. As public health measures are implemented, connectivity in the graph decreases, resulting in lower effective reproductive numbers, and reduced viral transmission. For COVID-19, model parameters were derived from the coronavirus epidemic in China, validated by epidemic data in Italy, then applied to the United States. We calculate that, in the U.S., the public is able to contain viral transmission by limiting the average number of contacts per person to less than 7 unique individuals over each 5 day period. This increases the average social distance between individuals to 10 degrees of separation.
ogqsi3ns
ogqsi3ns
2020-03-27
10.1101/2020.03.23.20041798
1.5
Hydroxychloroquine has no effect on SARS-CoV-2 load in nasopharynx of patients with mild form of COVID-19
Due to the urgent need to stop the spread of the COVID-19 attempts to find the drug with anti SARS-CoV-2 effects among ones already available on a market are actively being made. A number of in vitro as well as in vivo model animal studies have shown that widely used compound hydroxychloroquine (HCQ) is able to cause anti-viral effect on SARS-CoV-2. While there is no enough clinical data to support the use of HCQ, several countries including Russia have already approved HCQ as treatment and prophylactic option. In the current study we analyzed the dynamics of the SARS-CoV-2 RNA quantity change in nasopharynx swabs of infected patients in mild condition and compared that of patients receiving HCQ and receiving no antiviral pharmacological therapy. We found that most of the patients demonstrated gradual decrease in the number of SARS-CoV-2 RNA copies in the swab regardless of the HCQ receiving. Noteworthy that patients with RNA load higher than 106 copies were hospitalized due to condition deteriorating significantly more frequently compared to those with RNA load below 106 copies even with HCQ administration. In addition, the results of the current study indicate that recovering patients may produce viruses at least during 18 days from the onset of symptoms and HCQ therapy does not block or reduce it.
ohyvt3i0
ohyvt3i0
2020-07-03
10.1101/2020.06.30.20143289
5
Characterization of canine coronavirus spread among domestic dogs in Vietnam
Canine coronavirus (CCoV) is an important pathogen that causes enteritis in dogs, but there is no information on CCoV infection in Vietnam. To examine the prevalence of CCoV infection among Vietnamese dogs, 201 serum samples were analyzed by virus-neutralization (VN) test. The results showed that antibody against CCoV-II was present in 87 dogs (43.3%). To detect genes of CCoV, fecal samples collected from 30 diarrheic and 50 healthy dogs were examinated by RT-PCR, confirming that 2 diarrheic dogs and 5 healthy dogs were positive for CCoV. Nucleotide sequences of N-terminal region of spike (S) gene indicated that CCoV strains were divided into two subgenotypes, CCoV-IIa and -IIb, respectively. Furthemore, we succeeded in isolating CCoV/dog/HCM47/2015, the isolate was plaque-purified three times, and 3’-terminal one-third of the genome was analyzed. Interestingly, the plaque-purified virus had a large deletion in ORF3abc and E genes (1,165 nt), and a short deletion in ORF7b gene (60 nt), suggesting that these regions are not necessary for in vitro replication of CCoV. Next, the antigenicity between the isolated CCoV-IIb and the other CCoV-IIa was compared by VN test, revealing that antigenicty of the isolated CCoV is equal or higher than that of the other CCoV. In summary, two subgenotypes of CCoV-II are spreading among Vietnamese dogs. The isolated virus with a large deletion after in vitro passage may be useful for the development of vaccine, owing to its antigenicity and efficient viral growth in vitro.
okplmmtd
okplmmtd
2016-11-14
10.1292/jvms.16-0538
3
The Battle Against COVID-19: Where Do We Stand Now?
ol13v4ld
ol13v4ld
2020-03-16
10.30476/ijms.2020.46357
1.5
Inflammation resolution: a dual-pronged approach to averting cytokine storms in COVID-19?
Severe coronavirus disease (COVID-19) is characterized by pulmonary hyper-inflammation and potentially life-threatening “cytokine storms”. Controlling the local and systemic inflammatory response in COVID-19 may be as important as anti-viral therapies. Endogenous lipid autacoid mediators, referred to as eicosanoids, play a critical role in the induction of inflammation and pro-inflammatory cytokine production. SARS-CoV-2 may trigger a cell death (“debris”)-induced “eicosanoid storm”, including prostaglandins and leukotrienes, which in turn initiates a robust inflammatory response. A paradigm shift is emerging in our understanding of the resolution of inflammation as an active biochemical process with the discovery of novel endogenous specialized pro-resolving lipid autacoid mediators (SPMs), such as resolvins. Resolvins and other SPMs stimulate macrophage-mediated clearance of debris and counter pro-inflammatory cytokine production, a process called inflammation resolution. SPMs and their lipid precursors exhibit anti-viral activity at nanogram doses in the setting of influenza without being immunosuppressive. SPMs also promote anti-viral B cell antibodies and lymphocyte activity, highlighting their potential use in the treatment of COVID-19. Soluble epoxide hydrolase (sEH) inhibitors stabilize arachidonic acid-derived epoxyeicosatrienoic acids (EETs), which also stimulate inflammation resolution by promoting the production of pro-resolution mediators, activating anti-inflammatory processes, and preventing the cytokine storm. Both resolvins and EETs also attenuate pathological thrombosis and promote clot removal, which is emerging as a key pathology of COVID-19 infection. Thus, both SPMs and sEH inhibitors may promote the resolution of inflammation in COVID-19, thereby reducing acute respiratory distress syndrome (ARDS) and other life-threatening complications associated with robust viral-induced inflammation. While most COVID-19 clinical trials focus on “anti-viral” and “anti-inflammatory” strategies, stimulating inflammation resolution is a novel host-centric therapeutic avenue. Importantly, SPMs and sEH inhibitors are currently in clinical trials for other inflammatory diseases and could be rapidly translated for the management of COVID-19 via debris clearance and inflammatory cytokine suppression. Here, we discuss using pro-resolution mediators as a potential complement to current anti-viral strategies for COVID-19.
on1nclkj
on1nclkj
2020-05-08
10.1007/s10555-020-09889-4
4
In silico ADMET and molecular docking study on searching potential inhibitors from limonoids and triterpenoids for COVID-19
The computational strategies like molecular docking, simulation, in silico ADMET and drug-likeness prediction were adopted to search potential compounds that can inhibit the effects of SARS-CoV-2. Considering the published literatures on medicinal importance, total 154 phytochemicals with analogous structure from limonoids and triterpenoids were selected to search potential inhibitors for the five protein targets of SARS-CoV-2, i.e., 3CLpro (main protease), PLpro (papain like protease), SGp-RBD (spike glycoprotein-receptor binding domain), RdRp (RNA dependent RNA polymerase, ACE2 (angiotensin converting enzyme 2). Analyses of the in silico computational results and reported medicinal uses, the phytochemicals such as 7-deacetyl-7-benzoylgedunin, epoxyazadiradione, limonin, maslinic acid, glycyrrhizic acid and ursolic acid were found to be effective against the target proteins of SARS-CoV-2. The protein-ligand interaction study revealed that these phytochemicals bind at the main active site of the target proteins. Therefore, the core structure of these potential hits can be used for further lead optimization to design drugs for SARS-CoV-2. Also, the plants extracts like neem, tulsi, citrus and olives containing these phytochemicals can be used to formulate suitable therapeutics approaches in traditional medicines.
onereai5
onereai5
2020-05-16
5
Knowledge-based structural models of SARS-CoV-2 proteins and their complexes with potential drugs
The World Health Organization (WHO) has declared the coronavirus disease 2019 (COVID-19) caused by the novel coronavirus SARS-CoV-2 a pandemic. There is, however, no confirmed anti-COVID-19 therapeutic currently. In order to assist structure-based discovery efforts for repurposing drugs against this disease, we constructed knowledge-based models of SARS-CoV-2 proteins and compared the ligand molecules in the template structures with approved/experimental drugs and components of natural medicines. Our theoretical models suggest several drugs, such as carfilzomib, sinefungin, tecadenoson, and trabodenoson, that could be further investigated for their potential for treating COVID-19.
onskc3u9
onskc3u9
2020
3.5
COVID-19, an emerging coronavirus infection: advances and prospects in designing and developing vaccines, immunotherapeutics, and therapeutics
The novel coronavirus infection (COVID-19 or Coronavirus disease 2019) that emerged from Wuhan, Hubei province of China has spread to many countries worldwide. Efforts have been made to develop vaccines against human coronavirus (CoV) infections such as MERS and SARS in the past decades. However, to date, no licensed antiviral treatment or vaccine exists for MERS and SARS. Most of the efforts for developing CoV vaccines and drugs target the spike glycoprotein or S protein, the major inducer of neutralizing antibodies. Although a few candidates have shown efficacy in in vitro studies, not many have progressed to randomized animal or human trials, hence may have limited use to counter COVID-19 infection. This article highlights ongoing advances in designing vaccines and therapeutics to counter COVID-19 while also focusing on such experiences and advances as made with earlier SARS- and MERS-CoVs, which together could enable efforts to halt this emerging virus infection.
ooboeurk
ooboeurk
2020
4.5
Insights into The Codon Usage Bias of 13 Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Isolates from Different Geo-locations
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of Coronavirus disease 2019 (COVID-19) which is an infectious disease that spread throughout the world and was declared as a pandemic by the World Health Organization (WHO). In the present study, we analyzed genome-wide codon usage patterns in 13 SARS-CoV-2 isolates from different geo-locations (countries) by utilizing different CUB measurements. Nucleotide and di-nucleotide compositions displayed bias toward A/U content in all codon positions and CpU-ended codons preference, respectively. Relative Synonymous Codon Usage (RSCU) analysis revealed 8 common putative preferred codons among all the 13 isolates. Interestingly, all of the latter codons are A/U-ended (U-ended: 7, A-ended: 1). Cluster analysis (based on RSCU values) was performed and showed comparable results to the phylogenetic analysis (based on their whole genome sequences) indicating that the CUB pattern may reflect the evolutionary relationship between the tested isolates. To investigate the force (mutation and/or selection) influencing the pattern of CUB in SARS-CoV-2 coding sequences, we employed the following; (i). Effective number of codons (ENc), (ii). ENc-GC3 plot, (iii). Neutrality plot, and (iv) Codon adaptation index (CAI). According to their results, natural selection and/or other factors (not investigated in this study) may be the dominant force driving SARS-CoV-2 CUB. It is also worth mentioning that, by using the most expressed genes in human lung tissues as a reference set, some viral genes such as Nucleocapsid phosphoprotein, ORF7a protein, and surface glycoprotein had high CAI values which may indicate for selection force acting on their codon usage, as they play important roles in viral assembly and may help viruses avoid the host immune system. The outcome of our study may help in understanding the underlying factors involved in the evolution of SARS-CoV-2 viruses, and the interactions with their host. Also, it may aid in vaccine design strategies.
ooj9yqbx
ooj9yqbx
2020-04-04
10.1101/2020.04.01.019463
1.5
Morphological Cell Profiling of SARS-CoV-2 Infection Identifies Drug Repurposing Candidates for COVID-19
The global spread of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and the associated disease COVID-19, requires therapeutic interventions that can be rapidly translated to clinical care. Unfortunately, traditional drug discovery methods have a >90% failure rate and can take 10–15 years from target identification to clinical use. In contrast, drug repurposing can significantly accelerate translation. We developed a quantitative high-throughput screen to identify efficacious single agents and combination therapies against SARS-CoV-2. Quantitative high-content morphological profiling was coupled with an AI-based machine learning strategy to classify features of cells for infection and stress. This assay detected multiple antiviral mechanisms of action (MOA), including inhibition of viral entry, propagation, and modulation of host cellular responses. From a library of 1,425 FDA-approved compounds and clinical candidates, we identified 16 dose-responsive compounds with antiviral effects. In particular, we discovered that lactoferrin is an effective inhibitor of SARS-CoV-2 infection with an IC(50) of 308 nM and that it potentiates the efficacy of both remdesivir and hydroxychloroquine. Lactoferrin also stimulates an antiviral host cell response and retains inhibitory activity in iPSC-derived alveolar epithelial cells, a model for the primary site of infection. Given its safety profile in humans, these data suggest that lactoferrin is a readily translatable therapeutic adjunct for COVID-19. Additionally, several commonly prescribed drugs were found to exacerbate viral infection and warrant clinical investigation. We conclude that morphological profiling for drug repurposing is an effective strategy for the selection and optimization of drugs and drug combinations as viable therapeutic options for COVID-19 pandemic and other emerging infectious diseases.
ort27p77
ort27p77
2020-06-10
10.1101/2020.05.27.117184
4
Lymphopenic community acquired pneumonia as signature of severe COVID-19 infection
osbk041e
osbk041e
2020-05-31
10.1016/j.jinf.2020.02.029
1.5
α-Ketoamides as Broad-Spectrum Inhibitors of Coronavirus and Enterovirus Replication: Structure-Based Design, Synthesis, and Activity Assessment
[Image: see text] The main protease of coronaviruses and the 3C protease of enteroviruses share a similar active-site architecture and a unique requirement for glutamine in the P1 position of the substrate. Because of their unique specificity and essential role in viral polyprotein processing, these proteases are suitable targets for the development of antiviral drugs. In order to obtain near-equipotent, broad-spectrum antivirals against alphacoronaviruses, betacoronaviruses, and enteroviruses, we pursued a structure-based design of peptidomimetic α-ketoamides as inhibitors of main and 3C proteases. Six crystal structures of protease–inhibitor complexes were determined as part of this study. Compounds synthesized were tested against the recombinant proteases as well as in viral replicons and virus-infected cell cultures; most of them were not cell-toxic. Optimization of the P2 substituent of the α-ketoamides proved crucial for achieving near-equipotency against the three virus genera. The best near-equipotent inhibitors, 11u (P2 = cyclopentylmethyl) and 11r (P2 = cyclohexylmethyl), display low-micromolar EC(50) values against enteroviruses, alphacoronaviruses, and betacoronaviruses in cell cultures. In Huh7 cells, 11r exhibits three-digit picomolar activity against the Middle East Respiratory Syndrome coronavirus.
ou61mf3k
ou61mf3k
2020-02-11
10.1021/acs.jmedchem.9b01828
2
An Overview of the Most Significant Zoonotic Viral Pathogens Transmitted from Animal to Human in Saudi Arabia
Currently, there has been an increasing socioeconomic impact of zoonotic pathogens transmitted from animals to humans worldwide. Recently, in the Arabian Peninsula, including in Saudi Arabia, epidemiological data indicated an actual increase in the number of emerging and/or reemerging cases of several viral zoonotic diseases. Data presented in this review are very relevant because Saudi Arabia is considered the largest country in the Peninsula. We believe that zoonotic pathogens in Saudi Arabia remain an important public health problem; however, more than 10 million Muslim pilgrims from around 184 Islamic countries arrive yearly at Makkah for the Hajj season and/or for the Umrah. Therefore, for health reasons, several countries recommend vaccinations for various zoonotic diseases among preventive protocols that should be complied with before traveling to Saudi Arabia. However, there is a shortage of epidemiological data focusing on the emerging and reemerging of zoonotic pathogens transmitted from animal to humans in different densely populated cities and/or localities in Saudi Arabia. Therefore, further efforts might be needed to control the increasing impacts of zoonotic viral disease. Also, there is a need for a high collaboration to enhance the detection and determination of the prevalence, diagnosis, control, and prevention as well as intervention and reduction in outbreaks of these diseases in Saudi Arabia, particularly those from other countries. Persons in the health field including physicians and veterinarians, pet owners, pet store owners, exporters, border guards, and people involved in businesses related to animal products have adopted various preventive strategies. Some of these measures might pave the way to highly successful prevention and control results on the different transmission routes of these viral zoonotic diseases from or to Saudi Arabia. Moreover, the prevention of these viral pathogens depends on socioeconomic impacts, available data, improved diagnosis, and highly effective therapeutics or prophylaxis.
oudj079q
oudj079q
2019-02-22
10.3390/pathogens8010025
1
Small Animal Models of Respiratory Viral Infection Related to Asthma
Respiratory viral infections are strongly associated with asthma exacerbations. Rhinovirus is most frequently-detected pathogen; followed by respiratory syncytial virus; metapneumovirus; parainfluenza virus; enterovirus and coronavirus. In addition; viral infection; in combination with genetics; allergen exposure; microbiome and other pathogens; may play a role in asthma development. In particular; asthma development has been linked to wheezing-associated respiratory viral infections in early life. To understand underlying mechanisms of viral-induced airways disease; investigators have studied respiratory viral infections in small animals. This report reviews animal models of human respiratory viral infection employing mice; rats; guinea pigs; hamsters and ferrets. Investigators have modeled asthma exacerbations by infecting mice with allergic airways disease. Asthma development has been modeled by administration of virus to immature animals. Small animal models of respiratory viral infection will identify cell and molecular targets for the treatment of asthma.
ow0t4mcl
ow0t4mcl
2018-12-01
10.3390/v10120682
1.5
Biosafety and data quality considerations for animal experiments with highly infectious agents at ABSL-3 facilities
Abstract Animal models are crucial for the study of severe infectious diseases, which is essential for determining their pathogenesis and the development of vaccines and drugs. Animal experiments involving risk grade 3 agents such as SARS CoV, HIV, M.tb, H7N9, and Brucella must be conducted in an Animal Biosafety Level 3 (ABSL-3) facility. Because of the in vivo work, the biosafety risk in ABSL-3 facilities is higher than that in BSL-3 facilities. Undoubtedly, management practices must be strengthened to ensure biosafety in the ABSL-3 facility. Meanwhile, we cannot ignore the reliable scientific results obtained from animal experiments conducted in ABSL-3 laboratories. It is of great practical significance to study the overall biosafety concepts that can increase the scientific data quality. Based on the management of animal experiments in the ABSL-3 Laboratory of Wuhan University, combined with relevant international and domestic literature, we indicate the main safety issues and factors affecting animal experiment results at ABSL-3 facilities. Based on these issues, management practices regarding animal experiments in ABSL-3 facilities are proposed, which take into account both biosafety and scientifically sound data.
ow7r8xsf
ow7r8xsf
2019-03-31
10.1016/j.jobb.2018.12.011
1
Virtual Screening of Plant Metabolites against Main protease, RNA-dependent RNA polymerase and Spike protein of SARS-CoV-2: Therapeutics option of COVID-19
Covid-19, a serious respiratory complications caused by SARS-CoV-2 has become one of the global threat to human healthcare system. The present study evaluated the possibility of plant originated approved 117 therapeutics against the main protease protein (MPP), RNA-dependent RNA polymerase (RdRp) and spike protein (S) of SARS-CoV-2 including drug surface analysis by using molecular docking through drug repurposing approaches. The molecular interaction study revealed that Rifampin (-16.3 kcal/mol) were topmost inhibitor of MPP where Azobechalcone were found most potent plant therapeutics for blocking the RdRp (-15.9 kcal /mol) and S (-14.4 kcal/mol) protein of SARS-CoV-2. After the comparative analysis of all docking results, Azobechalcone, Rifampin, Isolophirachalcone, Tetrandrine and Fangchinoline were exhibited as the most potential inhibitory plant compounds for targeting the key proteins of SARS-CoV-2. However, amino acid positions; H41, C145, and M165 of MPP played crucial roles for the drug surface interaction where F368, L371, L372, A375, W509, L514, Y515 were pivotal for RdRP. In addition, the drug interaction surface of S proteins also showed similar patterns with all of its maximum inhibitors. ADME analysis also strengthened the possibility of screened plant therapeutics as the potent drug candidates against SARS-C with the highest drug friendliness.
oyc2djxk
oyc2djxk
2020-05-22
4.5
Novel Coronavirus: Current Understanding of Clinical Features, Diagnosis, Pathogenesis, and Treatment Options
Since December 2019, coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has resulted in devastating consequences worldwide and infected more than 350,000 individuals and killed more than 16,000 people. SARS-CoV-2 is the seventh member of the coronavirus family to affect humans. Symptoms of COVID-19 include fever (88%), cough (68%), vomiting (5%) and diarrhoea (3.7%), and transmission of SARS-CoV-2 is thought to occur from human to human via respiratory secretions released by the infected individuals when coughing and sneezing. COVID-19 can be detected through computed tomography scans and confirmed through molecular diagnostics tools such as polymerase chain reaction. Currently, there are no effective treatments against SARS-CoV-2, hence antiviral drugs have been used to reduce the development of respiratory complications by reducing viral load. The purpose of this review is to provide a comprehensive update on the pathogenesis, clinical aspects, diagnosis, challenges and treatment of SARS-CoV-2 infections.
oyr03uw1
oyr03uw1
2020-04-17
10.3390/pathogens9040297
4
Prediction of repurposed drugs for treating lung injury in COVID-19
Coronavirus disease (COVID-19) is an infectious disease discovered in 2019 and currently in outbreak across the world. Lung injury with severe respiratory failure is the leading cause of death in COVID-19, brought by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). However, there still lacks efficient treatment for COVID-19 induced lung injury and acute respiratory failure. Inhibition of Angiotensin-converting enzyme 2 (ACE2) caused by spike protein of SARS-CoV-2 is the most plausible mechanism of lung injury in COVID-19. We propose two candidate drugs, COL-3 (a chemically modified tetracycline) and CGP-60474 (a cyclin-dependent kinase inhibitor), for treating lung injuries in COVID-19, based on their abilities to reverse the gene expression patterns in HCC515 cells treated with ACE2 inhibitor and in human COVID-19 patient lung tissues. Further bioinformatics analysis shows that twelve significantly enriched pathways (P-value<0.05) overlap between HCC515 cells treated with ACE2 inhibitor and human COVID-19 patient lung tissues, including signaling pathways known to be associated with lung injury such as TNF signaling, MAPK signaling and Chemokine signaling pathways. All these twelve pathways are targeted in COL-3 treated HCC515 cells, in which genes such as RHOA, RAC2, FAS, CDC42 have reduced expression. CGP-60474 shares eleven of twelve pathways with COL-3 with common target genes such as RHOA. It also uniquely targets genes related to lung injury, such as CALR and MMP14. In summary, this study shows that ACE2 inhibition is likely part of the mechanisms leading to lung injury in COVID-19, and that compounds such as COL-3 and CGP-60474 have the potential as repurposed drugs for its treatment.
p1iktm9v
p1iktm9v
2020-03-30
2.5
Lack of small animal model hinders MERS coronavirus research
p2iqzyv4
p2iqzyv4
2013-08-06
10.1038/nm0813-952
2
Genotype and phenotype of COVID-19: Their roles in pathogenesis
Abstract COVID-19 is a novel coronavirus with an outbreak of unusual viral pneumonia in Wuhan, China, and then pandemic. Based on its phylogenetic relationships and genomic structures the COVID-19 belongs to genera Betacoronavirus. Human Betacoronaviruses (SARS-CoV-2, SARS-CoV, and MERS-CoV) have many similarities, but also have differences in their genomic and phenotypic structure that can influence their pathogenesis. COVID-19 is containing single-stranded (positive-sense) RNA associated with a nucleoprotein within a capsid comprised of matrix protein. A typical CoV contains at least six ORFs in its genome. All the structural and accessory proteins are translated from the sgRNAs of CoVs. Four main structural proteins are encoded by ORFs 10, 11 on the one-third of the genome near the 3′-terminus. The genetic and phenotypic structure of COVID-19 in pathogenesis is important. This article highlights the most important of these features compared to other Betacoronaviruses.
p3gswh23
p3gswh23
2020-03-31
10.1016/j.jmii.2020.03.022
1
Functional pangenome analysis suggests inhibition of the protein E as a readily available therapy for COVID-2019
The spread of the novel coronavirus (SARS-CoV-2) has triggered a global emergency, that demands urgent solutions for detection and therapy to prevent escalating health, social and economic impacts. The spike protein (S) of this virus enables binding to the human receptor ACE2, and hence presents a prime target for vaccines preventing viral entry into host cells1. The S proteins from SARS-CoV-1 and SARS-CoV-2 are similar2, but structural differences in the receptor binding domain (RBD) preclude the use of SARS-CoV-1–specific neutralizing antibodies to inhibit SARS-CoV-23. Here we used comparative pangenomic analysis of all sequenced Betacoronaviruses to reveal that, among all core gene clusters present in these viruses, the envelope protein E shows a variant shared by SARS and SARS-Cov2 with two completely-conserved key functional features, an ion-channel and a PDZ-binding Motif (PBM). These features trigger a cytokine storm that activates the inflammasome, leading to increased edema in lungs causing the acute respiratory distress syndrome (ARDS)4-6, the leading cause of death in SARS-CoV-1 and SARS-CoV-2 infection7,8. However, three drugs approved for human use may inhibit SARS-CoV-1 and SARS-CoV-2 Protein E, either acting upon the ion channel (Amantadine and Hexamethylene amiloride9,10) or the PBM (SB2035805), thereby potentially increasing the survival of the host, as already demonstrated for SARS-CoV-1in animal models. Hence, blocking the SARS protein E inhibits development of ARDS in vivo. Given that our results demonstrate that the protein E subcluster for the SARS clade is quasi-identical for the key functional regions of SARS-CoV-1 and SARS-CoV-2, we conclude that use of approved drugs shown to act as SARS E protein inhibitors can help prevent further casualties from COVID-2019 while vaccines and other preventive measures are being developed.
p4q64ksa
p4q64ksa
2020-03-06
10.1101/2020.02.17.952895
0.5
Efficacy of glutathione therapy in relieving dyspnea associated with COVID-19 pneumonia: A report of 2 cases
PURPOSE: Infection with COVID-19 potentially can result in severe outcomes and death from “cytokine storm syndrome”, resulting in novel coronavirus pneumonia (NCP) with severe dyspnea, acute respiratory distress syndrome (ARDS), fulminant myocarditis and multiorgan dysfunction with or without disseminated intravascular coagulation. No published treatment to date has been shown to adequately control the inflammation and respiratory symptoms associated with COVID-19, apart from oxygen therapy and assisted ventilation. We evaluated the effects of using high dose oral and/or IV glutathione in the treatment of 2 patients with dyspnea secondary to COVID-19 pneumonia. METHODS: Two patients living in New York City (NYC) with a history of Lyme and tick-borne co-infections experienced a cough and dyspnea and demonstrated radiological findings consistent with novel coronavirus pneumonia (NCP). A trial of 2 g of PO or IV glutathione was used in both patients and improved their dyspnea within 1 h of use. Repeated use of both 2000 mg of PO and IV glutathione was effective in further relieving respiratory symptoms. CONCLUSION: Oral and IV glutathione, glutathione precursors (N-acetyl-cysteine) and alpha lipoic acid may represent a novel treatment approach for blocking NF-κB and addressing “cytokine storm syndrome” and respiratory distress in patients with COVID-19 pneumonia.
p60xy2ki
p60xy2ki
2020-04-21
10.1016/j.rmcr.2020.101063
2.5
Assessment of SARS-CoV-2 replication in the context of other respiratory viruses
p6agoqu8
p6agoqu8
2020-05-07
10.1016/s2213-2600(20)30227-7
4
Bioengineering tools to speed up the discovery and preclinical testing of vaccines for SARS-CoV-2 and therapeutic agents for COVID-19
This review provides an update for the international research community on the cell modeling tools that could accelerate the understanding of SARS-CoV-2 infection mechanisms and could thus speed up the development of vaccines and therapeutic agents against COVID-19. Many bioengineering groups are actively developing frontier tools that are capable of providing realistic three-dimensional (3D) models for biological research, including cell culture scaffolds, microfluidic chambers for the culture of tissue equivalents and organoids, and implantable windows for intravital imaging. Here, we review the most innovative study models based on these bioengineering tools in the context of virology and vaccinology. To make it easier for scientists working on SARS-CoV-2 to identify and apply specific tools, we discuss how they could accelerate the discovery and preclinical development of antiviral drugs and vaccines, compared to conventional models.
p6jnjigh
p6jnjigh
2020-05-27
10.7150/thno.47406
5
Clinical benefit of remdesivir in rhesus macaques infected with SARS-CoV-2
Background Effective therapeutics to treat COVID-19 are urgently needed. Remdesivir is a nucleotide prodrug with in vitro and in vivo efficacy against coronaviruses. Here, we tested the efficacy of remdesivir treatment in a rhesus macaque model of SARS-CoV-2 infection. Methods To evaluate the effect of remdesivir treatment on SARS-CoV-2 disease outcome, we used the recently established rhesus macaque model of SARS-CoV-2 infection that results in transient lower respiratory tract disease. Two groups of six rhesus macaques were infected with SARS-CoV-2 and treated with intravenous remdesivir or an equal volume of vehicle solution once daily. Clinical, virological and histological parameters were assessed regularly during the study and at necropsy to determine treatment efficacy. Results In contrast to vehicle-treated animals, animals treated with remdesivir did not show signs of respiratory disease and had reduced pulmonary infiltrates on radiographs. Virus titers in bronchoalveolar lavages were significantly reduced as early as 12hrs after the first treatment was administered. At necropsy on day 7 after inoculation, lung viral loads of remdesivir-treated animals were significantly lower and there was a clear reduction in damage to the lung tissue. Conclusions Therapeutic remdesivir treatment initiated early during infection has a clear clinical benefit in SARS-CoV-2-infected rhesus macaques. These data support early remdesivir treatment initiation in COVID-19 patients to prevent progression to severe pneumonia.
p6uliadr
p6uliadr
2020-04-22
10.1101/2020.04.15.043166
2
Evaluation of cotton rats as a model for severe acute respiratory syndrome.
Experimental studies were conducted to evaluate two species of cotton rats, Sigmodon hispidus and Sigmodon fulviventer, as a model for severe acute respiratory syndrome (SARS). Blood and turbinate wash samples, and lung tissue were collected from each animal at different time points after SARS coronavirus (CoV) infection for determining the growth curve of virus, if any, by the standard infectivity assay in Vero E6 cells. In addition, sections of the lung, liver, spleen, and kidney were taken and used for histology analysis. All animals were observed daily for signs of illness, and in some experiments, animals were weighed on the day when they were sacrificed. The results indicated that the cotton rat species, S. hispidus and S. fulviventer, were not a useful model for either SARS-CoV infection or disease. This observation was supported by the absence of any signs of illness, the failure to consistently demonstrate virus in the blood and tissues, and the absent of any notable histopathology. However, infected animals were capable of producing neutralizing antibodies against SARS-CoV, suggesting the seroconversion did occur. Further studies are warranted to consider other animal species in efforts to find better animal models for the evaluation of SARS-CoV vaccines and antiviral drugs.
p711pmu1
p711pmu1
2008
10.1089/vbz.2007.0210
1
Does SARS‐Cov‐2 invade the brain? Translational lessons from animal models
The current coronavirus disease (COVID‐19) outbreak, caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2), has raised the possibility of potential neurotropic properties of this virus. Indeed, neurological sequelae of SARS‐CoV‐2 infection have already been reported and highlight the relevance of considering the neurological impact of coronavirus (CoV) from a translational perspective. Animal models of SARS and Middle East respiratory syndrome, caused by structurally similar CoVs during the 2002 and 2012 epidemics, have provided valuable data on nervous system involvement by CoVs and the potential for central nervous system spread of SARS‐CoV‐2. One key finding that may unify these pathogens is that all require angiotensin‐converting enzyme 2 as a cell entry receptor. The CoV spike glycoprotein, by which SARS‐CoV‐2 binds to cell membranes, binds angiotensin‐converting enzyme 2 with a higher affinity compared with SARS‐CoV. The expression of this receptor in neurons and endothelial cells hints that SARS‐CoV‐2 may have higher neuroinvasive potential compared with previous CoVs. However, it remains to be determined how such invasiveness might contribute to respiratory failure or cause direct neurological damage. Both direct and indirect mechanisms may be of relevance. Clinical heterogeneity potentially driven by differential host immune‐mediated responses will require extensive investigation. Development of disease models to anticipate emerging neurological complications and to explore mechanisms of direct or immune‐mediated pathogenicity in the short and medium term is therefore of great importance. In this brief review, we describe the current knowledge from models of previous CoV infections and discuss their potential relevance to COVID‐19.
p93gxjm2
p93gxjm2
2020-05-22
10.1111/ene.14277
3
The novel coronavirus 2019 epidemic and kidneys
p94phf68
p94phf68
2020-03-07
10.1016/j.kint.2020.03.001
1.5
Design an efficient multi-epitope peptide vaccine candidate against SARS-CoV-2: An in silico analysis
Background To date, no specific vaccine or drug has been proven to be effective for SARS-CoV-2 infection. Therefore, we implemented immunoinformatics approach to design an efficient multi-epitopes vaccine against SARS-CoV-2. Results The designed vaccine construct has several immunodominant epitopes from structural proteins of Spike, Nucleocapsid, Membrane and Envelope. These peptides promote cellular and humoral immunity and Interferon gamma responses. In addition, these epitopes have antigenicity ability and no allergenicity probability. To enhance the vaccine immunogenicity, we used three potent adjuvants; Flagellin, a driven peptide from high mobility group box 1 as HP-91 and human beta defensin 3 protein. The physicochemical and immunological properties of the vaccine structure were evaluated. Tertiary structure of the vaccine protein was predicted and refined by I-Tasser and galaxi refine and validated using Rampage and ERRAT. Results of Ellipro showed 242 residues from vaccine might be conformational B cell epitopes. Docking of vaccine with Toll-Like Receptors 3, 5 and 8 proved an appropriate interaction between the vaccine and receptor proteins. In silico cloning demonstrated that the vaccine can be efficiently expressed in Escherichia coli. Conclusions The designed multi epitope vaccine is potentially antigenic in nature and has the ability to induce humoral and cellular immune responses against SARS-CoV-2. This vaccine can interact appropriately with the TLR3, 5, and 8. Also, this vaccine has high quality structure and suitable characteristics such as high stability and potential for expression in Escherichia coli.
p9507cwx
p9507cwx
2020-04-20
10.1101/2020.04.20.051557
2.5
The Forrest Gump approach to preventing severe COVID-19 – reverse the predisposing pro-inflammatory state with exercise
p9vbeffv
p9vbeffv
2020-05-06
10.1016/j.micinf.2020.05.003
4.5
Imbalanced Host Response to SARS-CoV-2 Drives Development of COVID-19
Viral pandemics, such as the one caused by SARS-CoV-2, pose an imminent threat to humanity. Because of its recent emergence, there is a paucity of information regarding viral behavior and host response following SARS-CoV-2 infection. Here we offer an in-depth analysis of the transcriptional response to SARS-CoV-2 compared with other respiratory viruses. Cell and animal models of SARS-CoV-2 infection, in addition to transcriptional and serum profiling of COVID-19 patients, consistently revealed a unique and inappropriate inflammatory response. This response is defined by low levels of type I and III interferons juxtaposed to elevated chemokines and high expression of IL-6. We propose that reduced innate antiviral defenses coupled with exuberant inflammatory cytokine production are the defining and driving features of COVID-19.
pcekcvwr
pcekcvwr
2020-05-15
10.1016/j.cell.2020.04.026
3
Focus on a 2019-novel coronavirus (SARS-CoV-2)
A new coronavirus, severe acute respiratory syndrome coronavirus 2, was first discovered in Wuhan, China, in December 2019. As of April 7, 2020, the new coronavirus has spread quickly to 184 countries and aroused the attention of the entire world. No targeted drugs have yet been available for intervention and treatment of this virus. The sharing of academic information is crucial to risk assessment and control activities in outbreak countries. In this review, we summarize the epidemiological, genetic and clinical characteristics of the virus as well as laboratory testing and treatments to understand the nature of the virus. We hope this review will be helpful to prevent viral infections in outbreak countries and regions.
pem059zk
pem059zk
2020-06-11
10.2217/fmb-2020-0063
4
SARS-CoV-2 detection from nasopharyngeal swab samples without RNA extraction
The ongoing COVID-19 pandemic has reached more than 200 countries and territories worldwide. Given the large requirement of SARS-CoV-2 diagnosis and considering that RNA extraction kits are in short supply, we investigated whether two commercial RT-qPCR kits were compatible with direct SARS-CoV-2 detection from nasopharyngeal swab samples. We show that one of the tested kits is fully compatible with direct SARS-CoV-2 detection suggesting that omission of an RNA extraction step should be considered in SARS-CoV-2 diagnosis.
pg6893i5
pg6893i5
2020-03-30
10.1101/2020.03.28.013508
1.5
A search for medications to treat COVID-19 via in silico molecular docking models of the SARS-CoV-2 spike glycoprotein and 3CL protease
Abstract Background The COVID-19 has now been declared a global pandemic by the World Health Organization. There is an emergent need to search for possible medications. Method Utilization of the available sequence information, homology modeling, and in slico docking a number of available medications might prove to be effective in inhibiting the SARS-CoV-2 two main drug targets, the spike glycoprotein, and the 3CL protease. Results Several compounds were determined from the in silico docking models that might prove to be effective inhibitors for SARS-CoV-2. Several antiviral medications: Zanamivir, Indinavir, Saquinavir, and Remdesivir show potential as and 3CLPRO main proteinase inhibitors and as a treatment for COVID-19. Conclusion Zanamivir, Indinavir, Saquinavir, and Remdesivir are among the exciting hits on the 3CLPRO main proteinase. It is also exciting to uncover that Flavin Adenine Dinucleotide (FAD) Adeflavin, B2 deficiency medicine, and Coenzyme A, a coenzyme, may also be potentially used for the treatment of SARS-CoV-2 infections. The use of these off-label medications may be beneficial in the treatment of the COVID-19.
pgxew3yk
pgxew3yk
2020-04-12
10.1016/j.tmaid.2020.101646
2
Pandemic COVID-19: current status and challenges of antiviral therapies
Abstract The pandemic COVID-19, caused by a new coronavirus SARS-CoV-2 infection, has infected over 6 million individuals and caused more than 364,000 death worldwide. Currently, there is no specific drug to treating this disease. Here we summarized the mechanisms of antiviral therapies and the clinic findings from different countries. Antiviral chemotherapies have been conducted by in multiple cohorts in different counties. Although FDA has fast approved remdesivir for treating COVID-19, it only speeds up recovery from COVID-19 with mildly reduced mortality. The chloroquine was suggested a potential drug against SARS-CoV-2 infection due to its in vitro antiviral effects, it is imperative high-quality data from worldwide clinical trials are necessitated for an approved therapy. In terms of hydroxychloroquine (HCQ) therapy, although WHO has stopped all the clinic trials due to its strong side-effects in COVID patients, large scale clinical trials with a long-term outcome follow-up may warrant HCQ and azithromycin combination in combating the virus. Convalescent plasma (CP) therapy suggested its safety use in SARS-CoV-2 infection; but both CP immunotherapy and NK cellular therapy must be manufactured and utilized according to scrupulous ethical and controlled conditions to guarantee a possible role of these products of human origin. Further research should be conducted to define the exact mechanism of SARS-CoV-2 pathogenesis, suitable animal models or ex vivo human lung tissues aid in studying replication, transmission and spread of the novel viruses, thereby facilitating highly effective therapies.
phby6ouv
phby6ouv
2020-07-07
10.1016/j.gendis.2020.07.001
5
A search for medications to treat COVID-19 via in silico molecular docking models of the SARS-CoV-2 spike glycoprotein and 3CL protease
BACKGROUND: The COVID-19 has now been declared a global pandemic by the World Health Organization. There is an emergent need to search for possible medications. METHOD: Utilization of the available sequence information, homology modeling, and in slico docking a number of available medications might prove to be effective in inhibiting the SARS-CoV-2 two main drug targets, the spike glycoprotein, and the 3CL protease. RESULTS: Several compounds were determined from the in silico docking models that might prove to be effective inhibitors for SARS-CoV-2. Several antiviral medications: Zanamivir, Indinavir, Saquinavir, and Remdesivir show potential as and 3CLPRO main proteinase inhibitors and as a treatment for COVID-19. CONCLUSION: Zanamivir, Indinavir, Saquinavir, and Remdesivir are among the exciting hits on the 3CLPRO main proteinase. It is also exciting to uncover that Flavin Adenine Dinucleotide (FAD) Adeflavin, B2 deficiency medicine, and Coenzyme A, a coenzyme, may also be potentially used for the treatment of SARS-CoV-2 infections. The use of these off-label medications may be beneficial in the treatment of the COVID-19.
phxu6usy
phxu6usy
2020
4.5
Research and Development on Therapeutic Agents and Vaccines for COVID-19 and Related Human Coronavirus Diseases
Since the outbreak of the novel coronavirus disease COVID-19, caused by the SARS-CoV-2 virus, this disease has spread rapidly around the globe. Considering the potential threat of a pandemic, scientists and physicians have been racing to understand this new virus and the pathophysiology of this disease to uncover possible treatment regimens and discover effective therapeutic agents and vaccines. To support the current research and development, CAS has produced a special report to provide an overview of published scientific information with an emphasis on patents in the CAS content collection. It highlights antiviral strategies involving small molecules and biologics targeting complex molecular interactions involved in coronavirus infection and replication. The drug-repurposing effort documented herein focuses primarily on agents known to be effective against other RNA viruses including SARS-CoV and MERS-CoV. The patent analysis of coronavirusrelated biologics includes therapeutic antibodies, cytokines, and nucleic acid-based therapies targeting virus gene expression as well as various types of vaccines. More than 500 patents disclose methodologies of these four biologics with the potential for treating and preventing coronavirus infections, which may be applicable to COVID-19. The information included in this report provides a strong intellectual groundwork for the ongoing development of therapeutic agents and vaccines.
pidar1gz
pidar1gz
2020-03-12
10.1021/acscentsci.0c00272
1
A highly conserved cryptic epitope in the receptor-binding domains of SARS-CoV-2 and SARS-CoV
The outbreak of COVID-19 caused by SARS-CoV-2 virus has now become a pandemic, but there is currently very little understanding of the antigenicity of the virus. We therefore determined the crystal structure of CR3022, a neutralizing antibody previously isolated from a convalescent SARS patient, in complex with the receptor-binding domain (RBD) of the SARS-CoV-2 spike (S) protein to 3.1 Å. CR3022 targets a highly conserved epitope, distal from the receptor-binding site, that enables cross-reactive binding between SARS-CoV-2 and SARS-CoV. Structural modeling further demonstrates that the binding epitope can only be accessed by CR3022 when at least two RBD on the trimeric S protein are in the “up” conformation and slightly rotated. Overall, this study provides molecular insights into antibody recognition of SARS-CoV-2.
pkxc2219
pkxc2219
2020-04-03
10.1126/science.abb7269
3.5
Animal models for emerging coronavirus: progress and new insights
The emergences of coronaviruses have caused a serious global public health problem because their infection in humans caused the severe acute respiratory disease and deaths. The outbreaks of lethal coronaviruses have taken place for three times within recent two decades (SARS-CoV in 2002, MERS-CoV in 2012 and SARS-CoV-2 in 2019). Much more serious than SARS-CoV in 2002, the current SARS-CoV-2 infection has been spreading to more than 213 countries, areas or territories and causing more than two million cases up to date (17 April 2020). Unfortunately, no vaccine and specific anti-coronavirus drugs are available at present time. Current clinical treatment at hand is inadequate to suppress viral replication and inflammation, and reverse organ failure. Intensive research efforts have focused on increasing our understanding of viral biology of SARS-CoV-2, improving antiviral therapy and vaccination strategies. The animal models are important for both the fundamental research and drug discovery of coronavirus. This review aims to summarize the animal models currently available for SARS-CoV and MERS-CoV, and their potential use for the study of SARS-CoV-2. We will discuss the benefits and caveats of these animal models and present critical findings that might guide the fundamental studies and urgent treatment of SARS-CoV-2-caused diseases.
pld0clpd
pld0clpd
2020-05-13
10.1080/22221751.2020.1764871
3
Prevalence, Severity and Mortality associated with COPD and Smoking in patients with COVID-19: A Rapid Systematic Review and Meta-Analysis
Background: Coronavirus disease 2019 (COVID-19) is an evolving infectious disease that dramatically spread all over the world in the early part of 2020. No studies have yet summarised the potential severity and mortality risks caused by COVID-19 in patients with chronic obstructive pulmonary disease (COPD), and we update information in smokers. Methods: We systematically searched electronic databases from inception to March 24, 2020. Data were extracted by two independent authors in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines. Study quality was assessed using a modified version of the Newcastle Ottawa Scale. We synthesised a narrative from eligible studies and conducted a meta-analysis using a random-effects model to calculate pooled prevalence rates and 95% confidence intervals (95%CI). Results: In total, 123 abstracts were screened and 61 full-text manuscripts were reviewed. A total of 15 studies met the inclusion criteria, which included a total of 2473 confirmed COVID-19 patients. All studies were included in the meta-analysis. The crude case fatality rate of COVID-19 was 6.4%. The pooled prevalence rates of COPD patients and smokers in COVID-19 cases were 2% (95% CI, 1%-3%) and 9% (95% CI, 4%-14%) respectively. COPD patients were at a higher risk of more severe disease (risk of severity = 63%, (22/35) compared to patients without COPD 33.4% (409/1224) [calculated RR, 1.88 (95% CI, 1.4-2.4)]. This was associated with higher mortality (60%). Our results showed that 22% (31/139) of current smokers and 46% (13/28) of ex-smokers had severe complications. The calculated RR showed that current smokers were 1.45 times more likely [95% CI: 1.03-2.04] to have severe complications compared to former and never smokers. Current smokers also had a higher mortality rate of 38.5%. Conclusion: Although COPD prevalence in COVID-19 cases was low in current reports, COVID-19 infection was associated with substantial severity and mortality rates in COPD. Compared to former and never smokers, current smokers were at greater risk of severe complications and higher mortality rate. Effective preventive measures are required to reduce COVID-19 risk in COPD patients and current smokers.
plfjkp5f
plfjkp5f
2020-03-27
10.1101/2020.03.25.20043745
1
Acetazolamide, Nifedipine and Phosphodiesterase Inhibitors: Rationale for Their Utilization as Adjunctive Countermeasures in the Treatment of Coronavirus Disease 2019 (COVID-19)
Effective treatments for Coronavirus Disease 2019 (COVID-19) outbreak are urgently needed. While anti-viral approaches and vaccines are being considered immediate countermeasures are unavailable. The aim of this article is to outline a perspective on the pathophysiology of COVID-19 in the context of the currently available clinical data published in the literature. This article appreciates clinical data published on COVID-19 in the context of another respiratory illness - high altitude pulmonary edema (HAPE). Both conditions have significant similarities that portend pathophysiologic trajectories. Following this potential treatment options emerge. Both COVID-19 and HAPE exhibit a decreased ratio of arterial oxygen partial pressure to fractional inspired oxygen with concomitant hypoxia and tachypnea. There also appears to be a tendency for low carbon dioxide levels in both as well. Radiologic findings of ground glass opacities are present in up to 86% of patients with COVID-19 in addition to patchy infiltrates. Patients with HAPE also exhibit patchy infiltrates throughout the pulmonary fields, often in an asymmetric pattern and CT findings reveal increased lung markings and ground glass-like changes as well. Widespread ground-glass opacities are most commonly a manifestation of hydrostatic pulmonary edema. Similarly, elevated fibrinogen levels in both conditions are likely an epiphenomenon of edema formation rather than coagulation activation. Autopsy results of a COVID-19 fatality revealed bilateral diffuse alveolar damage associated with pulmonary edema, pro-inflammatory concentrates, and indications of early-phase acute respiratory distress syndrome (ARDS). HAPE itself is initially caused by an increase in pulmonary capillary pressure and induces altered alveolar-capillary permeability via high pulmonary artery hydrostatic pressures that lead to a protein-rich and mildly hemorrhagic edema. It appears that COVID-19 and HAPE both discretely converge on ARDS. In light of this, a countermeasure that has been shown to be effective in the analogous condition of HAPE is Acetazolamide. Acetazolamide has a myriad of effects on different organ systems, potently reduces hypoxic pulmonary vasoconstriction, improves minute ventilation and expired vital capacity. Other therapeutics to consider that are also directed towards decreased pulmonary pressure include Nifedipine and Phosphodiesterase inhibitors. This review describes COVID-19 in parallel to HAPE. Deranged respiratory parameters that are present in both conditions are highlighted. The utilization of medications found to be effective in HAPE, for the treatment of COVID-19, is proposed. Given the medical emergency of a growing contagion and the thousands of lives at stake, expedient attempts to improve survival are needed. Acetazolamide, Nifedipine and Phosphodiesterase inhibitors may be potential countermeasures.
plpwjj4s
plpwjj4s
2020-03-20
10.7759/cureus.7343
1.5
SARS-CoV-2: an Emerging Coronavirus that Causes a Global Threat
An ongoing outbreak of pneumonia caused by a novel coronavirus, currently designated as the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), was reported recently. However, as SARS-CoV-2 is an emerging virus, we know little about it. In this review, we summarize the key events occurred during the early stage of SARS-CoV-2 outbreak, the basic characteristics of the pathogen, the signs and symptoms of the infected patients as well as the possible transmission pathways of the virus. Furthermore, we also review the current knowledge on the origin and evolution of the SARS-CoV-2. We highlight bats as the potential natural reservoir and pangolins as the possible intermediate host of the virus, but their roles are waiting for further investigation. Finally, the advances in the development of chemotherapeutic options are also briefly summarized.
plxz5mkg
plxz5mkg
2020-03-15
10.7150/ijbs.45053
0.5
An investigation into the identification of potential inhibitors of SARS-CoV-2 main protease using molecular docking study
A new strain of a novel infectious disease affecting millions of people, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has recently been declared as a pandemic by the World Health Organization (WHO). Currently, several clinical trials are underway to identify specific drugs for the treatment of this novel virus. The inhibition of the SARS-CoV-2 main protease is necessary for the blockage of the viral replication. Here, in this study, we have utilized a blind molecular docking approach to identify the possible inhibitors of the SARS-CoV-2 main protease, by screening a total of 33 molecules which includes natural products, anti-virals, anti-fungals, anti-nematodes and anti-protozoals. All the studied molecules could bind to the active site of the SARS-CoV-2 protease (PDB: 6Y84), out of which rutin (a natural compound) has the highest inhibitor efficiency among the 33 molecules studied, followed by ritonavir (control drug), emetine (anti-protozoal), hesperidin (a natural compound), lopinavir (control drug) and indinavir (anti-viral drug). All the molecules, studied out here could bind near the crucial catalytic residues, HIS41 and CYS145 of the main protease, and the molecules were surrounded by other active site residues like MET49, GLY143, HIS163, HIS164, GLU166, PRO168, and GLN189. As this study is based on molecular docking, hence being particular about the results obtained, requires extensive wet-lab experimentation and clinical trials under in vitro as well as in vivo conditions. Communicated by Ramaswamy H. Sarma
pn2zieek
pn2zieek
2020-05-13
10.1080/07391102.2020.1763201
5
Identification of Human Single-Domain Antibodies against SARS-CoV-2
The worldwide spread of COVID-19 highlights the need for an efficient approach to rapidly develop therapeutics and prophylactics against SARS-CoV-2. The SARS-CoV-2 spike protein, containing the receptor-binding domain (RBD) and S1 subunit involved in receptor engagement, is a potential therapeutic target. We describe the development of a phage-displayed single-domain antibody library by grafting naive complementarity-determining regions (CDRs) into framework regions of a human germline immunoglobulin heavy chain variable region (IGHV) allele. Panning this library against SARS-CoV-2 RBD and S1 subunit identified fully human single-domain antibodies targeting five distinct epitopes on SARS-CoV-2 RBD with subnanomolar to low nanomolar affinities. Some of these antibodies neutralize SARS-CoV-2 by targeting a cryptic epitope located in the spike trimeric interface. Collectively, this work presents a versatile platform for rapid antibody isolation and identifies promising therapeutic anti-SARS-CoV-2 antibodies as well as the diverse immogneic profile of the spike protein.
ppdsgi9o
ppdsgi9o
2020
3.5
The SARS-CoV-2 receptor, ACE-2, is expressed on many different cell types: implications for ACE-inhibitor- and angiotensin II receptor blocker-based cardiovascular therapies
SARS-CoV-2 is characterized by a spike protein allowing viral binding to the angiotensin-converting enzyme (ACE)-2, which acts as a viral receptor and is expressed on the surface of several pulmonary and extra-pulmonary cell types, including cardiac, renal, intestinal and endothelial cells. There is evidence that also endothelial cells are infected by SARS-COV-2, with subsequent occurrence of systemic vasculitis, thromboembolism and disseminated intravascular coagulation. Those effects, together with the "cytokine storm" are involved in a worse prognosis. In clinical practice, angiotensin-converting enzyme inhibitors (ACE-Is) and angiotensin II receptor blockers (ARBs) are extensively used for the treatment of hypertension and other cardiovascular diseases. In in vivo studies, ACE-Is and ARBs seem to paradoxically increase ACE-2 expression, which could favour SARS-CoV-2 infection of host's cells and tissues. By contrast, in patients treated with ACE-Is and ARBs, ACE-2 shows a downregulation at the mRNA and protein levels in kidney and cardiac tissues. Yet, it has been claimed that both ARBs and ACE-Is could result potentially useful in the clinical course of SARS-CoV-2-infected patients. As detected in China and as the Italian epidemiological situation confirms, the most prevalent comorbidities in deceased patients with COVID-19 are hypertension, diabetes and cardiovascular diseases. Older COVID-19-affected patients with cardiovascular comorbidities exhibit a more severe clinical course and a worse prognosis, with many of them being also treated with ARBs or ACE-Is. Another confounding factor is cigarette smoking, which has been reported to increase ACE-2 expression in both experimental models and humans. Sex also plays a role, with chromosome X harbouring the gene coding for ACE-2, which is one of the possible explanations of why mortality in female patients is lower. Viral entry also depends on TMPRSS2 protease activity, an androgen dependent enzyme. Despite the relevance of experimental animal studies, to comprehensively address the question of the potential hazards or benefits of ACE-Is and ARBs on the clinical course of COVID-19-affected patients treated by these anti-hypertensive drugs, we will need randomized human studies. We claim the need of adequately powered, prospective studies aimed at answering the following questions of paramount importance for cardiovascular, internal and emergency medicine: Do ACE-Is and ARBs exert similar or different effects on infection or disease course? Are such effects dangerous, neutral or even useful in older, COVID-19-affected patients? Do they act on multiple cell types? Since ACE-Is and ARBs have different molecular targets, the clinical course of SARS-CoV-2 infection could be also different in patients treated by one or the other of these two drug classes. At present, insufficient detailed data from trials have been made available.
ppo3ryi5
ppo3ryi5
2020
4
Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) and the Central Nervous System
Emerging evidence indicates that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the etiologic agent of COVID-19, can cause neurological complications. We provide a brief overview of these recent observations and discuss some of their possible implications. In particular, given the global dimension of the current pandemic, we highlight the need to consider the possible long-term impact of COVID-19, potentially including neurological and neurodegenerative disorders.
prxzcp1x
prxzcp1x
2020-04-21
10.1016/j.tins.2020.04.004
2.5
Towards a solution to MERS: protective human monoclonal antibodies targeting different domains and functions of the MERS-coronavirus spike glycoprotein
The Middle-East respiratory syndrome coronavirus (MERS-CoV) is a zoonotic virus that causes severe and often fatal respiratory disease in humans. Efforts to develop antibody-based therapies have focused on neutralizing antibodies that target the receptor binding domain of the viral spike protein thereby blocking receptor binding. Here, we developed a set of human monoclonal antibodies that target functionally distinct domains of the MERS-CoV spike protein. These antibodies belong to six distinct epitope groups and interfere with the three critical entry functions of the MERS-CoV spike protein: sialic acid binding, receptor binding and membrane fusion. Passive immunization with potently as well as with poorly neutralizing antibodies protected mice from lethal MERS-CoV challenge. Collectively, these antibodies offer new ways to gain humoral protection in humans against the emerging MERS-CoV by targeting different spike protein epitopes and functions.
psfusppi
psfusppi
2019-04-02
10.1080/22221751.2019.1597644
1
UniProt: a worldwide hub of protein knowledge
The UniProt Knowledgebase is a collection of sequences and annotations for over 120 million proteins across all branches of life. Detailed annotations extracted from the literature by expert curators have been collected for over half a million of these proteins. These annotations are supplemented by annotations provided by rule based automated systems, and those imported from other resources. In this article we describe significant updates that we have made over the last 2 years to the resource. We have greatly expanded the number of Reference Proteomes that we provide and in particular we have focussed on improving the number of viral Reference Proteomes. The UniProt website has been augmented with new data visualizations for the subcellular localization of proteins as well as their structure and interactions. UniProt resources are available under a CC-BY (4.0) license via the web at https://www.uniprot.org/.
pt7v3gb4
pt7v3gb4
2019-01-08
10.1093/nar/gky1049
1.5
Asymptomatic carrier state, acute respiratory disease, and pneumonia due to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2): Facts and myths
Abstract Since the emergence of coronavirus disease 2019 (COVID-19) (formerly known as the 2019 novel coronavirus [2019-nCoV]) in Wuhan, China in December 2019, which is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), more than 75,000 cases have been reported in 32 countries/regions, resulting in more than 2000 deaths worldwide. Despite the fact that most COVID-19 cases and mortalities were reported in China, the WHO has declared this outbreak as the sixth public health emergency of international concern. The COVID-19 can present as an asymptomatic carrier state, acute respiratory disease, and pneumonia. Adults represent the population with the highest infection rate; however, neonates, children, and elderly patients can also be infected by SARS-CoV-2. In addition, nosocomial infection of hospitalized patients and healthcare workers, and viral transmission from asymptomatic carriers are possible. The most common finding on chest imaging among patients with pneumonia was ground-glass opacity with bilateral involvement. Severe cases are more likely to be older patients with underlying comorbidities compared to mild cases. Indeed, age and disease severity may be correlated with the outcomes of COVID-19. To date, effective treatment is lacking; however, clinical trials investigating the efficacy of several agents, including remdesivir and chloroquine, are underway in China. Currently, effective infection control intervention is the only way to prevent the spread of SARS-CoV-2.
pth2d40p
pth2d40p
2020-03-04
10.1016/j.jmii.2020.02.012
1.5
Effectiveness and safety of antiviral or antibody treatments for coronavirus: A rapid review
Background: To identify safe and effective medical countermeasures (e.g., antivirals/antibodies) to address the current outbreak of a novel coronavirus (COVID-19) Methods: Comprehensive literature searches were developed by an experienced librarian for MEDLINE, EMBASE, the Cochrane Library, and biorxiv.org/medrxiv.org; additional searches for ongoing trials and unpublished studies were conducted in clinicaltrials.gov and the Global Infectious Diseases and Epidemiology Network (GIDEON). Title/abstract and full-text screening, data abstraction, and risk of bias appraisal were carried out by single reviewers. Results: 54 studies were included in the review: three controlled trials, 10 cohort studies, seven retrospective medical record/database studies, and 34 case reports or series. These studies included patients with severe acute respiratory syndrome (SARs, n=33), middle east respiratory syndrome (MERS, n=16), COVID-19 (n=3), and unspecified coronavirus (n=2). The most common treatment was ribavirin (n=41), followed by oseltamivir (n=10) and the combination of lopinavir/ritonavir (n=7). Additional therapies included broad spectrum antibiotics (n=30), steroids (n=39) or various interferons (n=12). No eligible studies examining monoclonal antibodies for COVID-19 were identified. One trial found that ribavirin prophylactic treatment statistically significantly reduced risk of MERS infection in people who had been exposed to the virus. Of the 21 studies reporting rates of ICU admission in hospitalized SARS or MERS patients, none reported statistically significant results in favour of or against antiviral therapies. Of the 40 studies reporting mortality rates in hospitalized SARS or MERS patients, one cohort study (MERS) and one retrospective study (SARS) found a statistically significant increase in the mortality rate for patients treated with ribavirin. Eighteen studies reported potential drug-related adverse effects including gastrointestinal symptoms, anemia, and altered liver function in patients receiving ribavirin. Conclusion: The current evidence for the effectiveness and safety of antiviral therapies for coronavirus is inconclusive and suffers from a lack of well-designed prospective trials or observational studies, preventing any treatment recommendations from being made. However, it is clear that the existing body of evidence is weighted heavily towards ribavirin (41/54 studies), which has not shown conclusive evidence of effectiveness and may cause harmful adverse events so future investigations may consider focusing on other candidates for antiviral therapy.
ptnmtvzj
ptnmtvzj
2020-03-23
10.1101/2020.03.19.20039008
1.5
Molecular mechanism of action of repurposed drugs and traditional Chinese medicine used for the treatment of patients infected with COVID-19: A systematic review
The emergence of COVID-19 as a pandemic has resulted in the need for urgent development of vaccines and drugs and the conduction of clinical trials to fight the outbreak. Because of the time constraints associated with the development of vaccines and effective drugs, drug repurposing and other alternative treatment methods have been used to treat patients that have been infected by the SARS-CoV-2 virus and have acquired COVID-19. In this systematic review, we provide an overview of the molecular mechanism of action of repurposed drugs or alternative treatment medicines used to attenuate COVID-19 disease. The research articles or grey literature, including theses, government reports, and official news online, were identified from 4 databases and 1 search engine. The full content of a total of 160 articles that fulfilled our inclusion criteria was analyzed and information about 6 drugs (ritonavir, lopinavir, oseltamivir, remdesivir, favipiravir, and chloroquine) and 4 traditional Chinese medicines (Shuang Huang Lian Kou Fu Ye, TCM combination of Bu Huan Jin Zheng Qi San and Da Yuan Yin, Xue Bi Jing Injection and Qing Fei Pai Du Tang) were extracted. All of the drug treatment options depend on the ability of the drug to inhibit the proliferation of the SARS-CoV-2 virus by binding to enzyme active sites, viral chain termination, or triggering of the molecular pathway, whereas traditional Chinese medicine has a pivotal role in triggering the inflammation pathway, such as the neuraminidase blocker, to fight the SARS-CoV-2 virus. This review provides an insight to experimental validation of drugs and alternative medicine used for the treatment and control of COVID-19.
pu6wni0e
pu6wni0e
2020-04-14
10.1101/2020.04.10.20060376
2
Remdesivir, the antiviral hope against SARS-CoV-2/ Remdesivir, la esperanza antiviral frente al SARS-CoV-2
On December 31, 2019 a pneumonia outbreak caused by a new coronavirus (SARS-CoV-2) was detected in the city of Wuhan (China) Due to the high capacity of diffusion and human infection it has become a new zoonotic pandemic The absence of a vaccine has determined the search for antiviral drugs with the capacity to inhibit the replication of the new virus Among them, remdesivir, an analogue of adenosine, is what seems to have a more promising future This drug has shown in vitro and in animals a high capacity to block infection and viral replication with attainable concentrations in human plasma Although all studies have been carried out with SARS-CoV and MERS-CoV, it seems that by virological and functional analogy, remdesivir is one of the few antiviral drugs with proven efficacy However, studies and clinical trials in humans are required to know the result of their application in them
puc13jf1
puc13jf1
2020
10.37201/req/098.2020
3
The molecular biology of intracellular events during Coronavirus infection cycle
CoV-2 which is the causative agent of COVID-19 belongs to genus betacoronaviruses. The sequence analysis of S protein of CoV-2 has shown that it has acquired a ‘polybasic cleavage site’ consisting of 12 aminoacids that has been predicted to enable its cleavage by other cellular proteases possibly increasing its transmissibility. The aminoacids present in receptor binding domain of S protein of SARS CoV which are critical for its binding to cellular receptor are different in CoV-2. The presence of heptanucleotide slippery sequence in ORF1 resulting in ribosomal frameshifting, and presence of transcription regulatory sequences between ORFs resulting in discontinuous transcription, are peculiar features of Coronavirus infection cycle. The exonuclease activity of nsp14 provides possible proofreading ability to RNA polymerase makes coronaviruses different from other RNA viruses allowing coronaviruses to maintain their relatively large genome size. This mini-review summarizes the peculiar features of Coronaviruses genome and the critical events during the infection cycle with focus on CoV-2.
pulb3lhf
pulb3lhf
2020-05-04
10.1007/s13337-020-00591-1
3
In silico comparison of spike protein-ACE2 binding affinities across species; significance for the possible origin of the SARS-CoV-2 virus
The devastating impact of the COVID19 pandemic caused by SARS coronavirus 2 (SARSCoV2) has raised important questions on the origins of this virus, the mechanisms of any zoonotic transfer from exotic animals to humans, whether companion animals or those used for commercial purposes can act as reservoirs for infection, and the reasons for the large variations in susceptibilities across animal species. Traditional lab-based methods will ultimately answer many of these questions but take considerable time. In silico modeling methods provide the opportunity to rapidly generate information on newly emerged pathogens to aid countermeasure development and also to predict potential future behaviors. We used a structural homology modeling approach to characterize the SARSCoV2 spike protein and predict its binding strength to the human ACE2 receptor. We then explored the possible transmission path by which SARSCoV2 might have crossed to humans by constructing models of ACE2 receptors of relevant species, and calculating the binding energy of SARSCoV2 spike protein to each. Notably, SARSCoV2 spike protein had the highest overall binding energy for human ACE2, greater than all the other tested species including bat, the postulated source of the virus. This indicates that SARSCoV2 is a highly adapted human pathogen. Of the species studied, the next highest binding affinity after human was pangolin, which is most likely explained by a process of convergent evolution. Binding of SARSCoV2 for dog and cat ACE2 was similar to affinity for bat ACE2, all being lower than for human ACE2, and is consistent with only occasional observations of infections of these domestic animals. Overall, the data indicates that SARSCoV2 is uniquely adapted to infect humans, raising questions as to whether it arose in nature by a rare chance event or whether its origins lie elsewhere.
puqcbf8t
puqcbf8t
2020-05-13
3
Broad-spectrum antiviral activity of naproxen: from Influenza A to SARS-CoV-2 Coronavirus
There is an urgent need for specific antiviral drugs directed against SARS-CoV-2 both to prevent the most severe forms of COVID-19 and to reduce viral excretion and subsequent virus dissemination; in the present pandemic context, drug repurposing is a priority. Targeting the nucleoprotein N of the SARS-CoV-2 coronavirus in order to inhibit its association with viral RNA could be a strategy to impeding viral replication and possibly other essential functions associated with viral N. The antiviral properties of naproxen, belonging to the NSAID family, previously demonstrated against Influenza A virus, were evaluated against SARS-CoV-2. Naproxen binding to the nucleoprotein of SARS-CoV2 was shown by molecular modeling. In VeroE6 cells and reconstituted human primary respiratory epithelium models of SARS-CoV-2 infection, naproxen inhibited viral replication and protected the bronchial epithelia against SARS-CoV-2 induced-damage. The benefit of naproxen addition to the standard of care is tested in an on-going clinical study.
pvfk33i8
pvfk33i8
2020-05-01
10.1101/2020.04.30.069922
3
Boceprevir, GC-376, and calpain inhibitors II, XII inhibit SARS-CoV-2 viral replication by targeting the viral main protease
A new coronavirus SARS-CoV-2, also called novel coronavirus 2019 (2019-nCoV), started to circulate among humans around December 2019, and it is now widespread as a global pandemic. The disease caused by SARS-CoV-2 virus is called COVID-19, which is highly contagious and has an overall mortality rate of 6.35% as of May 26, 2020. There is no vaccine or antiviral available for SARS-CoV-2. In this study, we report our discovery of inhibitors targeting the SARS-CoV-2 main protease (M(pro)). Using the FRET-based enzymatic assay, several inhibitors including boceprevir, GC-376, and calpain inhibitors II, and XII were identified to have potent activity with single-digit to submicromolar IC(50) values in the enzymatic assay. The mechanism of action of the hits was further characterized using enzyme kinetic studies, thermal shift binding assays, and native mass spectrometry. Significantly, four compounds (boceprevir, GC-376, calpain inhibitors II and XII) inhibit SARS-CoV-2 viral replication in cell culture with EC(50) values ranging from 0.49 to 3.37 µM. Notably, boceprevir, calpain inhibitors II and XII represent novel chemotypes that are distinct from known substrate-based peptidomimetic M(pro) inhibitors. A complex crystal structure of SARS-CoV-2 M(pro) with GC-376, determined at 2.15 Å resolution with three protomers per asymmetric unit, revealed two unique binding configurations, shedding light on the molecular interactions and protein conformational flexibility underlying substrate and inhibitor binding by M(pro). Overall, the compounds identified herein provide promising starting points for the further development of SARS-CoV-2 therapeutics.
px1qsx8q
px1qsx8q
2020-06-15
10.1038/s41422-020-0356-z
4.5
Traditional Chinese medicine herbal extracts of Cibotium barometz, Gentiana scabra, Dioscorea batatas, Cassia tora, and Taxillus chinensis inhibit SARS-CoV replication
Abstract Development of anti-severe acute respiratory syndrome associated coronavirus (SARS-CoV) agents is pivotal to prevent the reemergence of the life-threatening disease, SARS. In this study, more than 200 extracts from Chinese medicinal herbs were evaluated for anti-SARS-CoV activities using a cell-based assay that measured SARS-CoV-induced cytopathogenic effect (CPE) in vitro on Vero E6 cells. Six herbal extracts, one each from Gentianae Radix (龍膽 lóng dǎn; the dried rhizome of Gentiana scabra), Dioscoreae Rhizoma (山藥 shān yào; the tuber of Dioscorea batatas), Cassiae Semen (決明子 jué míng zǐ; the dried seed of Cassia tora) and Loranthi Ramus (桑寄生 sāng jì shēng; the dried stem, with leaf of Taxillus chinensis) (designated as GSH, DBM, CTH and TCH, respectively), and two from Rhizoma Cibotii (狗脊 gǒu jǐ; the dried rhizome of Cibotium barometz) (designated as CBE and CBM), were found to be potent inhibitors of SARS-CoV at concentrations between 25 and 200μg/ml. The concentrations of the six extracts needed to inhibit 50% of Vero E6 cell proliferation (CC50) and 50% of viral replication (EC50) were determined. The resulting selective index values (SI=CC50/EC50) of the most effective extracts CBE, GSH, DBM, CTH and TCH were>59.4,> 57.5,> 62.1,> 59.4, and>92.9, respectively. Among these extracts, CBM and DBM also showed significant inhibition of SARS-CoV 3CL protease activity with IC50 values of 39μg/ml and 44μg/ml, respectively. Our findings suggest that these six herbal extracts may have potential as candidates for future development of anti-SARS therapeutics.
pxev5bgo
pxev5bgo
2011-12-31
10.1016/s2225-4110(16)30055-4
1
A Unique Protease Cleavage Site Predicted in the Spike Protein of the Novel Pneumonia Coronavirus (2019-nCoV) Potentially Related to Viral Transmissibility
pxezk012
pxezk012
2020-03-20
10.1007/s12250-020-00212-7
3
SEIR and Regression Model based COVID-19 outbreak predictions in India
COVID-19 pandemic has become a major threat to the country. Till date, well tested medication or antidote is not available to cure this disease. According to WHO reports, COVID-19 is a severe acute respiratory syndrome which is transmitted through respiratory droplets and contact routes. Analysis of this disease requires major attention by the Government to take necessary steps in reducing the effect of this global pandemic. In this study, outbreak of this disease has been analysed for India till 30th March 2020 and predictions have been made for the number of cases for the next 2 weeks. SEIR model and Regression model have been used for predictions based on the data collected from John Hopkins University repository in the time period of 30th January 2020 to 30th March 2020. The performance of the models was evaluated using RMSLE and achieved 1.52 for SEIR model and 1.75 for the regression model. The RMSLE error rate between SEIR model and Regression model was found to be 2.01. Also, the value of R0 which is the spread of the disease was calculated to be 2.02. Expected cases may rise between 5000-6000 in the next two weeks of time. This study will help the Government and doctors in preparing their plans for the next two weeks. Based on the predictions for short-term interval, these models can be tuned for forecasting in long-term intervals.
pxhott2p
pxhott2p
2020-04-01
2.5
Teicoplanin potently blocks the cell entry of 2019-nCoV
Since December 2019, the outbreak of a new coronavirus, named 2019-nCoV, has greatly threatened the public health in China and raised great concerns worldwide. No specific treatment for this infection is currently available. We previously reported that teicoplanin, a glycopeptide antibiotic which has routinely been used in the clinic to treat bacterial infection with low toxicity, significantly inhibits the invasion of cells by Ebola virus, SARS-CoV and MERS-CoV, via specifically inhibiting the activity of cathepsin L. Here, we tested the efficacy of teicoplanin against 2019-nCoV virus infection and found that teicoplanin potently prevents the entrance of 2019-nCoV-Spike-pseudoviruses into the cytoplasm, with an IC50 of 1.66 μM. Although the inhibitory effect upon the replication of wildtype viruses ex vivo and in vivo remains to be determined, our preliminary result indicates that the potential antiviral activity of teicoplanin could be applied for the treatment of 2019-nCoV virus infection.
py6qu4tl
py6qu4tl
2020-02-13
10.1101/2020.02.05.935387
1
A fast and simple one-step duplex PCR assay for canine distemper virus (CDV) and canine coronavirus (CCoV) detection
The one-step polymerase chain reaction (one-step PCR) detection assay is an innovative PCR detection method, eliminating nucleic acid extraction steps, in which samples can be directly added to PCR reagents for testing. For simultaneous detection of CDV and CCoV, a sensitive and specific one-step duplex PCR (one-step dPCR) assay was developed with two pairs of primers that were designed based on H and M gene sequences of CDV and CCoV, respectively. The one-step dPCR with optimized detection conditions has high specificity and sensitivity; independent sequencing assays further verified these results.
q068aybo
q068aybo
2018-08-23
10.1007/s00705-018-3982-8
3
SARS-CoV-2, an evolutionary perspective of interaction with human ACE2 reveals undiscovered amino acids necessary for complex stability
The emergence of SARS-CoV-2 has resulted in more than 200,000 infections and nearly 9,000 deaths globally so far. This novel virus is thought to have originated from an animal reservoir, and acquired the ability to infect human cells using the SARS-CoV cell receptor hACE2. In the wake of a global pandemic it is essential to improve our understanding of the evolutionary dynamics surrounding the origin and spread of a novel infectious disease. One way theory predicts selection pressures should shape viral evolution is to enhance binding with host cells. We first assessed evolutionary dynamics in select betacoronavirus spike protein genes to predict where these genomic regions are under directional or purifying selection between divergent viral lineages at various scales of relatedness. With this analysis, we determine a region inside the receptor-binding domain with putative sites under positive selection interspersed among highly conserved sites, which are implicated in structural stability of the viral spike protein and its union with human receptor hACE2. Next, to gain further insights into factors associated with coronaviruses recognition of the human host receptor, we performed modeling studies of five different coronaviruses and their potential binding to hACE2. Modeling results indicate that interfering with the salt bridges at hot spot 353 could be an effective strategy for inhibiting binding, and hence for the prevention of coronavirus infections. We also propose that a glycine residue at the receptor binding domain of the spike glycoprotein can have a critical role in permitting bat variants of the coronaviruses to infect human cells.
q0yqnlyl
q0yqnlyl
2020-03-23
10.1101/2020.03.21.001933
1.5
19th ICAR Abstracts:
q58x6xb0
q58x6xb0
2006-03-13
10.1016/j.antiviral.2006.02.001
2
Virtual screening and repurposing of FDA approved drugs against COVID-19 main protease
AIMS: In December 2019, the Coronavirus disease-2019 (COVID-19) virus has emerged in Wuhan, China. In this research, the first resolved COVID-19 crystal structure (main protease) was targeted in a virtual screening study by of FDA approved drugs dataset. In addition, a knowledge gap in relations of COVID-19 with the previously known fatal Coronaviruses (CoVs) epidemics, SARS and MERS CoVs, was covered by investigation of sequence statistics and phylogenetics. MATERIALS AND METHODS: Molecular modeling, virtual screening, docking, sequence comparison statistics and phylogenetics of the COVID-19 main protease were investigated. KEY FINDINGS: COVID-19 Mpro formed a phylogenetic group with SARS CoV that was distant from MERS CoV. The identity% was 96.061 and 51.61 for COVID-19/SARS and COVID-19/MERS CoV sequence comparisons, respectively. The top 20 drugs in the virtual screening studies comprised a broad-spectrum antiviral (ribavirin), anti-hepatitis B virus (telbivudine), two vitamins (vitamin B12 and nicotinamide) and other miscellaneous systemically acting drugs. Of special interest, ribavirin had been used in treating cases of SARS CoV. SIGNIFICANCE: The present study provided a comprehensive targeting of the first resolved COVID+19 structure of Mpro and found a suitable save drugs for repurposing against the viral Mpro. Ribavirin, telbivudine, vitamin B12 and nicotinamide can be combined and used for COVID treatment. This initiative relocates already marketed and approved safe drugs for potential use in COVID-treatment.
q5fhgq6q
q5fhgq6q
2020
3
Development of a homogeneous screening assay for automated detection of antiviral agents active against severe acute respiratory syndrome-associated coronavirus
Abstract The severity and global spread of the 2003 outbreak of the severe acute respiratory syndrome-associated coronavirus (SARS-CoV) highlighted the risks to human health posed by emerging viral diseases and emphasized the need for specific therapeutic agents instead of relying on existing broadly active antiviral compounds. The development of rapid screening assays is essential for antiviral drug discovery. Thus, a screening system for anti-SARS-CoV agents was developed, which evaluated compound potency, specificity and cytotoxicity at the initial screening phase. Cell lines were engineered to constitutively express an enhanced green fluorescent protein (EGFP) and used to detect (1) antiviral potency in SARS-CoV infection tests; (2) antiviral specificity in tests using the porcine coronavirus transmissible gastroenteritis virus (TGEV); and (3) cytotoxicity in the same assays without virus challenge. The assay system involves minimal manipulation after assay set-up, facilitates automated read-out and minimizes risks associated with hazardous viruses. The suitability of this assay system in drug discovery was demonstrated by screening of 3388 small molecule compounds. The results show that these assays can be applied to high-throughput screening for identification of inhibitors selectively active against SARS-CoV.
q60ege66
q60ege66
2005-10-31
10.1016/j.jviromet.2005.05.010
4.5
Medical treatment options for COVID-19
Therapeutic options for coronavirus disease 2019 are desperately needed to respond to the ongoing severe acute respiratory syndrome coronavirus 2 pandemic. Both antiviral drugs and immunomodulators might have their place in the management of coronavirus disease 2019. Unfortunately, no drugs have been approved yet to treat infections with human coronaviruses. As it will take years to develop new therapies for severe acute respiratory syndrome coronavirus 2, the current focus is on the repurposing of drugs that have been approved or are in development for other conditions. Several clinical trials have already been conducted or are currently ongoing to evaluate the efficacy of such drugs. Here, we discuss the potential of these therapies for the treatment of coronavirus disease 2019.
q6ejkn83
q6ejkn83
2020-05-04
10.1177/2048872620922790
4
Immunoglobulin fragment F(ab’)2 against RBD potently neutralizes SARS-CoV-2 in vitro
COVID-19 caused by the emerging human coronavirus, SARS-CoV-2, has become a global pandemic, leading a serious threat to human health. So far, there is none vaccines or specific antiviral drugs approved for that. Therapeutic antibodies for SARS-CoV-2, was obtained from hyper immune equine plasma in this study. Herein, SARS-CoV-2 RBD with gram level were obtained through Chinese hamster ovary cells high-density fermentation. The binding of RBD to SARS-CoV-2 receptor, human ACE2, was verified and the efficacy of RBD in vivo was tested on mice and then on horses. As a result, RBD triggered high-titer neutralizing antibodies in vivo, and immunoglobulin fragment F(ab’)2 was prepared from horse antisera through removing Fc. Neutralization test demonstrated that RBD-specific F(ab’)2 inhibited SARS-CoV-2 with EC50 at 0.07 μg/ml, showing a potent inhibitory effect on SARS-CoV-2. These results highlights as RBD-specific F(ab’)2 as therapeutic candidate for SARS-CoV-2.
q6j6rkqh
q6j6rkqh
2020-04-09
10.1101/2020.04.07.029884
2.5
Emerging pharmacotherapies for COVID-19
Novel Corona-virus Disease 2019 (nCOVID 19) is caused by a novel virulent corona virus and leads to potentially fatal virulent pneumonia and severe respiratory distress syndrome. It was initially declared as public health emergency if international concern by WHO followed by Pandemic on 12(th) March 2020. As of 10(th) April 2020, more than 1.5 million people are affected globally with around 95000 deaths. Vaccines for this deadly virus are currently under development and many drugs used for other indications have been repurposed and investigated for prophylaxis and treatment of COVID 19. As per SOLIDARITY trial by WHO, some of the most promising candidates include chloroquine phosphate and hydroxychloroquine which are anti-malarial medications, Remdesivir, Lopinavir-Ritonavir combination with or without interferon which are anti-HIV drugs and convalescent plasma therapy. The current evidence of efficacy and ongoing research has been elaborated in the article. Besides, there has been evidence regarding inflammatory pathogenesis of this virus leading to cytokine storm in susceptible individuals. Thus, anti-proinflammatory cytokine drugs like Anakinra and Tocilizumab are undergoing multiple trials and some results are encouraging. Similarly, use of anti-inflammatory cytokines like IL-37 and IL-38 is hypothesised to be useful and is under research. The situation is still evolving and hence there is yet no definitive therapy but to conclude the use of repurposed medications can be a boon till a definitive therapy and vaccines are developed.
q6px4r3j
q6px4r3j
2020-05-14
10.1016/j.biopha.2020.110267
3
The reproductive number R0 of COVID-19 based on estimate of a statistical time delay dynamical system
In this paper, we estimate the reproductive number R0 of COVID-19 based on Wallinga and Lipsitch framework {11} and a novel statistical time delay dynamic system. We use the observed data reported in CCDC's paper to estimate distribution of the generation interval of the infection and apply the simulation results from the time delay dynamic system as well as released data from CCDC to fit the growth rate. The conclusion is: Based our Fudan-CCDC model, the growth rate r of COVID-19 is almost in [0.30, 0.32] which is larger than the growth rate 0.1 estimated by CCDC {9}, and the reproductive number R0 of COVID-19 is estimated by 3.25≤ R0 ≤3.4 if we simply use R=1+r*Tc with Tc=7.5, which is bigger than that of SARS. Some evolutions and predictions are listed.
q6pz6l2b
q6pz6l2b
2020-02-20
10.1101/2020.02.17.20023747
1
Natural small molecules as inhibitors of coronavirus lipid-dependent attachment to host cells: a possible strategy for reducing SARS-COV-2 infectivity?
BACKGROUND Viral infectivity depends on interactions between components of the host cell plasma membrane and the virus envelope. Here we review strategies that could help stem the advance of the SARS-COV-2 epidemic. METHODS AND RESULTS We focus on the role of lipid structures, such as lipid rafts and cholesterol, involved in the process, mediated by endocytosis, by which viruses attach to and infect cells. Previous studies have shown that many naturally derived substances, such as cyclodextrin and sterols, could reduce the infectivity of many types of viruses, including the coronavirus family, through interference with lipid-dependent attachment to human host cells. CONCLUSIONS Certain molecules prove able to reduce the infectivity of some coronaviruses, possibly by inhibiting viral lipid-dependent attachment to host cells. More research into these molecules and methods would be worthwhile as it could provide insights the mechanism of transmission of SARS-COV-2 and, into how they could become a basis for new antiviral strategies.
q7y0bjaz
q7y0bjaz
2020-03-19
10.23750/abm.v91i1.9402
3
ACE2-Variants Indicate Potential SARS-CoV-2-Susceptibility in Animals: An Extensive Molecular Dynamics Study
Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) emerged in late 2019 and since evolved into a global threat with nearly 4.4 million infected people and over 290,000 confirmed deaths worldwide.1 SARS-CoV-2 is an enveloped virus presenting spike (S) glycoproteins on its outer surface. Binding of S to host cell angiotensin converting enzyme 2 (ACE2) is thought to be critical for cellular entry. The host range of the virus extends far beyond humans and non-human primates. Natural and experimental infections have confirmed high susceptibility of cats, ferrets, and hamsters, whereas dogs, mice, rats, pigs, and chickens seem refractory to SARS-CoV-2 infection. To investigate the reason for the variable susceptibility observed in different species, we have developed molecular descriptors to efficiently analyze our dynamic simulation models of complexes between SARS-CoV-2 S and ACE2. Based on our analyses we predict that: (i) the red squirrel is likely susceptible to SARS-CoV-2 infection and (ii) specific mutations in ACE2 of dogs, rats, and mice render them susceptible to SARS-CoV-2 infection.
q814d6l7
q814d6l7
2020-05-14
10.1101/2020.05.14.092767
4.5
Dynamics of COVID‐19 epidemics: SEIR models underestimate peak infection rates and overestimate epidemic duration
Compartment models of infectious diseases, such as SEIR, are being used extensively to model the COVID-19 epidemic. Transitions between compartments are modelled either as instantaneous rates in differential equations, or as transition probabilities in discrete time difference or matrix equations. These models give accurate estimates of the position of equilibrium points, when the rate at which individuals enter each stage is equal to the rate at which they exit from it. However, they do not accurately capture the distribution of times that an individual spends in each compartment, so do not accurately capture the transient dynamics of epidemics. Here we show how matrix models can provide a straightforward route to accurately model stage durations, and thus correctly reproduce epidemic dynamics. We apply this approach to modelling the dynamics of a COVID-19 epidemic. We show that a SEIR model underestimates peak infection rates (by a factor of three using published parameter estimates based on the progress of the epidemic in Wuhan) and substantially overestimates epidemic persistence after the peak has passed.
q8539o41
q8539o41
2020-04-06
10.1101/2020.04.02.20050674
1
Single-dose intranasal administration with mDEF201 (adenovirus vectored mouse interferon-alpha) confers protection from mortality in a lethal SARS-CoV BALB/c mouse model
Interferons (IFNs) are a first line of defense against viral infection. Herein we describe the use of an adenovirus vectored mouse IFN alpha gene (mDEF201) as a prophylactic and treatment countermeasure in a SARS-CoV-infected BALB/c mouse model. Complete survival protection was observed in mice given a single dose of mDEF201 administered intranasally 1, 3, 5, 7, or 14 days prior to lethal SARS-CoV challenge (p<0.001), and body weights of these treated mice were unaffected by the challenge. In addition, low doses of mDEF201 protected lungs in a dose dependent manner as measured by a reduction in gross pathology. Intranasal treatment with mDEF201 ranging from 10(6) to 10(8) PFU significantly protected mice against a lethal SARS-CoV infection in a dose dependent manner up to 12 h post infection (P<0.001). The data suggest that mDEF201 is a new class of antiviral agent further development as treatment for SARS-CoV infections.
q9tstj31
q9tstj31
2011-01-01
10.1016/j.antiviral.2010.11.007
0.5
Mice transgenic for human angiotensin-converting enzyme 2 provide a model for SARS coronavirus infection.
To establish a small animal model of severe acute respiratory syndrome (SARS), we developed a mouse model of human severe acute respiratory syndrome coronavirus (SARS-CoV) infection by introducing the human gene for angiotensin-converting enzyme 2 (hACE2) (the cellular receptor of SARS-CoV), driven by the mouse ACE2 promoter, into the mouse genome. The hACE2 gene was expressed in lung, heart, kidney, and intestine. We also evaluated the responses of wild-type and transgenic mice to SARS-CoV inoculation. At days 3 and 7 postinoculation, SARS-CoV replicated more efficiently in the lungs of transgenic mice than in those of wild-type mice. In addition, transgenic mice had more severe pulmonary lesions, including interstitial hyperemia and hemorrhage, monocytic and lymphocytic infiltration, protein exudation, and alveolar epithelial cell proliferation and desquamation. Other pathologic changes, including vasculitis, degeneration, and necrosis, were found in the extrapulmonary organs of transgenic mice, and viral antigen was found in brain. Therefore, transgenic mice were more susceptible to SARS-CoV than were wild-type mice, and susceptibility was associated with severe pathologic changes that resembled human SARS infection. These mice will be valuable for testing potential vaccine and antiviral drug therapies and for furthering our understanding of SARS pathogenesis.
qabxcrnf
qabxcrnf
2007
4.5
Prohibitin plays a critical role in Enterovirus 71 neuropathogenesis
A close relative of poliovirus, enterovirus 71 (EV71) is regarded as an important neurotropic virus of serious public health concern. EV71 causes Hand, Foot and Mouth Disease and has been associated with neurological complications in young children. Our limited understanding of the mechanisms involved in its neuropathogenesis has hampered the development of effective therapeutic options. Here, using a two-dimensional proteomics approach combined with mass spectrometry, we have identified a unique panel of host proteins that were differentially and dynamically modulated during EV71 infection of motor-neuron NSC-34 cells, which are found at the neuromuscular junctions where EV71 is believed to enter the central nervous system. Meta-analysis with previously published proteomics studies in neuroblastoma or muscle cell lines revealed minimal overlapping which suggests unique host-pathogen interactions in NSC-34 cells. Among the candidate proteins, we focused our attention on prohibitin (PHB), a protein that is involved in multiple cellular functions and the target of anti-cancer drug Rocaglamide (Roc-A). We demonstrated that cell surface-expressed PHB is involved in EV71 entry into neuronal cells specifically, while membrane-bound mitochondrial PHB associates with the virus replication complex and facilitates viral replication. Furthermore, Roc-A treatment of EV71-infected neuronal cells reduced significantly virus yields. However, the inhibitory effect of Roc-A on PHB in NSC-34 cells was not through blocking the CRAF/MEK/ERK pathway as previously reported. Instead, Roc-A treated NSC-34 cells had lower mitochondria-associated PHB and lower ATP levels that correlated with impaired mitochondria integrity. In vivo, EV71-infected mice treated with Roc-A survived longer than the vehicle-treated animals and had significantly lower virus loads in their spinal cord and brain, whereas virus titers in their limb muscles were comparable to controls. Together, this study uncovers PHB as the first host factor that is specifically involved in EV71 neuropathogenesis and a potential drug target to limit neurological complications.
qaogpxy9
qaogpxy9
2018-01-11
10.1371/journal.ppat.1006778
1.5
Identification of chymotrypsin-like protease inhibitors of SARS-CoV-2 via integrated computational approach
Recently, the world has witnessed outbreak of a novel Coronavirus (SARS-CoV-2), the virus which initially emerged in Wuhan, China has now made its way to a large part of the world, resulting in a public emergency of international concern. The functional importance of Chymotrypsin-like protease (3CLpro) in viral replication and maturation turns it into an attractive target for the development of effective antiviral drugs against SARS and other coronaviruses. At present, there is no standard drug regime nor any vaccine available against the infection. The rapid development and identification of efficient interventions against SARS-CoV-2 remains a major challenge. Based on the available knowledge of closely related coronavirus and their safety profiles, repurposing of existing antiviral drugs and screening of available databases is considered a near term strategic and economic way to contain the SARS-CoV-2 pandemic. Herein, we applied computational drug design methods to identify Chymotrypsin-like protease inhibitors from FDA approved antiviral drugs and our in-house database of natural and drug-like compounds of synthetic origin. As a result three FDA approved drugs (Remdesivir, Saquinavir and Darunavir) and two natural compounds (. flavone and coumarine derivatives) were identified as promising hits. Further, MD simulation and binding free energy calculations were performed to evaluate the dynamic behavior, stability of protein-ligand contact, and binding affinity of the hit compounds. Our results indicate that the identified compounds can inhibit the function of Chymotrypsin-like protease (3CLpro) of Coronavirus. Considering the severity of the spread of coronavirus, the current study is in-line with the concept of finding the new inhibitors against the vital pathway of the corona virus to expedite the process of drug discovery.Communicated by Ramaswamy H. Sarma.
qato562y
qato562y
2020
3.5
Polymerases of Coronaviruses: Structure, Function, and Inhibitors
Coronaviruses (CoVs) are a major group of viruses known to be responsible for wide spectrum of diseases in multiple species. The CoVs affecting human population are referred to as human coronaviruses (HCoVs). They lead to multiple respiratory diseases, such as common cold, pneumonia, bronchitis, severe acute respiratory syndrome, and Middle East respiratory syndrome. CoVs are RNA viruses that require RNA-dependent RNA polymerases (RdRPs) for various steps in their life cycle. Action of RdRP is needed in several steps in the life cycle of CoVs and thus RdRPs constitute potential targets for drugs and other therapeutic interventions for the treatment of diseases caused by CoVs. The chapter therefore presents a detailed discussion on the structure and functions of CoV polymerases and the development of their potential inhibitors.
qbnepwfa
qbnepwfa
2018-11-02
10.1016/b978-0-12-815422-9.00010-3
2.5
Development of multi-specific humanized llama antibodies blocking SARS-CoV-2/ACE2 interaction with high affinity and avidity
Coronaviruses cause severe human viral diseases including SARS, MERS and COVID-19. Most recently SARS-CoV-2 virus (causing COVID-19) has led to a pandemic with no successful therapeutics. The SARS-CoV-2 infection relies on trimeric spike (S) proteins to facilitate virus entry into host cells by binding to ACE2 receptor on host cell membranes. Therefore, blocking this interaction with antibodies are promising agents against SARS-CoV-2. Here we describe using humanized llama antibody VHHs against SARS-CoV-2 that would overcome the limitations associated with polyclonal and monoclonal combination therapies. From two llama VHH libraries, unique humanized VHHs that bind to S protein and block the S/ACE2 interaction were identified. Furthermore, pairwise combination of VHHs showed synergistic blocking. Multi-specific antibodies with enhanced affinity and avidity, and improved S/ACE2 blocking are currently being developed using an in-silico approach that also fuses VHHs to Fc domains. Importantly, our current bi-specific antibody shows potent S/ACE2 blocking (KD - 0.25 nM, IC100 â¼ 36.7 nM, IC95 â¼ 12.2 nM, IC50 â¼ 1 nM) which is significantly better than individual monoclonal VHH-Fcs. Overall, this design would equip the VHH-Fcs multiple mechanisms of actions against SARS-CoV-2. Thus, we aim to contribute to the battle against COVID-19 by developing therapeutic antibodies as well as diagnostics.
qbyz4uz5
qbyz4uz5
2020
4.5
The potential of drug repositioning as a short-term strategy for the control and treatment of COVID-19 (SARS-CoV-2): a systematic review
The novel human coronavirus (SARS-CoV-2), the causative agent of COVID-19, has quickly become a threat to the public health and economy worldwide. Despite the severity of some cases, there are no current pathogen-specific antivirals available to treat the disease. Therefore, many studies have focused on the evaluation of the anti-SARS-CoV-2 activity of clinically available drugs. Here, we conducted a systematic review to describe the drug repositioning strategy against SARS-CoV-2 and to discuss the clinical impact of this approach in the current pandemic context. The systematic review was performed on March 23, 2020, using PubMed/MEDLINE, Scopus, Cochrane Library, and Biblioteca Virtual de Saúde (BVS). The data were summarized in tables and critically analyzed. After the database search, 12 relevant studies were identified as eligible for the review. Among the drugs reported in these studies, 57 showed some evidence of antiviral activity. Antivirals, especially antiretrovirals, are the main class of therapeutic agents evaluated against COVID-19. Moreover, studies have reported the anti-SARS-CoV-2 activity of antitumor (16%; 9/57), antimalarial (7%, 4/57), and antibacterial (5%; 3/57) agents. Additionally, seven pharmacological agents (chloroquine, tetrandrine, umifenovir (arbidol), carrimycin, damageprevir, lopinavir/ritonavir) are in phase IV of clinical trials. Due to the evidence of the anti-SARS-CoV-2 activity of various clinically available agents, drug repositioning stands out as a promising strategy for a short-term response in the fight against the novel coronavirus. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s00705-020-04693-5) contains supplementary material, which is available to authorized users.
qci7khki
qci7khki
2020-06-08
10.1007/s00705-020-04693-5
4
Face mask use in the general population and optimal resource allocation during the COVID-19 pandemic
The ongoing novel coronavirus disease (COVID-19) pandemic has rapidly spread in early 2020, causing tens of thousands of deaths, over a million cases and widespread socioeconomic disruption. With no vaccine available and numerous national healthcare systems reaching or exceeding capacity, interventions to limit transmission are urgently needed. While there is broad agreement that travel restrictions and closure of non-essential businesses and schools are beneficial in limiting local and regional spread, recommendations around the use of face masks for the general population are less consistent internationally. In this study, we examined the role of face masks in mitigating the spread of COVID-19 in the general population, using epidemic models to estimate the total reduction of infections and deaths under various scenarios. In particular, we examined the optimal deployment of face masks when resources are limited, and explored a range of supply and demand dynamics. We found that face masks, even with a limited protective effect, can reduce infections and deaths, and can delay the peak time of the epidemic. We consistently found that a random distribution of masks in the population was a suboptimal strategy when resources were limited. Prioritizing coverage among the elderly was more beneficial, while allocating a proportion of available resources for diagnosed infected cases provided further mitigation under a range of scenarios. In summary, face mask use, particularly for a pathogen with relatively common asymptomatic carriage, can effectively provide some mitigation of transmission, while balancing provision between vulnerable healthy persons and symptomatic persons can optimize mitigation efforts when resources are limited.
qdamvwxl
qdamvwxl
2020-04-07
10.1101/2020.04.04.20052696
1
Unrevealing sequence and structural features of novel coronavirus using in silico approaches: The main protease as molecular target
Direct-acting antivirals are effective tools to control viral infections. SARS-CoV-2 is a coronavirus associated with the epidemiological outbreak in late 2019. Previous reports showed that HIV-1 protease inhibitors could block SARS-CoV main protease. Based on that and using an in silico approach, we evaluated SARS-CoV-2 main protease as a target for HIV-1 protease inhibitors to reveal the structural features related to their antiviral effect. Our results showed that several HIV inhibitors such as lopinavir, ritonavir, and saquinavir produce strong interaction with the active site of SARS-CoV-2 main protease. Furthermore, broad library protease inhibitors obtained from PubChem and ZINC (www.zinc.docking.org) were evaluated. Our analysis revealed 20 compounds that could be clustered into three groups based on their chemical features. Then, these structures could serve as leading compounds to develop a series of derivatives optimizing their activity against SARS-CoV-2 and other coronaviruses. Altogether, the results presented in this work contribute to gain a deep understanding of the molecular pharmacology of SARS-CoV-2 treatment and validate the use of protease inhibitors against SARS-CoV-2.
qdt90c22
qdt90c22
2020-03-17
10.17179/excli2020-1189
0.5
SARS-CoV Replication and Pathogenesis in an In Vitro Model of the Human Conducting Airway Epithelium
SARS coronavirus (SARS-CoV) emerged in 2002 as an important cause of severe lower respiratory tract infection in humans and in vitro models of the lung are needed to elucidate cellular targets and the consequences of viral infection. The severe and sudden onset of symptoms, resulting in an atypical pneumonia with dry cough and persistent high fever in cases of severe acute respiratory virus brought to light the importance of coronaviruses as potentially lethal human pathogens and the identification of several zoonotic reservoirs has made the reemergence of new strains and future epidemics all the more possible. In this chapter, we describe the pathology of SARS-CoV infection in humans and explore the use of two models of the human conducting airway to develop a better understanding of the replication and pathogenesis of SARS-CoV in relevant in vitro systems. The first culture model is a human bronchial epithelial cell line Calu3 that can be inoculated by viruses either as a non-polarized monolayer of cells or polarized cells with tight junctions and microvilli. The second model system, derived from primary cells isolated from human airway epithelium and grown on Transwells, form a pseudostratified mucociliary epithelium that recapitulates the morphological and physiological features of the human conducting airway in vivo. Experimental results using these lung epithelial cell models demonstrate that in contrast to the pathology reported in late stage cases SARS-CoV replicates to high titers in epithelial cells of the conducting airway. The SARS-CoV receptor, human angiotensin 1 converting enzyme 2 (hACE2), was detected exclusively on the apical surface of cells in polarized Calu3 cells and human airway epithelial cultures (HAE), indicating that hACE2 was accessible by SARS-CoV after airway lumenal delivery. Furthermore, in HAE, hACE2 was exclusively localized to ciliated airway epithelial cells. In support of the hACE2 localization data, the most productive route of inoculation and progeny virion egress in both polarized Calu3 and ciliated cells of HAE was the apical surface suggesting mechanisms to release large quantities of virus into the lumen of the human lung. Preincubation of the apical surface of cultures with antisera directed against hACE2 reduced viral titers by 2 logs while antisera against DC-SIGN/DC-SIGNR did not reduce viral replication levels suggesting that hACE2 is the primary receptor for entry of SARS-CoV into the ciliated cells of HAE cultures. To assess infectivity in ciliated airway cultures derived from susceptible animal species we generated a recombinant SARS-CoV by deletion of open reading frame 7a/7b (ORF 7a/b) and insertion of the green fluorescent protein (GFP) resulting in SARS-CoV GFP. SARS-CoV GFP replicated to similar titers as wild type viruses in Vero E6, MA104, and CaCo2 cells. In addition, SARS-CoV replication in airway epithelial cultures generated from Golden Syrian hamster tracheas reached similar titers to the human cultures by 72 hours post infection. Efficient SARS-CoV infection of ciliated cell-types in HAE provides a useful in vitro model of human lung origin to study characteristics of SARS-CoV replication and pathogenesis.
qdwl8llw
qdwl8llw
2008-04-01
10.1016/j.virusres.2007.03.013
4.5
A data-driven drug repositioning framework discovered a potential therapeutic agent targeting COVID-19
The global spread of SARS-CoV-2 requires an urgent need to find effective therapeutics for the treatment of COVID-19. We developed a data-driven drug repositioning framework, which applies both machine learning and statistical analysis approaches to systematically integrate and mine large-scale knowledge graph, literature and transcriptome data to discover the potential drug candidates against SARS-CoV-2. The retrospective study using the past SARS-CoV and MERS-CoV data demonstrated that our machine learning based method can successfully predict effective drug candidates against a specific coronavirus. Our in silico screening followed by wet-lab validation indicated that a poly-ADP-ribose polymerase 1 (PARP1) inhibitor, CVL218, currently in Phase I clinical trial, may be repurposed to treat COVID-19. Our in vitro assays revealed that CVL218 can exhibit effective inhibitory activity against SARS-CoV-2 replication without obvious cytopathic effect. In addition, we showed that CVL218 is able to suppress the CpG-induced IL-6 production in peripheral blood mononuclear cells, suggesting that it may also have anti-inflammatory effect that is highly relevant to the prevention immunopathology induced by SARS-CoV-2 infection. Further pharmacokinetic and toxicokinetic evaluation in rats and monkeys showed a high concentration of CVL218 in lung and observed no apparent signs of toxicity, indicating the appealing potential of this drug for the treatment of the pneumonia caused by SARS-CoV-2 infection. Moreover, molecular docking simulation suggested that CVL218 may bind to the N-terminal domain of nucleocapsid (N) protein of SARS-CoV-2, providing a possible model to explain its antiviral action. We also proposed several possible mechanisms to explain the antiviral activities of PARP1 inhibitors against SARS-CoV-2, based on the data present in this study and previous evidences reported in the literature. In summary, the PARP1 inhibitor CVL218 discovered by our data-driven drug repositioning framework can serve as a potential therapeutic agent for the treatment of COVID-19.
qebbkr6d
qebbkr6d
2020-03-12
10.1101/2020.03.11.986836
0.5
Screening of FDA-approved drugs using a MERS-CoV clinical isolate from South Korea identifies potential therapeutic options for COVID-19
In 2015, the Middle East respiratory syndrome coronavirus (MERS-CoV) reached the Republic of Korea, resulting from nosocomial transmission, and was the largest epidemic outside of the Arabian Peninsula. To date, despite various strategies to identify CoV interventions, there are only limited therapeutic options available. To address these unmet medical needs, we used a South Korean MERS-CoV clinical isolate and screened 5,406 compounds, including US Food and Drug Administration (FDA)-approved drugs and bioactive molecules, confirmed 221 hits by dose-response curve analysis in the primary assay, and selected 54 hits with a therapeutic index (TI) greater than 6. Time-of-addition studies with 12 FDA-approved drugs demonstrated that eight and four therapeutics act on the early- and late stages of the viral life cycle, respectively. Among the early acting drugs, three therapeutics with a TI greater than 100 were cardiotonic agents. Together, our results identify potential therapeutic options for treatment of MERS-CoV infections and could provide a basis for a wider range of coronaviruses, including the currently emerging coronavirus disease 2019 (COVID-19) outbreak.
qefiw4ho
qefiw4ho
2020-03-02
10.1101/2020.02.25.965582
1.5
Rational evaluation of various epidemic models based on the COVID-19 data of China
During the study of epidemics, one of the most significant and also challenging problems is to forecast the future trends, on which all follow-up actions of individuals and governments heavily rely. However, to pick out a reliable predictable model/method is far from simple, a rational evaluation of various possible choices is eagerly needed, especially under the severe threat of COVID-19 epidemics which is spreading worldwide right now. In this paper, based on the public COVID-19 data of seven provinces/cities in China reported during the spring of 2020, we make a systematical investigation on the forecast ability of eight widely used empirical functions, four statistical inference methods and five dynamical models widely used in the literature. We highlight the significance of a well balance between model complexity and accuracy, over-fitting and under-fitting, as well as model robustness and sensitivity. We further introduce the Akaike information criterion, root mean square errors and robustness index to quantify these three golden means and to evaluate various epidemic models/methods. Through extensive simulations, we find that the inflection point plays a crucial role in the choice of the size of dataset in forecasting. Before the inflection point, no model considered here could make a reliable prediction. We further notice the Logistic function steadily underestimate the final epidemic size, while the Gomertz's function makes an overestimation in all cases. Since the methods of sequential Bayesian and time-dependent reproduction number take the non-constant nature of the effective reproduction number with the progression of epidemics into consideration, we suggest to employ them especially in the late stage of an epidemic. The transition-like behavior of exponential growth method from underestimation to overestimation with respect to the inflection point might be useful for constructing a more reliable forecast. Towards the dynamical models based on ODEs, it is observed that the SEIR-QD and SEIR-PO models generally show a better performance than SIR, SEIR and SEIR-AHQ models on the COVID-19 epidemics, whose success could be attributed to the inclusion of self-protection and quarantine, and a proper trade-off between model complexity and fitting accuracy.
qejmwvst
qejmwvst
2020-03-16
10.1101/2020.03.12.20034595
1
Structure-based design of antiviral drug candidates targeting the SARS-CoV-2 main protease
SARS-CoV-2 is the etiological agent responsible for the global COVID-19 outbreak. The main protease (M(pro)) of SARS-CoV-2 is a key enzyme that plays a pivotal role in mediating viral replication and transcription. We designed and synthesized two lead compounds (11a and 11b) targeting M(pro). Both exhibited excellent inhibitory activity and potent anti-SARS-CoV-2 infection activity. The X-ray crystal structures of SARS-CoV-2 M(pro) in complex with 11a or 11b, both determined at 1.5 Å resolution, showed that the aldehyde groups of 11a and 11b are covalently bound to Cys145 of M(pro). Both compounds showed good PK properties in vivo, and 11a also exhibited low toxicity, suggesting that these compounds are promising drug candidates.
qffqgd08
qffqgd08
2020-04-22
10.1126/science.abb4489
2.5
Antiviral Treatment Guidelines for Middle East Respiratory Syndrome
Middle East respiratory syndrome (MERS) is an acute infectious disease of the respiratory system caused by the new betacoronavirus (MERS coronavirus, MERS-CoV), which shows high mortality rates. The typical symptoms of MERS are fever, cough, and shortness of breath, and it is often accompanied by pneumonia. The MERS-CoV was introduced to Republic of Korea in May 2015 by a patient returning from Saudi Arabia. The disease spread mostly through hospital infections, and by the time the epidemic ended in August, the total number of confirmed diagnoses was 186, among which 36 patients died. Reflecting the latest evidence for antiviral drugs in the treatment of MERS-CoV infection and the experiences of treating MERS patients in Republic of Korea, these guidelines focus on antiviral drugs to achieve effective treatment of MERS-CoV infections.
qg73804g
qg73804g
2015-09-30
10.3947/ic.2015.47.3.212
0.5
[Preliminary study of the relationship between novel coronavirus pneumonia and liver function damage: a multicenter study].
Objective: To analyze the clinical characteristics of cases of novel coronavirus pneumonia and a preliminary study to explore the relationship between different clinical classification and liver damage. Methods: Consecutively confirmed novel coronavirus infection cases admitted to seven designated hospitals during January 23, 2020 to February 8, 2020 were included. Clinical classification (mild, moderate, severe, and critical) was carried out according to the diagnosis and treatment program of novel coronavirus pneumonia (Trial Fifth Edition) issued by the National Health Commission. The research data were analyzed using SPSS19.0 statistical software. Quantitative data were expressed as median (interquartile range), and qualitative data were expressed as frequency and rate. Results: 32 confirmed cases that met the inclusion criteria were included. 28 cases were of mild or moderate type (87.50%), and four cases (12.50%) of severe or critical type. Four cases (12.5%) were combined with one underlying disease (bronchial asthma, coronary heart disease, malignant tumor, chronic kidney disease), and one case (3.13%) was simultaneously combined with high blood pressure and malignant tumor. The results of laboratory examination showed that the alanine aminotransferase (ALT), aspartate aminotransferase (AST), albumin (ALB), and total bilirubin (TBil) for entire cohort were 26.98 (16.88 ~ 46.09) U/L and 24.75 (18.71 ~ 31.79) U/L, 39.00 (36.20 ~ 44.20) g/L and 16.40 (11.34- ~ 21.15) mmol/L, respectively. ALT, AST, ALB and TBil of the mild or moderate subgroups were 22.75 (16.31- ~ 37.25) U/L, 23.63 (18.71 ~ 26.50) U/L, 39.70 (36.50 ~ 46.10) g/L, and 15.95 (11.34 ~ 20.83) mmol/L, respectively. ALT, AST, ALB and TBil of the severe or critical subgroups were 60.25 (40.88 ~ 68.90) U/L, 37.00 (20.88 ~ 64.45) U/L, 35.75 (28.68 ~ 42.00) g/L, and 20.50 (11.28 ~ 25.00) mmol/L, respectively. Conclusion: The results of this multicenter retrospective study suggests that novel coronavirus pneumonia combined with liver damage is more likely to be caused by adverse drug reactions and systemic inflammation in severe patients receiving medical treatment. Therefore, liver function monitoring and evaluation should be strengthened during the treatment of such patients.
qi50p9w5
qi50p9w5
2020-02-20
10.3760/cma.j.issn.1007-3418.2020.02.003
2
En route to Peptide Therapeutics for COVID 19: Harnessing Potential Antigenic Mimicry Between Viral and Human Proteins
Molecular mimicry is a general strategy used by pathogens to infect the host cells. The emergence of SARS-CoV-2 virus has resulted in more than 6,700,000 infections and 390,000 deaths worldwide. Coronavirus disease (COVID-19) is an infectious disease caused by this virus. In this project concept, we aim to focus on the peptide-protein interaction analysis using two important drug targets in SARS-CoV-2 such as spike (S) protein and nucleocapsid (N) protein. These proteins play an important role in the virus entry and encapsidation of the viral particles. Motifs or functional regions in these two proteins must be sharing sequence homology with human protein (ACE2) which may be involved in the binding mechanism. The results will show a set of motif regions which can disrupt the viral infection. Once we identify these sets of antigenic determinant regions, antibody binding activity studies can be performed by in vitro methods. Our results from this study may suggest the existence of antigenic mimicry between SARS-CoV-2 and host proteins. The hit peptide components will have therapeutic applications to be developed into a wide variety of medicinal formulations against SARS-CoV-2 such as vaccine, intranasal and inhalation formulations. Also, the choice of conserved regions will lead to development of cross protective therapeutics against wide range of coronaviruses.
qj81xbn0
qj81xbn0
2020-06-21
10.1007/s41403-020-00132-8
5
Immune-epidemiological parameters of the novel coronavirus – a perspective
Introduction: At the end of 2019, Wuhan, a city in China with a population of about 11 million, witnessed the outbreak of unusual pneumonia. As of 29 March 2020, the disease has spread to more 199 countries and territories worldwide. The 2019 novel coronavirus, 2019-nCoV, is known as the probable causative agent of the illness. Areas covered: Here, the epidemiological dynamics of the coronavirus disease 2019 (COVID-19) that stand in close relation to distinct immunogenetic characters of the pathogen are discussed, to understand the ability and inability of the immune system in combatting COVID-19. Expert opinion: The elderly population is at increased risk of developing and dying from COVID-19. Comorbidity is present in more than 30% of cases with COVID-19. Except for less than 1% of the total, a chronic condition has been found in all cases that died from COVID-19. Men are more than 1.5 times more likely to die from COVID-19. Evidence links aging to cytokine dysregulation and T-cell repertoire reduction, male population to relatively reduced anti-viral immunity, and COVID-19-related comorbidities to hyper inflammation. The transmission of COVID-19 is influenced by the host-related factors that are known to be associated with immune dysregulation.
qje6ycq0
qje6ycq0
2020-04-06
10.1080/1744666x.2020.1750954
4
Middle East respiratory syndrome coronavirus infection: virus-host cell interactions and implications on pathogenesis
Middle-East Respiratory Syndrome coronavirus (MERS-CoV) was identified to cause severe respiratory infection in humans since 2012. The continuing MERS epidemic with a case-fatality of more than 30 % poses a major threat to public health worldwide. Currently, the pathogenesis of human MERS-CoV infection remains poorly understood. We reviewed experimental findings from human primary cells and ex vivo human lung tissues, as well as those from animal studies, so as to understand the pathogenesis and high case-fatality of MERS. Human respiratory epithelial cells are highly susceptible to MERS-CoV and can support productive viral replication. However, the induction of antiviral cytokines and proinflammatory cytokines/chemokines are substantially dampened in the infected epithelial cells, due to the antagonistic mechanisms evolved by the virus. MERS-CoV can readily infect and robustly replicate in human macrophages and dendritic cells, triggering the aberrant production of proinflammatory cytokines/chemokines. MERS-CoV can also effectively infect human primary T cells and induce massive apoptosis in these cells. Although data from clinical, in vitro and ex vivo studies suggested the potential for virus dissemination, extrapulmonary involvement in MERS patients has not been ascertained due to the lack of autopsy study. In MERS-CoV permissive animal models, although viral RNA can be detected from multiple organs of the affected animals, the brain of human DPP4-transgenic mouse was the only extrapulmonary organ from which the infectious virus can be recovered. More research findings on the pathogenesis of MERS and the tissue tropisms of MERS-CoV may help to improve the treatment and infection control of MERS.
qjnetu71
qjnetu71
2015-12-22
10.1186/s12985-015-0446-6
1.5
AI-aided design of novel targeted covalent inhibitors against SARS-CoV-2
The focused drug repurposing of known approved drugs (such as lopinavir/ritonavir) has been reported failed for curing SARS-CoV-2 infected patients. It is urgent to generate new chemical entities against this virus. As a key enzyme in the life-cycle of coronavirus, the 3C-like main protease (3CLpro or Mpro) is the most attractive for antiviral drug design. Based on a recently solved structure (PDB ID: 6LU7), we developed a novel advanced deep Q-learning network with the fragment-based drug design (ADQN-FBDD) for generating potential lead compounds targeting SARS-CoV-2 3CLpro. We obtained a series of derivatives from those lead compounds by our structure-based optimization policy (SBOP). All the 47 lead compounds directly from our AI-model and related derivatives based on SBOP are accessible in our molecular library at https://github.com/tbwxmu/2019-nCov. These compounds can be used as potential candidates for researchers in their development of drugs against SARS-CoV-2.
qmg58cgr
qmg58cgr
2020-03-08
10.1101/2020.03.03.972133
0.5
An efficient pattern growth approach for mining fault tolerant frequent itemsets
Abstract Mining fault tolerant (FT) frequent itemsets from transactional databases are computationally more expensive than mining exact matching frequent itemsets. Previous algorithms mine FT frequent itemsets using Apriori heuristic. Apriori-like algorithms generate exponential number of candidate itemsets including the itemsets that do not exist in the database. These algorithms require multiple scans of database for counting the support of candidate FT itemsets. In this paper we present a novel algorithm, which mines FT frequent itemsets using frequent pattern growth approach (FT-PatternGrowth). FT-PatternGrowth adopts a divide-and-conquer technique and recursively projects transactional database into a set of smaller projected transactional databases and mines FT frequent itemsets in each projected database by exploring only locally frequent items. This mines the complete set of FT frequent itemsets and substantially reduces those candidate itemsets that do not exist in the database. FT-PatternGrowth stores the transactional database in a highly condensed much smaller data structure called frequent pattern tree (FP-tree). The support of candidate itemsets are counted directly from the FP-tree without scanning the original database multiple times. This improves the processing speed of algorithm. Our experiments on benchmark databases indicates mining FT frequent itemsets using FT-PatternGrowth is highly efficient than Apriori-like algorithms.
qndr28n6
qndr28n6
2020-04-01
10.1016/j.eswa.2019.113046
1
Ferrets as a Novel Animal Model for Studying Human Respiratory Syncytial Virus Infections in Immunocompetent and Immunocompromised Hosts
Human respiratory syncytial virus (HRSV) is an important cause of severe respiratory tract disease in immunocompromised patients. Animal models are indispensable for evaluating novel intervention strategies in this complex patient population. To complement existing models in rodents and non-human primates, we have evaluated the potential benefits of an HRSV infection model in ferrets (Mustela putorius furo). Nine- to 12-month-old HRSV-seronegative immunocompetent or immunocompromised ferrets were infected with a low-passage wild-type strain of HRSV subgroup A (10(5) TCID(50)) administered by intra-tracheal or intra-nasal inoculation. Immune suppression was achieved by bi-daily oral administration of tacrolimus, mycophenolate mofetil, and prednisolone. Throat and nose swabs were collected daily and animals were euthanized four, seven, or 21 days post-infection (DPI). Virus loads were determined by quantitative virus culture and qPCR. We observed efficient HRSV replication in both the upper and lower respiratory tract. In immunocompromised ferrets, virus loads reached higher levels and showed delayed clearance as compared to those in immunocompetent animals. Histopathological evaluation of animals euthanized 4 DPI demonstrated that the virus replicated in the respiratory epithelial cells of the trachea, bronchi, and bronchioles. These animal models can contribute to an assessment of the efficacy and safety of novel HRSV intervention strategies.
qohrco5h
qohrco5h
2016-06-14
10.3390/v8060168
4.5
Mutated COVID-19 may foretell a great risk for mankind in the future
Coronavirus disease 2019 SARS-CoV-2 (COVID-19) is a zoonotic virus causing a variety of severe respiratory diseases. SARS-CoV-2 is closest to SARS-CoV and MERS-CoV in structure. The high prevalence of COVID-19 is a result of a lack of symptoms at onset. Our study aimed to present an overview of the virus in terms of structure, epidemiology, symptoms, treatment and prevention. Whole genome sequences and some viral proteins were investigated to determine gaps and changes in alternation of nucleotides and amino acid sequences. We evaluate 11 complete genome sequences of different coronaviruses using BAST and MAFFT software. We also selected seven types of structural proteins. We conclude that COVID-19 might produce new mutations, specifically in glycoproteins, so caution and complete preparation by health authorities is required.
qopcs6jy
qopcs6jy
2020-04-04
10.1016/j.nmni.2020.100673
1
Coronavirus disease 2019: What we know?
In late December 2019, a cluster of unexplained pneumonia cases has been reported in Wuhan, China. A few days later, the causative agent of this mysterious pneumonia was identified as a novel coronavirus. This causative virus has been temporarily named as severe acute respiratory syndrome coronavirus 2 and the relevant infected disease has been named as coronavirus disease 2019 (COVID‐19) by the World Health Organization, respectively. The COVID‐19 epidemic is spreading in China and all over the world now. The purpose of this review is primarily to review the pathogen, clinical features, diagnosis, and treatment of COVID‐19, but also to comment briefly on the epidemiology and pathology based on the current evidence.
qpcvxwti
qpcvxwti
2020-03-28
10.1002/jmv.25766
2.5
In Vitro and Animal Models for SARS-CoV-2 research
Basic research on SARS-CoV-2 is essential to understand its detailed pathophysiology and identify best drug targets. Models that can faithfully reproduce the viral life cycle and reproduce the pathology of COVID-19 are required. Here, we briefly review the cell lines, organoids, and animal models that are currently being used in COVID-19 research.
qpim47hf
qpim47hf
2020
5
Predicting the epidemic trend of COVID-19 in China and across the world using the machine learning approach
Background: Although COVID-19 has been well controlled in China, it is rapidly spreading outside the country and may have catastrophic results globally without implementation of necessary mitigation measures. Because the COVID-19 outbreak has made comprehensive and profound impacts on the world, an accurate prediction of its epidemic trend is significant. Although many studies have predicted the COVID-19 epidemic trend, most have used early-stage data and focused on Chinese cases. Methods: We first built models to predict daily numbers of cumulative confirmed cases (CCCs), new cases (NCs), and death cases (DCs) of COVID-19 in China based on data from January 20, 2020, to March 1, 2020. Based on these models, we built models to predict the epidemic trend across the world (outside China). We also built models to predict the epidemic trend in Italy, Spain, Germany, France, UK, and USA where COVID-19 is rapidly spreading. Findings: The COVID-19 outbreak will have peaked on February 22, 2020, in China and will peak on May 22, 2020, across the world. It will be basically under control in early April 2020 in China and end-August 2020 across the world. The total number of COVID-19 cases will reach around 89,000 in China and 6,126,000 across the world during the epidemic. Around 4,000 and 290,000 people will die of COVID-19 in China and across the world, respectively. The COVID-19 outbreak will have peaked recently in Italy and will peak in Spain, Germany, France, UK, and USA within two weeks. Interpretation: The COVID-19 outbreak is controllable in the foreseeable future if comprehensive and stringent control measures are taken.
qpt5dj8p
qpt5dj8p
2020-03-20
10.1101/2020.03.18.20038117
1
Identifying Human Interactors of SARS-CoV-2 Proteins and Drug Targets for COVID-19 using Network-Based Label Propagation
Motivated by the critical need to identify new treatments for COVID-19, we present a genome-scale, systems-level computational approach to prioritize drug targets based on their potential to regulate host-virus interactions or their downstream signaling targets. We adapt and specialize network label propagation methods to this end. We demonstrate that these techniques can predict human-SARS-CoV-2 protein interactors with high accuracy. The top-ranked proteins that we identify are enriched in host biological processes that are potentially coopted by the virus. We present cases where our methodology generates promising insights such as the potential role of HSPA5 in viral entry. We highlight the connection between endoplasmic reticulum stress, HSPA5, and anti-clotting agents. We identify tubulin proteins involved in ciliary assembly that are targeted by anti-mitotic drugs. Drugs that we discuss are already undergoing clinical trials to test their efficacy against COVID-19. Our prioritized list of human proteins and drug targets is available as a general resource for biological and clinical researchers who are repositioning existing and approved drugs or developing novel therapeutics as anti-COVID-19 agents.
qrfx165d
qrfx165d
2020-06-02
4.5
Treatment options for COVID-19: The reality and challenges
An outbreak related to the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was first reported in Wuhan, China in December 2019. An extremely high potential for dissemination resulted in the global coronavirus disease 2019 (COVID-19) pandemic in 2020. Despite the worsening trends of COVID-19, no drugs are validated to have significant efficacy in clinical treatment of COVID-19 patients in large-scale studies. Remdesivir is considered the most promising antiviral agent; it works by inhibiting the activity of RNA-dependent RNA polymerase (RdRp). A large-scale study investigating the clinical efficacy of remdesivir (200 mg on day 1, followed by 100 mg once daily) is on-going. The other excellent anti-influenza RdRp inhibitor favipiravir is also being clinically evaluated for its efficacy in COVID-19 patients. The protease inhibitor lopinavir/ritonavir (LPV/RTV) alone is not shown to provide better antiviral efficacy than standard care. However, the regimen of LPV/RTV plus ribavirin was shown to be effective against SARS-CoV in vitro. Another promising alternative is hydroxychloroquine (200 mg thrice daily) plus azithromycin (500 mg on day 1, followed by 250 mg once daily on day 2-5), which showed excellent clinical efficacy on Chinese COVID-19 patients and anti-SARS-CoV-2 potency in vitro. The roles of teicoplanin (which inhibits the viral genome exposure in cytoplasm) and monoclonal and polyclonal antibodies in the treatment of SARS-CoV-2 are under investigation. Avoiding the prescription of non-steroidal anti-inflammatory drugs, angiotensin converting enzyme inhibitors, or angiotensin II type I receptor blockers is advised for COVID-19 patients.
qsd49pvm
qsd49pvm
2020
3.5
Vaccines for SARS-CoV-2: Lessons from Other Coronavirus Strains
The emergence of the strain of coronavirus SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) and its impact on global health have made imperative the development of effective and safe vaccines for this lethal strain. SARS-CoV-2 now adds to the list of coronavirus diseases that have threatened global health, along with the SARS (severe acute respiratory syndrome) and MERS (Middle East respiratory syndrome) coronaviruses that emerged in 2002/2003 and 2012, respectively. As of April 2020, no vaccine is commercially available for these coronavirus strains. Nevertheless, the knowledge obtained from the vaccine development efforts for MERS and SARS can be of high value for COVID-19 (coronavirus disease 2019). Here, we review the past and ongoing vaccine development efforts for clinically relevant coronavirus strains with the intention that this information helps in the development of effective and safe vaccines for COVID-19. In addition, information from naturally exposed individuals and animal models to coronavirus strains is described for the same purpose of helping into the development of effective vaccines against COVID-19.
qu7ddcw9
qu7ddcw9
2020-04-23
10.1007/s40121-020-00300-x
3
COVID-19 and veterinarians for one health, zoonotic- and reverse-zoonotic transmissions
A novel coronavirus emerged in human populations and spread rapidly to cause the global coronavirus disease 2019 pandemic. Although the origin of the associated virus (severe acute respiratory syndrome coronavirus 2 [SARS-CoV-2]) remains unclear, genetic evidence suggests that bats are a reservoir host of the virus, and pangolins are a probable intermediate. SARS-CoV-2 has crossed the species barrier to infect humans and other animal species, and infected humans can facilitate reverse-zoonotic transmission to animals. Considering the rapidly changing interconnections among people, animals, and ecosystems, traditional roles of veterinarians should evolve to include transdisciplinary roles.
qutdsod1
qutdsod1
2020-05-22
10.4142/jvs.2020.21.e51
4
A global treatments for coronaviruses including COVID‐19
In late December 2019 in Wuhan, China, several patients with viral pneumonia were identified as 2019 novel coronavirus (2019‐nCoV). So far, there are no specific treatments for patients with coronavirus disease‐19 (COVID‐19), and the treatments available today are based on previous experience with similar viruses such as severe acute respiratory syndrome‐related coronavirus (SARS‐CoV), Middle East respiratory syndrome coronavirus (MERS‐CoV), and Influenza virus. In this article, we have tried to reach a therapeutic window of drugs available to patients with COVID‐19. Cathepsin L is required for entry of the 2019‐nCoV virus into the cell as target teicoplanin inhibits virus replication. Angiotensin‐converting‐enzyme 2 (ACE2) in soluble form as a recombinant protein can prevent the spread of coronavirus by restricting binding and entry. In patients with COVID‐19, hydroxychloroquine decreases the inflammatory response and cytokine storm, but overdose causes toxicity and mortality. Neuraminidase inhibitors such as oseltamivir, peramivir, and zanamivir are invalid for 2019‐nCoV and are not recommended for treatment but protease inhibitors such as lopinavir/ritonavir (LPV/r) inhibit the progression of MERS‐CoV disease and can be useful for patients of COVID‐19 and, in combination with Arbidol, has a direct antiviral effect on early replication of SARS‐CoV. Ribavirin reduces hemoglobin concentrations in respiratory patients, and remdesivir improves respiratory symptoms. Use of ribavirin in combination with LPV/r in patients with SARS‐CoV reduces acute respiratory distress syndrome and mortality, which has a significant protective effect with the addition of corticosteroids. Favipiravir increases clinical recovery and reduces respiratory problems and has a stronger antiviral effect than LPV/r. currently, appropriate treatment for patients with COVID‐19 is an ACE2 inhibitor and a clinical problem reducing agent such as favipiravir in addition to hydroxychloroquine and corticosteroids.
qxdakdk0
qxdakdk0
2020-05-11
10.1002/jcp.29785
4
Molecular targets for diagnostics and therapeutics of severe acute respiratory syndrome (SARS-CoV).
PURPOSE The large number of deaths in a short period of time due to the spread of severe acute respiratory syndrome (SARS) infection led to the unparalleled collaborative efforts world wide to determine and characterize the new coronavirus (SARS-CoV). The full genome sequence was determined within weeks of the first outbreak by the Canadian group with international collaboration. As per the World Health Organization (WHO), the continual lack of a rapid laboratory test to aid the early diagnosis of suspected cases of SARS makes this area a priority for future research. To prevent deaths in the future, early diagnosis and therapy of this infectious disease is of paramount importance. METHODS This review describes the specific molecular targets for diagnostics and therapeutics of viral infection. RESULTS The three major diagnostic methods available for SARS includes viral RNA detection by reverse transcription polymerase chain reaction (RT-PCR), virus induced antibodies by immunofluorescence assay (IFA) or by enzyme linked immunosorbant assay (ELISA) of nucleocapsid protein (NP). The spike glycoprotein of SARS-CoV is the major inducer of neutralizing antibodies. The receptor binding domain (RBD) in the S1 region of the spike glycoprotein contains multiple conformational epitopes that induces highly potent neutralizing antibodies. The genetically engineered attenuated form of the virus or viral vector vaccine encoding for the SARS-CoV spike glycoprotein has been shown to elicit protective immunity in vaccinated animals. CONCLUSION NP is the preferred target for routine detection of SARS-CoV infection by ELISA which is an economical method compared to other methods. The RBD of the spike glycoprotein is both a functional domain for cell receptor binding and also a major neutralizing determinant of SARS-CoV. The progress in evaluating a therapeutic or vaccine would depend on the avail ability of clinically relevant animal model.
qxiyo47f
qxiyo47f
2008
3.5
Evidence for SARS-CoV-2 Infection of Animal Hosts
COVID-19 is the first known pandemic caused by a coronavirus, SARS-CoV-2, which is the third virus in the family Coronaviridae to cause fatal infections in humans after SARS-CoV and MERS-CoV Animals are involved in the COVID-19 pandemic This review summarizes the role of animals as reservoirs, natural hosts and experimental models SARS-CoV-2 originated from animal reservoir, most likely bats and/or pangolins Anthroponotic transmission has been reported in cats, dogs, tigers, lions and minks As of now, there is no a strong evidence for natural animal-to-human transmission or sustained animal-to-animal transmission of SARS-CoV-2 Experimental infections conducted by several research groups have shown that monkeys, hamsters, ferrets, cats, tree shrews, transgenic mice and fruit bats were permissive, while dogs, pigs and poultry were resistant There is an urgent need to understand the zoonotic potential of different viruses in animals, particularly in bats, before they transmit to humans Vaccines or antivirals against SARS-CoV-2 should be evaluated not only for humans, but also for the protection of companion animals (particularly cats) and susceptible zoo and farm animals
qyg8hn56
qyg8hn56
2020
10.3390/pathogens9070529
5
Broad-Spectrum Coronavirus Fusion Inhibitors to Combat COVID-19 and Other Emerging Coronavirus Diseases
In the past 17 years, three novel coronaviruses have caused severe acute respiratory syndrome (SARS), Middle East respiratory syndrome (MERS), and the coronavirus disease 2019 (COVID-19). As emerging infectious diseases, they were characterized by their novel pathogens and transmissibility without available clinical drugs or vaccines. This is especially true for the newly identified COVID-19 caused by SARS coronavirus 2 (SARS-CoV-2) for which, to date, no specific antiviral drugs or vaccines have been approved. Similar to SARS and MERS, the lag time in the development of therapeutics is likely to take months to years. These facts call for the development of broad-spectrum anti-coronavirus drugs targeting a conserved target site. This review will systematically describe potential broad-spectrum coronavirus fusion inhibitors, including antibodies, protease inhibitors, and peptide fusion inhibitors, along with a discussion of their advantages and disadvantages.
qyz0zu2p
qyz0zu2p
2020-05-28
10.3390/ijms21113843
5
Why the lower reported prevalence of asthma in patients diagnosed with COVID-19 validates repurposing EDTA solutions to prevent and manage treat COVID-19 disease
There currently is no specific antiviral drug or a vaccine for SARS-CoV-2/COVID-19 infections; now exceeding 3,500,000 infections worldwide. In the absence of animal models to test drugs, we need to find molecular explanations for any unforeseen peculiarities in clinical data, especially the recent reports describing an unexpected asthma paradox. Asthma is considered a high medical risk factor for susceptibility to SARS-CoV-2/COVID-19 infection, yet asthma is not on the list of top 10 chronic health problems suffered by people who died from SARS-CoV-2/COVID-19. Resolving this paradox requires looking beyond the binary model of a viral receptor-binding domain (RBD) attaching to the ACE-2 receptor. A pBlast analysis revealed that the SARS-CoV-2 surface spike protein contains two calcium-dependent fusion domains that were recently discovered SARS-CoV-1. These viral calcium-dependent binding domains can facilitate membrane fusion only after cleavage by the host surface protease TMPRSS2. Importantly, TMPRSS2 also requires calcium for its SRCR (scavenger receptor cysteine-rich) domain and its LDLRA (LDL receptor class A) domain. Thus, the presence of EDTA excipients in nebulized β(2)-agonist medicines can disrupt SARS-CoV-2/COVID-19 infection and can explain the asthma paradox. This model validates repurposing EDTA in nebulizer solutions from a passive excipient to an active drug for treating COVID-19 infections. Repurposed EDTA delivery to respiratory tissues at an initial target dose of 2.4 mg per aerosol treatment is readily achievable with standard nebulizer and mechanical ventilator equipment. EDTA warrants further investigation as a potential treatment for SARS-CoV-2 /COVID-19 in consideration of the new calcium requirements for virus infection and the regular presence of EDTA excipients in common asthma medications such as Metaproterenol. Finally, the natural history of Coronavirus diseases and further analysis of the fusion loop homologies between the Betacorona SARS-CoV-2 virus and the less pathogenic Alphacorona HC0V-229E virus suggest how to engineer a hybrid virus suitable for an attenuated alpha-beta SARS-CoV-2/COVID-19 vaccine. Thus, replacing SARS-CoV-2 fusion loops (amino acids 816-855) with the less pathogenic HCoV-229E fusion loop (amino acids 923-982) may provide antigenicity of COVID-19, but limit the pathogenicity to the level of HCoV-229E.
qzeabqh4
qzeabqh4
2020-06-26
10.1016/j.mehy.2020.110027
5
Synthesis, modification and docking studies of 5-sulfonyl isatin derivatives as SARS-CoV 3C-like protease inhibitors
Abstract The Severe Acute Respiratory Syndrome (SARS) is a serious life-threatening and strikingly mortal respiratory illness caused by SARS-CoV. SARS-CoV which contains a chymotrypsin-like main protease analogous to that of the main picornavirus protease, 3CLpro. 3CLpro plays a pivotal role in the viral replication cycle and is a potential target for SARS inhibitor development. A series of isatin derivatives as possible SARS-CoV 3CLpro inhibitors was designed, synthesized, and evaluated by in vitro protease assay using fluorogenic substrate peptide, in which several showed potent inhibition against the 3CLpro. Structure–activity relationship was analyzed, and possible binding interaction modes were proposed by molecular docking studies. Among all compounds, 8k1 showed most potent inhibitory activity against 3CLpro (IC50 =1.04μM). These results indicated that these inhibitors could be potentially developed into anti-SARS drugs.
r0h2zhj2
r0h2zhj2
2014-01-01
10.1016/j.bmc.2013.11.028
3
Emerging viral diseases from a vaccinology perspective: preparing for the next pandemic
Emerging infectious diseases will continue to threaten public health and are sustained by global commerce, travel and disruption of ecological systems. Most pandemic threats are caused by viruses from either zoonotic sources or vector-borne sources. Developing better ways to anticipate and manage the ongoing microbial challenge will be critical for achieving the United Nations Sustainable Development Goals and, conversely, each such goal will affect the ability to control infectious diseases. Here we discuss how technology can be applied effectively to better prepare for and respond to new viral diseases with a focus on new paradigms for vaccine development.
r0nzgu8m
r0nzgu8m
2017-12-14
10.1038/s41590-017-0007-9
1
Prioritization of Anti-SARS-Cov-2 Drug Repurposing Opportunities Based on Plasma and Target Site Concentrations Derived from their Established Human Pharmacokinetics
There is a rapidly expanding literature on the in vitro antiviral activity of drugs that may be repurposed for therapy or chemoprophylaxis against severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2). However, this has not been accompanied by a comprehensive evaluation of the target plasma and lung concentrations of these drugs following approved dosing in humans. Accordingly, concentration 90% (EC90 ) values recalculated from in vitro anti-SARS-CoV-2 activity data was expressed as a ratio to the achievable maximum plasma concentration (Cmax ) at an approved dose in humans (Cmax /EC90 ratio). Only 14 of the 56 analyzed drugs achieved a Cmax /EC90 ratio above 1. A more in-depth assessment demonstrated that only nitazoxanide, nelfinavir, tipranavir (ritonavir-boosted), and sulfadoxine achieved plasma concentrations above their reported anti-SARS-CoV-2 activity across their entire approved dosing interval. An unbound lung to plasma tissue partition coefficient (Kp Ulung ) was also simulated to derive a lung Cmax /half-maximal effective concentration (EC50 ) as a better indicator of potential human efficacy. Hydroxychloroquine, chloroquine, mefloquine, atazanavir (ritonavir-boosted), tipranavir (ritonavir-boosted), ivermectin, azithromycin, and lopinavir (ritonavir-boosted) were all predicted to achieve lung concentrations over 10-fold higher than their reported EC50 . Nitazoxanide and sulfadoxine also exceeded their reported EC50 by 7.8-fold and 1.5-fold in lung, respectively. This analysis may be used to select potential candidates for further clinical testing, while deprioritizing compounds unlikely to attain target concentrations for antiviral activity. Future studies should focus on EC90 values and discuss findings in the context of achievable exposures in humans, especially within target compartments, such as the lungs, in order to maximize the potential for success of proposed human clinical trials.
r0zyfamz
r0zyfamz
2020
5
Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro
r22x7gnu
r22x7gnu
2020-02-04
10.1038/s41422-020-0282-0
1
FDA-approved thiol-reacting drugs that potentially bind into the SARS-CoV-2 main protease, essential for viral replication
Emergent novel SARS-CoV-2 is responsible for the current pandemic outbreak of severe acute respiratory syndrome with high mortality among the symptomatic population worldwide. Given the absence of a current vaccine or specific antiviral treatment, it is urgent to search for FDA-approved drugs that can potentially inhibit essential viral enzymes. The inhibition of 3CL(pro) has potential medical application, due to the fact that it is required for processing of the first translated replicase polyproteins into a series of native proteins, which are essential for viral replication in the host cell. We employed an in silico approach to test if disulfiram, as well as its metabolites, and captopril could be used as potential antiviral drugs against COVID-19. We provide data on the potential covalent interaction of disulfiram and its metabolites with the substrate binding subsite of 3CL(pro) and propose a possible mechanism for the irreversible protease inactivation thought the reaction of the aforementioned compounds with the Cys145. Although, captopril is shown to be a potential ligand of 3CL(pro), it is not recommended anti-COVID-19 therapy, due to the fact that it can induce the expression of the viral cellular receptor such as, angiotensin-converting enzyme ACE-2, and thus, making the patient potentially more susceptible to infection. On the other hand, disulfiram, an alcoholism-averting drug, has been previously proposed as an antimicrobial and anti-SARS and MERS agent, safe to use even at higher doses with low side effects, it is recommended to be tested for control of SARS-CoV-2 infection. Communicated by Ramaswamy H. Sarma
r3rlykli
r3rlykli
2020-05-14
10.1080/07391102.2020.1764393
4
Molecular dynamic simulations analysis of ritronavir and lopinavir as SARS-CoV 3CLpro inhibitors
Abstract Since the emergence of the severe acute respiratory syndrome (SARS) to date, neither an effective antiviral drug nor a vaccine against SARS is available. However, it was found that a mixture of two HIV-1 proteinase inhibitors, lopinavir and ritonavir, exhibited some signs of effectiveness against the SARS virus. To understand the fine details of the molecular interactions between these proteinase inhibitors and the SARS virus via complexation, molecular dynamics simulations were carried out for the SARS-CoV 3CLpro free enzyme (free SARS) and its complexes with lopinavir (SARS–LPV) and ritonavir (SARS–RTV). The results show that flap closing was clearly observed when the inhibitors bind to the active site of SARS-CoV 3CLpro. The binding affinities of LPV and RTV to SARS-CoV 3CLpro do not show any significant difference. In addition, six hydrogen bonds were detected in the SARS–LPV system, while seven hydrogen bonds were found in SARS–RTV complex.
r49ox9x9
r49ox9x9
2008-10-21
10.1016/j.jtbi.2008.07.030
1.5
COVID-19: A primer for Neuroradiologists
The potential for central nervous system (CNS) involvement in coronavirus disease 2019 (COVID-19) is a matter of grave concern and there is a relevant body of evidence in the basic sciences to support this possibility. A neuroradiologist should be aware of the potential mechanisms involved in the neuropathogenesis of this virus, as we begin to see cases with abnormal brain scans emerging from all parts of the world.
r4argyel
r4argyel
2020-04-28
10.1007/s00234-020-02437-5
4.5
The discrepant epidemiology of Middle East respiratory syndrome coronavirus (MERS-CoV)
The Middle East respiratory syndrome coronavirus (MERS-CoV) is a newly emerged infection in humans affecting the Arabian Peninsula, Europe, and North Africa. The source and persistence of the infection in humans remains unknown. The aim of this paper was to apply a risk analysis approach to the epidemiology of MERS-CoV and to understand the source of ongoing infections. The epidemiology of MERS-CoV was reviewed and compared to SARS. Each observed feature of MERS-CoV epidemiology was summarized and fitted to either an epidemic or one of two sporadic scenarios (either animal or deliberate release). As of May 2014, MERS-CoV has infected over 681 people and killed a further 204 over 2 years. In contrast, there were 8,273 cases and 775 deaths from SARS within 8 months. MERS-CoV has a more sporadic pattern unlike the clear epidemic pattern seen with SARS, and an unusual concentration of cases in the Middle East, without epidemics in other countries to which it has spread. SARS, with a higher reproductive number (R0), was eliminated from humans within 8 months of emerging, yet MERS-CoV, with a low R0 has persisted in humans over a far more prolonged period. This is at odds with the expected behavior of a virus with a low R0, which theoretically should not persist unless there are ongoing introductions of infection into humans, and poses the question “what is the source of continuing infections in humans?” A hospital outbreak in Al Ahsa, the Kingdom of Saudi Arabia (KSA), had a classic epidemic pattern with some human-to-human transmission. However, 3 different strains were identified in that outbreak, an unexpected and unexplained finding for what appears to be a single source outbreak. Since this outbreak in April 2013, there has been a large increase in new cases, mainly in KSA in April and May 2014, with no corresponding epidemics in other countries. Yet MERS-CoV was present in KSA over several mass gatherings (which predispose to epidemics), including the Hajj pilgrimage, without an epidemic arising. Furthermore, although the virus has been identified in bats and camels, the mode of ongoing transmission to humans remains uncertain. Although some cases appear to be transmitted from human to human, and a few have animal or camel exposure, many cases have no history of contact with either animals or human cases. A high proportion of asymptomatic or otherwise undetected cases have been postulated as an explanation for the unusual epidemiology, yet active surveillance does not support this. When the observed data were fitted to different disease patterns, the features of MERS-CoV fit better with a sporadic pattern, with evidence for either deliberate release or an animal source. There are many discrepancies in the observed epidemiology of MERS-CoV, which better fits a sporadic than an epidemic pattern. Possible explanations of the unusual features of the epidemiology include human-to-human transmission with a large proportion of undetected cases; or sporadic ongoing infections from a non-human source; or a combination of both. Possible sources of ongoing sporadic infection in humans include animals (camels appear the most likely source), or deliberate release. The latter could explain 3 strains being present in a single hospital outbreak. Genetic testing should be conducted to determine whether the virus is evolving to be more transmissible. Better ascertainment of mild or asymptomatic cases is also needed. Finally, the discrepant epidemiology warrants critical analysis of all possible explanations, and involvement of all stakeholders in biosecurity, and deliberate release must be seriously considered and at least acknowledged as a possibility.
r55fe25x
r55fe25x
2014-07-25
10.1007/s10669-014-9506-5
0.5
COVID-19: Immunology and treatment options
Abstract The novel coronavirus SARS-CoV2 causes COVID-19, a pandemic threatening millions. As protective immunity does not exist in humans and the virus is capable of escaping innate immune responses, it can proliferate, unhindered, in primarily infected tissues. Subsequent cell death results in the release of virus particles and intracellular components to the extracellular space, which result in immune cell recruitment, the generation of immune complexes and associated damage. Infection of monocytes/macrophages and/or recruitment of uninfected immune cells can result in massive inflammatory responses later in the disease. Uncontrolled production of pro-inflammatory mediators contributes to ARDS and cytokine storm syndrome. Antiviral agents and immune modulating treatments are currently being trialled. Understanding immune evasion strategies of SARS-CoV2 and the resulting delayed massive immune response will result in the identification of biomarkers that predict outcomes as well as phenotype and disease stage specific treatments that will likely include both antiviral and immune modulating agents.
r7ahl9gd
r7ahl9gd
2020-04-27
10.1016/j.clim.2020.108448
2.5
Crystal structure of SARS-CoV-2 nucleocapsid protein RNA binding domain reveals potential unique drug targeting sites
The outbreak of coronavirus disease (COVID-19) in China caused by SARS-CoV-2 virus continually lead to worldwide human infections and deaths. It is currently no specific viral protein targeted therapeutics yet. Viral nucleocapsid protein is a potential antiviral drug target, serving multiple critical functions during the viral life cycle. However, the structural information of SARS-CoV-2 nucleocapsid protein is yet to be clear. Herein, we have determined the 2.7 Å crystal structure of the N-terminal RNA binding domain of SARS-CoV-2 nucleocapsid protein. Although overall structure is similar with other reported coronavirus nucleocapsid protein N-terminal domain, the surface electrostatic potential characteristics between them are distinct. Further comparison with mild virus type HCoV-OC43 equivalent domain demonstrates a unique potential RNA binding pocket alongside the β-sheet core. Complemented by in vitro binding studies, our data provide several atomic resolution features of SARS-CoV-2 nucleocapsid protein N-terminal domain, guiding the design of novel antiviral agents specific targeting to SARS-CoV-2.
r88hpbxp
r88hpbxp
2020-03-07
10.1101/2020.03.06.977876
1.5
Suramin inhibits SARS-CoV-2 infection in cell culture by interfering with early steps of the replication cycle
The SARS-CoV-2 pandemic that originated from Wuhan, China, in December 2019 has impacted public health, society and economy and the daily lives of billions of people in an unprecedented manner. There are currently no specific registered antiviral drugs to treat or prevent SARS-CoV-2 infections. Therefore, drug repurposing would be the fastest route to provide at least a temporary solution while better, more specific drugs are being developed. Here we demonstrate that the antiparasitic drug suramin inhibits SARS-CoV-2 replication, protecting Vero E6 cells with an EC50 of ∼20 µM, which is well below the maximum attainable level in human serum. Suramin also decreased the viral load by 2-3 logs when Vero E6 cells or cells of a human lung epithelial cell line (Calu-3) were treated. Time of addition and plaque reduction assays showed that suramin acts on early steps of the replication cycle, possibly preventing entry of the virus. In a primary human airway epithelial cell culture model, suramin also inhibited the progression of infection. The results of our preclinical study warrant further investigation and suggest it is worth evaluating whether suramin provides any benefit for COVID-19 patients, which obviously requires well-designed, properly controlled randomized clinical trials.
r9dyt0n5
r9dyt0n5
2020-05-07
10.1101/2020.05.06.081968
3
Multinational modeling of SARS-CoV-2 spreading dynamics: Insights on the heterogeneity of COVID-19 transmission and its potential healthcare burden
Background: Modelling and projections of COVID-19 using a single set of transmission parameters can be an elaborated because the application of different levels of containment measures at different stages of the worldwide COVID-19 outbreak. Methods: We developed a piecewise fitting SEIR methodology to fit the progress of the COVID-19 that can be applied on any of the 185 countries listed in John Hopkins Coronavirus Resource Center. The contagious contact rate, the rate of removal and the initially exposed population were obtained at three different stages of the pandemic for a set of 18 countries, and globally for the total number of cases worldwide. The active number of infections and the removed populations were fitted simultaneously to validate the SEIR model against the available time series reports on the number of confirmed infections, recoveries and deaths. We evaluate the effect of a reduction of contagious contact rate on the level of burden put on local healthcare infrastructure considering different levels of intervention. As a guideline for future public health interventions, we also estimated the maximum number of future cases and its potential peak date. Findings: We project that the peak in the number of infections worldwide will take place after the third quarter of 2020 with a decline rate that might extend beyond 2020. For 12 out of the 18 countries analyzed, we observe that, following the trend at the date of this study, the number of severe infections will surpass their healthcare capacity. For a 90% reduction scenario of the contagious contact rate, four out of the 18 countries analyzed will undergo a significant delay in the peak of infection, extending the course of the epidemic further than our simulation window (365 days). Interpretation: We identify three stages for the COVID-19 transmission dynamics, which suggest that it is highly heterogeneous between countries and its contagious contact rate, is currently affected by both local responses of the public health interventions and to the population's adherence to the measures. Funding: No funding received.
raelqb6j
raelqb6j
2020-04-17
10.1101/2020.04.14.20064956
2.5
Structures of human antibodies bound to SARS-CoV-2 spike reveal common epitopes and recurrent features of antibodies
Summary Neutralizing antibody responses to coronaviruses mainly target the receptor-binding domain (RBD) of the trimeric spike. Here, we characterized polyclonal IgGs and Fabs from COVID-19 convalescent individuals for recognition of coronavirus spikes. Plasma IgGs differed in their focus on RBD epitopes, recognition of alpha- and beta-coronaviruses, and contributions of avidity to increased binding/neutralization of IgGs over Fabs. Using electron microscopy, we examined specificities of polyclonal plasma Fabs, revealing recognition of both S1A and RBD epitopes on SARS-CoV-2 spike. Moreover, a 3.4Å cryo-EM structure of a neutralizing monoclonal Fab-spike complex revealed an epitope that blocks ACE2 receptor binding. Modeling based on these structures suggested different potentials for inter-spike crosslinking by IgGs on viruses and that characterized IgGs would not be affected by identified SARS-CoV-2 spike mutations. Overall, our studies structurally define a recurrent anti-SARS-CoV-2 antibody class derived from VH3-53/VH3-66 and similarity to a SARS-CoV VH3-30 antibody, providing criteria for evaluating vaccine-elicited antibodies.
ratbgibg
ratbgibg
2020-06-24
10.1016/j.cell.2020.06.025
5
Animal Model Prescreening: Pre-exposure to SARS-CoV-2 impacts responses in the NHP model
COVID-19 presents herculean challenges to research and scientific communities for producing diagnostic and treatment solutions. Any return to normalcy requires rapid development of countermeasures, with animal models serving as a critical tool in testing vaccines and therapeutics. Animal disease status and potential COVID-19 exposure prior to study execution may severely bias efficacy testing. We developed a toolbox of immunological and molecular tests to monitor countermeasure impact on disease outcome and evaluate pre-challenge COVID-19 status. Assay application showed critical necessity for animal pre-screening. Specifically, real-time PCR results documented pre-exposure of an African Green Monkey prior to SARS-CoV-2 challenge with sequence confirmation as a community-acquired exposure. Longitudinal monitoring of nasopharyngeal swabs and serum showed pre-exposure impacted both viral disease course and resulting immunological response. This study demonstrates utility in a comprehensive pre-screening strategy for animal models, which captured the first documented case of community-acquired, non-human primate infection. One Sentence Summary Pre-exposure to SARS-CoV-2 affects biomarker responses in animal models, highlighting a need for robust pre-screening protocols prior to medical countermeasure studies.
rbt84zet
rbt84zet
2020-07-06
10.1101/2020.07.06.189803
5
Repositioning PARP inhibitors for SARS‐CoV‐2 infection (COVID‐19); a new multi‐pronged therapy for ARDS?
Clinically approved PARP inhibitors (PARPi) have a mild adverse effect profile and are well‐tolerated as continuous daily oral therapy. We review the evidence that justifies the repurposing of PARPi to block the proliferation of SARS‐CoV‐2 and combat the life‐threatening sequelae of COVID‐19 by several mechanisms. PARPi’s can effectively decrease IL‐6, IL‐1 and TNFα levels (key interleukins in SARS‐CoV‐2‐induced cytokine storm) and can alleviate subsequent lung fibrosis, as demonstrated in murine experiments and clinical trials. PARPi can tune macrophages towards a tolerogenic phenotype. PARPi’s may also counteract SARS‐CoV‐2‐induced and inflammation‐induced cell death and support cell survival. PARPi’s had beneficial effects in animal models of acute respiratory distress syndrome (ARDS), asthma and ventilator‐induced lung injury. PARPi’s may potentiate the effectiveness of Tocilizumab, Anakinra, Sarilumab, Adalimumab, Canakinumab or Siltuximab therapy. In summary, the evidence suggests that PARPi therapy would benefit COVID‐19 patients and trials of these drugs should be undertaken.
rbxymftg
rbxymftg
2020-05-22
10.1111/bph.15137
4
The trinity of COVID-19: immunity, inflammation and intervention
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of the ongoing coronavirus disease 2019 (COVID-19) pandemic. Alongside investigations into the virology of SARS-CoV-2, understanding the fundamental physiological and immunological processes underlying the clinical manifestations of COVID-19 is vital for the identification and rational design of effective therapies. Here, we provide an overview of the pathophysiology of SARS-CoV-2 infection. We describe the interaction of SARS-CoV-2 with the immune system and the subsequent contribution of dysfunctional immune responses to disease progression. From nascent reports describing SARS-CoV-2, we make inferences on the basis of the parallel pathophysiological and immunological features of the other human coronaviruses targeting the lower respiratory tract — severe acute respiratory syndrome coronavirus (SARS-CoV) and Middle East respiratory syndrome coronavirus (MERS-CoV). Finally, we highlight the implications of these approaches for potential therapeutic interventions that target viral infection and/or immunoregulation.
rcdoewwv
rcdoewwv
2020-04-28
10.1038/s41577-020-0311-8
3.5
Immunogenicity, safety, and protective efficacy of an inactivated SARS-associated coronavirus vaccine in rhesus monkeys
An inactivated vaccine for severe acute respiratory syndrome (SARS)-associated coronavirus (SARS-CoV) was evaluated in rhesus monkeys. The monkeys were inoculated intramuscularly (i.m.) with 0.5, 5, 50, or 5000 μg of vaccine, or PBS as control, and boosted on day 7. After 3 weeks, they were challenged with the NS-1 strain of SARS-CoV. The humoral and mucosal immune responses, clinical signs, chemical indices and viremia were monitored following the immunization and challenge. The control animals who received PBS developed atypical SAR-CoV infection after viral challenge, according to clinical, virological and pathological findings. No systematic side effects were observed in vaccinated animals post-immunization, even in at the high dose of 5000 μg. The 50 μg dosage of vaccine elicited SARS-CoV specific immune responses against viral infection as compared to the partial immunity elicited by 0.5 and 5 μg doses. The results show that this inactivated vaccine can induce effective concomitant humoral and mucosal immunity against SARS-CoV infection, is safe in monkeys, and the vaccine maybe a good candidate for clinical trials.
rd5bd1ae
rd5bd1ae
2005-05-02
10.1016/j.vaccine.2004.11.075
1
Complement Activation Contributes to Severe Acute Respiratory Syndrome Coronavirus Pathogenesis
Acute respiratory distress syndrome (ARDS) is immune-driven pathologies that are observed in severe cases of severe acute respiratory syndrome coronavirus (SARS-CoV) infection. SARS-CoV emerged in 2002 to 2003 and led to a global outbreak of SARS. As with the outcome of human infection, intranasal infection of C57BL/6J mice with mouse-adapted SARS-CoV results in high-titer virus replication within the lung, induction of inflammatory cytokines and chemokines, and immune cell infiltration within the lung. Using this model, we investigated the role of the complement system during SARS-CoV infection. We observed activation of the complement cascade in the lung as early as day 1 following SARS-CoV infection. To test whether this activation contributed to protective or pathologic outcomes, we utilized mice deficient in C3 (C3(–/–)), the central component of the complement system. Relative to C57BL/6J control mice, SARS-CoV-infected C3(–/–) mice exhibited significantly less weight loss and less respiratory dysfunction despite equivalent viral loads in the lung. Significantly fewer neutrophils and inflammatory monocytes were present in the lungs of C3(–/–) mice than in C56BL/6J controls, and subsequent studies revealed reduced lung pathology and lower cytokine and chemokine levels in both the lungs and the sera of C3(–/–) mice than in controls. These studies identify the complement system as an important host mediator of SARS-CoV-induced disease and suggest that complement activation regulates a systemic proinflammatory response to SARS-CoV infection. Furthermore, these data suggest that SARS-CoV-mediated disease is largely immune driven and that inhibiting complement signaling after SARS-CoV infection might function as an effective immune therapeutic.
rdlinzrn
rdlinzrn
2018-10-09
10.1128/mbio.01753-18
4.5
Modelling COVID-19 transmission: from data to intervention
regguljf
regguljf
2020-04-01
10.1016/s1473-3099(20)30258-9
1
A rational roadmap for SARS‐CoV‐2/COVID‐19 pharmacotherapeutic research and development. IUPHAR Review 29
In this review, we identify opportunities for drug discovery in the treatment of COVID‐19 and in so doing, provide a rational roadmap whereby pharmacology and pharmacologists can mitigate against the global pandemic. We assess the scope for targetting key host and viral targets in the mid‐term, by first screening these targets against drugs already licensed; an agenda for drug re‐purposing, which should allow rapid translation to clinical trials. A simultaneous, multi‐pronged approach using conventional drug discovery methodologies aimed at discovering novel chemical and biological means targetting a short‐list of host and viral entities should extend the arsenal of anti‐SARS‐CoV‐2 agents. This longer‐term strategy would provide a deeper pool of drug choices for future‐proofing against acquired drug resistance. Second, there will be further viral threats, which will inevitably evade existing vaccines. This will require a coherent therapeutic strategy which pharmacology and pharmacologists are best placed to provide.
rfj9t99r
rfj9t99r
2020-05-01
10.1111/bph.15094
4
2017 ACVIM Forum Research Abstract Program
ri2w5iby
ri2w5iby
2017-06-15
10.1111/jvim.14778
1.5
A Phylogeny-Based Global Nomenclature System and Automated Annotation Tool for H1 Hemagglutinin Genes from Swine Influenza A Viruses
The H1 subtype of influenza A viruses (IAVs) has been circulating in swine since the 1918 human influenza pandemic. Over time, and aided by further introductions from nonswine hosts, swine H1 viruses have diversified into three genetic lineages. Due to limited global data, these H1 lineages were named based on colloquial context, leading to a proliferation of inconsistent regional naming conventions. In this study, we propose rigorous phylogenetic criteria to establish a globally consistent nomenclature of swine H1 virus hemagglutinin (HA) evolution. These criteria applied to a data set of 7,070 H1 HA sequences led to 28 distinct clades as the basis for the nomenclature. We developed and implemented a web-accessible annotation tool that can assign these biologically informative categories to new sequence data. The annotation tool assigned the combined data set of 7,070 H1 sequences to the correct clade more than 99% of the time. Our analyses indicated that 87% of the swine H1 viruses from 2010 to the present had HAs that belonged to 7 contemporary cocirculating clades. Our nomenclature and web-accessible classification tool provide an accurate method for researchers, diagnosticians, and health officials to assign clade designations to HA sequences. The tool can be updated readily to track evolving nomenclature as new clades emerge, ensuring continued relevance. A common global nomenclature facilitates comparisons of IAVs infecting humans and pigs, within and between regions, and can provide insight into the diversity of swine H1 influenza virus and its impact on vaccine strain selection, diagnostic reagents, and test performance, thereby simplifying communication of such data. IMPORTANCE A fundamental goal in the biological sciences is the definition of groups of organisms based on evolutionary history and the naming of those groups. For influenza A viruses (IAVs) in swine, understanding the hemagglutinin (HA) genetic lineage of a circulating strain aids in vaccine antigen selection and allows for inferences about vaccine efficacy. Previous reporting of H1 virus HA in swine relied on colloquial names, frequently with incriminating and stigmatizing geographic toponyms, making comparisons between studies challenging. To overcome this, we developed an adaptable nomenclature using measurable criteria for historical and contemporary evolutionary patterns of H1 global swine IAVs. We also developed a web-accessible tool that classifies viruses according to this nomenclature. This classification system will aid agricultural production and pandemic preparedness through the identification of important changes in swine IAVs and provides terminology enabling discussion of swine IAVs in a common context among animal and human health initiatives.
ri7v2ka3
ri7v2ka3
2016-12-14
10.1128/msphere.00275-16
1.5
Serological survey of SARS‐CoV‐2 for experimental, domestic, companion and wild animals excludes intermediate hosts of 35 different species of animals
The pandemic SARS‐CoV‐2 has been reported in 123 countries with more than 5,000 patients died from it. However, the original and intermediate hosts of the virus remain unknown. In this study, 1,914 serum samples from 35 animal species were used for detection of SARS‐CoV‐2‐specific antibodies using double‐antigen sandwich ELISA after validating its specificity and sensitivity. The results showed that no SARS‐CoV‐2‐specific antibodies were detected in above samples which excluded the possibility of 35 animal species as intermediate host for SARS‐CoV‐2. More importantly, companion animals including pet dogs (including one dog the SARS‐CoV‐2 patient kept and two dogs which had close contact with it) and cats, street dogs and cats also showed serological negative to SARS‐CoV‐2, which relieved the public concerns for the pets as SARS‐CoV‐2 carriers.
rifr5uub
rifr5uub
2020-05-07
10.1111/tbed.13577
4
COVID-19 Tragic Pandemic: Concerns over Unintentional “Directed Accelerated Evolution” of Novel Coronavirus (SARS-CoV-2) and Introducing a Modified Treatment Method for ARDS
Global health authorities are trying to work out the current status of the novel coronavirus (COVID-19) outbreak and explore methods to reduce the rate of its transmission to healthy individuals. In this viewpoint we provide insights concerning how health care professionals can unintentionally shift the novel coronavirus type to more drug-resistant forms. It is worth noting that viruses usually have different sensitivities to physical and chemical damaging agents such antiviral drugs, UV and heat ranging from extremely sensitive (ES) to extremely resistant (ER) based on a bell-shaped curve. Given this consideration, the widespread infection of people with such ER viruses would be a real disaster. Here, we introduce a modified treatment method for COVID-19-associated pneumonia. In this proposed method, COVID-19 patients will receive a single dose of 100, 180 or 250 mSv X-ray radiation that is less than the maximum annual radiation dose of the residents of high background radiation areas of Ramsar that is up to 260 mSv. In contrast with antiviral drugs, a single dose of either 100, 180 or 250 mSv of low LET X-rays cannot exert a significant selective pressure on the novel coronavirus (SARS-CoV-2) and hence does not lead to directed accelerated evolution of these viruses. Moreover, Low Dose Radiation (LDR) has the capacity of modulating excessive inflammatory responses, regulating lymphocyte counts, and controling bacterial co-infections in patients with COVID-19.
rjqq1lxx
rjqq1lxx
2020-04-01
10.31661/jbpe.v0i0.2003-1085
2
Coronaviral hypothetical and structural proteins were found in the intestinal surface enterocytes and pneumocytes of severe acute respiratory syndrome (SARS)
Severe acute respiratory syndrome (SARS) is a newly emerging infectious disease that haunted the world from November 2002 to July 2003. Little is known about the biology and pathophysiology of the novel coronavirus that causes SARS. The tissue and cellular distributions of coronaviral hypothetical and structural proteins in SARS were investigated. Antibodies against the hypothetical (SARS 3a, 3b, 6, 7a and 9b) and structural proteins (envelope, membrane, nucleocapsid and spike) of the coronavirus were generated from predicted antigenic epitopes of each protein. The presence of these proteins were first verified in coronavirus-infected Vero E6 tissue culture model. Immunohistochemical studies on different human tissues, including a cohort of nine autopsies, two liver biopsies and intestinal biopsies of SARS patients, further confirmed the existence of coronaviral hypothetical and structural proteins in the cytoplasm of pneumocytes and small intestinal surface enterocytes in SARS patients. With this vast array of antibodies, no signal was observed in other cell types including those organs in which reverse transcriptase-polymerase chain reactions were reported to be positive. Structural proteins and the functionally undefined hypothetical proteins were expressed in coronavirus-infected cells with distinct expression pattern in different organs in SARS patients. These antipeptide antibodies can be useful for the diagnosis of SARS at the tissue level.
rmlrhyf2
rmlrhyf2
2005-05-13
10.1038/modpathol.3800439
1
Functional and Genetic Analysis of Viral Receptor ACE2 Orthologs Reveals a Broad Potential Host Range of SARS-CoV-2
The pandemic of Coronavirus Disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is a major global health threat. Epidemiological studies suggest that bats are the natural zoonotic reservoir for SARS-CoV-2. However, the host range of SARS-CoV-2 and intermediate hosts that facilitate its transmission to humans remain unknown. The interaction of coronavirus with its host receptor is a key genetic determinant of host range and cross-species transmission. SARS-CoV-2 uses angiotensin-converting enzyme 2 (ACE2) as the receptor to enter host cells in a species-dependent manner. It has been shown that human, palm civet, pig and bat ACE2 can support virus entry, while the murine ortholog cannot. In this study, we characterized the ability of ACE2 from diverse species to support viral entry. We found that ACE2 is expressed in a wide range of species, with especially high conservation in mammals. By analyzing amino acid residues of ACE2 critical for virus entry, based on structure of SARS-CoV spike protein interaction with human, bat, palm civet, pig and ferret ACE2, we identified approximately eighty ACE2 proteins from mammals that could potentially mediate SARS-CoV-2 entry. Functional assays showed that 44 of these mammalian ACE2 orthologs, including those of domestic animals, pets, livestock, and animals commonly found in zoos and aquaria, could bind SARS-CoV-2 spike protein and support viral entry. In contrast, New World monkey ACE2 orthologs could not bind SARS-CoV-2 spike protein and support viral entry. We further identified the genetic determinant of New World monkey ACE2 that restricts viral entry using genetic and functional analyses. In summary, our study demonstrates that ACE2 from a remarkably broad range of species can facilitate SARS-CoV-2 entry. These findings highlight a potentially broad host tropism of SARS-CoV-2 and suggest that SARS-CoV-2 might be distributed much more widely than previously recognized, underscoring the necessity to monitor susceptible hosts to prevent future outbreaks.
rmmp3gms
rmmp3gms
2020-05-03
10.1101/2020.04.22.046565
2.5
New Nucleoside Analogues for the Treatment of Hemorrhagic Fever Virus Infections
Eight different compounds, all nucleoside analogues, could presently be considered as potential drug candidates for the treatment of Ebola virus (EBOV) and/or other hemorrhagic fever virus (HFV) infections. They can be considered as either (i) adenine analogues (3‐deazaneplanocin A, galidesivir, GS‐6620 and remdesivir) or (ii) guanine analogues containing the carboxamide entity (ribavirin, EICAR, pyrazofurin and favipiravir). All eight owe their mechanism of action to hydrogen bonded base pairing with either (i) uracil or (ii) cytosine. Four out of the eight compounds (galidesivir, GS‐6620, remdesivir and pyrazofurin) are C‐nucleosides, and two of them (GS‐6620, remdesivir) also contain a phosphoramidate part. The C‐nucleoside and phosphoramidate (and for the adenine analogues the 1′‐cyano group as well) may be considered as essential attributes for their antiviral activity.
rmxin1da
rmxin1da
2019-08-07
10.1002/asia.201900841
2
Syncytium formation is induced in the murine neuroblastoma cell cultures which produce pathogenic type G proteins of the rabies virus
Abstract We investigated comparatively the interactions of host cells with two types of rabies virus G protein, an avirulent type G (Gln) and a virulent type G (Arg) protein, having glutamine and arginine at position 333, respectively. For this purpose, we established four types of cell lines (referred to as G(Gln)-NA, G(Arg)-NA, G(Gln)-BHK, and G(Arg)-BHK cells, respectively) by transfecting either the G(Gln)-cDNA or G(Arg)-cDNA into two kinds of cells, murine neuroblastoma C1300 (clone NA) and nonneuronal BHK-21. Both G(Gln)-NA and G(Arg)-NA cells produced G proteins when they were treated with 5 mM sodium butyrate, but only G(Arg)-NA cells formed syncytia at the neutral pH, which was suppressed by anti-G antiserum. The sodium butyrate-treated G(Arg)-NA cells fused also with sodium butyrate-treated NA cells under coculture conditions, but neither with untreated NA cells nor with BHK-21 cells. On the other hand, both G(Gln)-BHK and G(Arg)-BHK cells constitutively produced G proteins, but no syncytium was produced at the neutral pH. G(Arg)-BHK cells, however, formed syncytia with the sodium butyrate-treated NA cells when they were cocultured. These results suggest that only G(Arg) has a potential ability to produce syncytia of NA cells regardless of cell types by which G(Arg) protein was produced and also suggest that a certain cellular factor(s) is required for the syncytium formation, the factor(s) which is lacking in BHK-21 and untreated NA cells but is produced by the sodium butyrate-treated NA cells.
rongrdai
rongrdai
1992-07-31
10.1016/0042-6822(92)90696-m
5
First genome sequences of buffalo coronavirus from water buffaloes in Bangladesh
We report the complete genome sequences of a buffalo coronavirus (BufCoV HKU26) detected from the faecal samples of two domestic water buffaloes (Bubalus bubalis) in Bangladesh. They possessed 98–99% nucleotide identities to bovine coronavirus (BCoV) genomes, supporting BufCoV HKU26 as a member of Betacoronavirus 1. Nevertheless, BufCoV HKU26 possessed distinct accessory proteins between spike and envelope compared to BCoV. Sugar-binding residues in the N-terminal domain of S protein in BCoV are conserved in BufCoV HKU26.
rpeqkfxc
rpeqkfxc
2016-03-03
10.1016/j.nmni.2016.02.011
3
A Novel Protein Drug, Novaferon, as the Potential Antiviral Drug for COVID-19
Abstract Background Novaferon, a novel protein drug approved for the treatment of chronic hepatitis B in China, exhibits potent antiviral activities. We aimed to determine the anti-SARS-CoV-2 effects of Novaferon in vitro, and conducted a randomized, open-label, parallel group study to explore the antiviral effects of Novaferon for COVID-19. Methods In laboratory, the inhibition of Novaferon on viral replication in cells infected with SARS-CoV-2, and on SARS-CoV-2 entry into healthy cells was determined. Antiviral effects of Novaferon were evaluated in COVID-19 patients with treatment of Novaferon, Novaferon plus Lopinavir/Ritonavir, or Lopinavir/Ritonavir. The primary endpoint was the SARS-CoV-2 clearance rates on day 6 of treatment, and the secondary endpoint was the time to the SARS-CoV-2 clearance in COVID-19 patients Results Novaferon inhibited the viral replication in infected cells (EC50=1.02 ng/ml), and protected healthy cells from SARS-CoV-2 infection (EC50=0.1 ng/ml). Results from the 89 enrolled COVID-19 patients showed that both Novaferon and Novaferon plus Lopinavir/Ritonavir groups had significantly higher SARS-CoV-2 clearance rates on day 6 than the Lopinavir/Ritonavir group (50.0% vs.24.1%, p = 0.0400, and 60.0% vs.24.1%, p = 0.0053). Median time to SARS-CoV-2 clearance were 6 days, 6 days, and 9 days for three groups respectively, suggesting a 3-dayreduction of time to SARS-CoV-2 clearance in both Novaferon and Novaferon plus Lopinavir/Ritonavir groups compared with Lopinavir/Ritonavir group. Conclusions Novaferon exhibited anti-SARS-CoV-2 effects in vitro and in COVID-19 patients. These data justified the further evaluation of Novaferon. Key words: COVID-19, SARS-CoV-2, Novaferon, Antiviral drug, Lopinavir/Ritonavir
rq5gh710
rq5gh710
2020-04-29
10.1101/2020.04.24.20077735
2.5
An animal model that reflects human disease: the common marmoset (Callithrix jacchus)
The common marmoset is a new world primate belonging to the Callitrichidae family weighing between 350 and 400g. The marmoset has been shown to be an outstanding model for studying aging, reproduction, neuroscience, toxicology, and infectious disease. With regard to their susceptibility to infectious agents, they are exquisite NHP models for viral, protozoan and bacterial agents, as well as prions. The marmoset provides the advantages of a small animal model in high containment coupled with the immunological repertoire of a nonhuman primate and susceptibility to wild type, non-adapted viruses.
rsbb913w
rsbb913w
2012-06-01
10.1016/j.coviro.2012.02.007
1
Classification of COVID-19 patients from chest CT images using multi-objective differential evolution–based convolutional neural networks
Early classification of 2019 novel coronavirus disease (COVID-19) is essential for disease cure and control. Compared with reverse-transcription polymerase chain reaction (RT-PCR), chest computed tomography (CT) imaging may be a significantly more trustworthy, useful, and rapid technique to classify and evaluate COVID-19, specifically in the epidemic region. Almost all hospitals have CT imaging machines; therefore, the chest CT images can be utilized for early classification of COVID-19 patients. However, the chest CT-based COVID-19 classification involves a radiology expert and considerable time, which is valuable when COVID-19 infection is growing at rapid rate. Therefore, an automated analysis of chest CT images is desirable to save the medical professionals’ precious time. In this paper, a convolutional neural networks (CNN) is used to classify the COVID-19-infected patients as infected (+ve) or not (−ve). Additionally, the initial parameters of CNN are tuned using multi-objective differential evolution (MODE). Extensive experiments are performed by considering the proposed and the competitive machine learning techniques on the chest CT images. Extensive analysis shows that the proposed model can classify the chest CT images at a good accuracy rate.
rtwko7mu
rtwko7mu
2020-04-27
10.1007/s10096-020-03901-z
3.5
Inhibition of the replication of SARS-CoV-2 in human cells by the FDA-approved drug chlorpromazine
Urgent action is needed to fight the ongoing COVID-19 pandemic by reducing the number of infected people along with the infection contagiousness and severity. Chlorpromazine (CPZ), the prototype of typical antipsychotics from the phenothiazine group, is known to inhibit clathrin-mediated endocytosis and acts as an antiviral, in particular against SARS-CoV-1 and MERS-CoV. In this study, we describe the in vitro testing of CPZ against a SARS-CoV-2 isolate in monkey and human cells. We evidenced an antiviral activity against SARS-CoV-2 with an IC50 of ∼10μM. Because of its high biodistribution in lung, saliva and brain, such IC50 measured in vitro may translate to CPZ dosage used in clinical routine. This extrapolation is in line with our observations of a higher prevalence of symptomatic and severe forms of COVID-19 infections among health care professionals compared to patients in psychiatric wards. These preclinical findings support the repurposing of CPZ, a largely used drug with mild side effects, in COVID-19 treatment.
rvnvwe21
rvnvwe21
2020-05-06
10.1101/2020.05.05.079608
3.5
Lessons Learned to Date on COVID-19 Hyperinflammatory Syndrome: Considerations for Interventions to Mitigate SARS-CoV-2 Viral Infection and Detrimental Hyperinflammation
The first case of human transmission of SARS-CoV-2 was reported in China in December 2019. A few months later, this viral infection had spread worldwide and became a pandemic. The disease caused by SARS-CoV-2, termed COVID-19, is multifactorial and associated with both specific antiviral as well as inflammatory responses, the extent of which may determine why some individuals are asymptomatic while others develop serious complications. Here we review possible life-threating immune events that can occur during disease progression to uncover key factors behind COVID-19 severity and provide suggestions for interventions with repurposed drugs in well-controlled and randomized clinical trials. These drugs include therapeutics with potential to inhibit SARS-CoV-2 entry into host cells such as serine protease inhibitors of the cellular protease TMPS2 and drugs targeting the renin-angiotensin system; antivirals with potential to block SARS-CoV-2 replication or factors that could boost the antiviral response; monoclonal antibodies targeting pro-inflammatory cytokines that drive the hyperinflammatory response during COVID-19 progression toward the severe stage and therapeutics that could ameliorate the function of the lungs. Furthermore, in order to help make more informed decisions on the timing of the intervention with the drugs listed in this review, we have grouped these therapeutics according to the stage of COVID-19 progression that we considered most appropriate for their mechanism of action.
rwx2lzxv
rwx2lzxv
2020-05-29
10.3389/fimmu.2020.01131
4.5
2019-nCoV (Wuhan virus), a novel Coronavirus: human-to-human transmission, travel-related cases, and vaccine readiness.
On 31 December 2019 the Wuhan Health Commission reported a cluster of atypical pneumonia cases that was linked to a wet market in the city of Wuhan, China. The first patients began experiencing symptoms of illness in mid-December 2019. Clinical isolates were found to contain a novel coronavirus with similarity to bat coronaviruses. As of 28 January 2020, there are in excess of 4,500 laboratory-confirmed cases, with > 100 known deaths. As with the SARS-CoV, infections in children appear to be rare. Travel-related cases have been confirmed in multiple countries and regions outside mainland China including Germany, France, Thailand, Japan, South Korea, Vietnam, Canada, and the United States, as well as Hong Kong and Taiwan. Domestically in China, the virus has also been noted in several cities and provinces with cases in all but one provinence. While zoonotic transmission appears to be the original source of infections, the most alarming development is that human-to-human transmission is now prevelant. Of particular concern is that many healthcare workers have been infected in the current epidemic. There are several critical clinical questions that need to be resolved, including how efficient is human-to-human transmission? What is the animal reservoir? Is there an intermediate animal reservoir? Do the vaccines generated to the SARS-CoV or MERS-CoV or their proteins offer protection against 2019-nCoV? We offer a research perspective on the next steps for the generation of vaccines. We also present data on the use of in silico docking in gaining insight into 2019-nCoV Spike-receptor binding to aid in therapeutic development. Diagnostic PCR protocols can be found at https://www.who.int/health-topics/coronavirus/laboratory-diagnostics-for-novel-coronavirus.
rxrlbw60
rxrlbw60
2020-01-31
10.3855/jidc.12425
1
Mouse model of SARS-CoV-2 reveals inflammatory role of type I interferon signaling
Severe Acute Respiratory Syndrome- Coronavirus 2 (SARS-Cov-2) has caused over 5,000,000 cases of Coronavirus disease (COVID-19) with significant fatality rate.(1–3) Due to the urgency of this global pandemic, numerous therapeutic and vaccine trials have begun without customary safety and efficacy studies.(4) Laboratory mice have been the stalwart of these types of studies; however, they do not support infection by SARS-CoV-2 due to the inability of its spike (S) protein to engage the mouse ortholog of its human entry receptor angiotensin-converting enzyme 2 (hACE2). While hACE2 transgenic mice support infection and pathogenesis,(5) these mice are currently limited in availability and are restricted to a single genetic background. Here we report the development of a mouse model of SARS-CoV-2 based on adeno associated virus (AAV)-mediated expression of hACE2. These mice support viral replication and antibody production and exhibit pathologic findings found in COVID-19 patients as well as non-human primate models. Moreover, we show that type I interferons are unable to control SARS-CoV2 replication and drive pathologic responses. Thus, the hACE2-AAV mouse model enables rapid deployment for in-depth analysis following robust SARS-CoV-2 infection with authentic patient-derived virus in mice of diverse genetic backgrounds. This represents a much-needed platform for rapidly testing prophylactic and therapeutic strategies to combat COVID-19.
rycluj9p
rycluj9p
2020-05-27
10.1101/2020.05.27.118893
4
Glecaprevir and Maraviroc are high-affinity inhibitors of SARS-CoV-2 main protease: possible implication in COVID-19 therapy
Due to the lack of efficient therapeutic options and clinical trial limitations, the FDA-approved drugs can be a good choice to handle Coronavirus disease (COVID-19). Many reports have enough evidence for the use of FDA-approved drugs which have inhibitory potential against target proteins of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). Here, we utilized a structure-based drug design approach to find possible drug candidates from the existing pool of FDA-approved drugs and checked their effectiveness against the SARS-CoV-2. We performed virtual screening of the FDA-approved drugs against the main protease (M(pro)) of SARS-CoV-2, an essential enzyme, and a potential drug target. Using well-defined computational methods, we identified Glecaprevir and Maraviroc (MVC) as the best inhibitors of SARS-CoV-2 M(pro). Both drugs bind to the substrate-binding pocket of SARS-CoV-2 M(pro) and form a significant number of non-covalent interactions. Glecaprevir and MVC bind to the conserved residues of substrate-binding pocket of SARS-CoV-2 M(pro). This work provides sufficient evidence for the use of Glecaprevir and MVC for the therapeutic management of COVID-19 after experimental validation and clinical manifestations.
rz205rqd
rz205rqd
2020-06-02
10.1042/bsr20201256
4
Immunodominant SARS Coronavirus Epitopes in Humans Elicited both Enhancing and Neutralizing Effects on Infection in Non-human Primates
[Image: see text] Severe acute respiratory syndrome (SARS) is caused by a coronavirus (SARS-CoV) and has the potential to threaten global public health and socioeconomic stability. Evidence of antibody-dependent enhancement (ADE) of SARS-CoV infection in vitro and in non-human primates clouds the prospects for a safe vaccine. Using antibodies from SARS patients, we identified and characterized SARS-CoV B-cell peptide epitopes with disparate functions. In rhesus macaques, the spike glycoprotein peptides S(471–503), S(604–625), and S(1164–1191) elicited antibodies that efficiently prevented infection in non-human primates. In contrast, peptide S(597–603) induced antibodies that enhanced infection both in vitro and in non-human primates by using an epitope sequence-dependent (ESD) mechanism. This peptide exhibited a high level of serological reactivity (64%), which resulted from the additive responses of two tandem epitopes (S(597–603) and S(604–625)) and a long-term human B-cell memory response with antisera from convalescent SARS patients. Thus, peptide-based vaccines against SARS-CoV could be engineered to avoid ADE via elimination of the S(597–603) epitope. We provide herein an alternative strategy to prepare a safe and effective vaccine for ADE of viral infection by identifying and eliminating epitope sequence-dependent enhancement of viral infection.
rzf0cw1x
rzf0cw1x
2016-04-11
10.1021/acsinfecdis.6b00006
2
A Mouse Model of SARS-CoV-2 Infection and Pathogenesis
Since December 2019, a novel coronavirus SARS-CoV-2 has emerged and rapidly spread throughout the world, resulting in a global public health emergency. The lack of vaccine and antivirals has brought an urgent need for an animal model. Human angiotensin-converting enzyme II (ACE2) has been identified as a functional receptor for SARS-CoV-2. In this study, we generated a mouse model expressing human ACE2 (hACE2) by using CRISPR/Cas9 knockin technology. In comparison with wild-type C57BL/6 mice, both young and aged hACE2 mice sustained high viral loads in lung, trachea, and brain upon intranasal infection. Although fatalities were not observed, interstitial pneumonia and elevated cytokines were seen in SARS-CoV-2 infected-aged hACE2 mice. Interestingly, intragastric inoculation of SARS-CoV-2 was seen to cause productive infection and lead to pulmonary pathological changes in hACE2 mice. Overall, this animal model described here provides a useful tool for studying SARS-CoV-2 transmission and pathogenesis and evaluating COVID-19 vaccines and therapeutics.
s0l801qv
s0l801qv
2020
4
Humanized Single Domain Antibodies Neutralize SARS-CoV-2 by Targeting Spike Receptor Binding Domain
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has spread across more than 200 countries and regions, leading to an unprecedented medical burden and live lost. SARS-CoV-2 specific antivirals or prophylactic vaccines are not available. Neutralizing antibodies provide efficient blockade for viral infection and are a promising category of biological therapies. Using SARS-CoV-2 spike RBD as a bait, we have discovered a panel of humanized single domain antibodies (sdAbs). These sdAbs revealed binding kinetics with the equilibrium dissociation constant (KD) of 0.7~33 nM. The monomeric sdAbs showed half maximal inhibitory concentration (IC50) of 0.003~0.3 μg/mL in pseudotyped particle neutralization assay, and 0.23~0.50 μg/mL in authentic SARS-CoV-2 neutralization assay. Competitive ligand-binding data suggested that the sdAbs either completely blocked or significantly inhibited the association between SARS-CoV-2 RBD and viral entry receptor ACE2. Finally, we showed that fusion of the human IgG1 Fc to sdAbs improved their neutralization activity by tens of times. These results reveal the novel SARS-CoV-2 RBD targeting sdAbs and pave a road for antibody drug development.
s19pa1z1
s19pa1z1
2020-04-15
10.1101/2020.04.14.042010
4
SARS: future research and vaccine
Summary Severe acute respiratory syndrome (SARS) is a new infectious disease of the 21st century that has pandemic potential. A novel coronavirus (CoV) was identified as its aetiological agent and its genome was sequenced within months of the World Health Organisation issuing a global threat on SARS. The high morbidity and mortality of this potentially pandemic infection demands a rapid research response to develop effective antiviral treatment and vaccine. This will depend on understanding the pathogenesis and immune response to SARS CoV. Further understanding of the ecology of SARS CoV in human and animals will help prevent future cross species transmission. Likewise for the super-spreading events, clarification of the underlying reasons will be important to prevent a large scale outbreak of SARS. Lastly it is of utmost importance that international research collaboration should be strengthened to deal with SARS and any other emerging infectious disease that can seriously threaten our future.
s2d3q4ob
s2d3q4ob
2004-12-31
10.1016/j.prrv.2004.07.005
0.5
New coronavirus: new challenges for pediatricians
s2ia7avo
s2ia7avo
2020-02-10
10.1007/s12519-020-00346-4
2
Breakthrough: Chloroquine phosphate has shown apparent efficacy in treatment of COVID-19 associated pneumonia in clinical studies.
The coronavirus disease 2019 (COVID-19) virus is spreading rapidly, and scientists are endeavoring to discover drugs for its efficacious treatment in China. Chloroquine phosphate, an old drug for treatment of malaria, is shown to have apparent efficacy and acceptable safety against COVID-19 associated pneumonia in multicenter clinical trials conducted in China. The drug is recommended to be included in the next version of the Guidelines for the Prevention, Diagnosis, and Treatment of Pneumonia Caused by COVID-19 issued by the National Health Commission of the People's Republic of China for treatment of COVID-19 infection in larger populations in the future.
s2j4qf0j
s2j4qf0j
2020-02-19
10.5582/bst.2020.01047
2.5
Detection of Covid-19 From Chest X-ray Images Using Artificial Intelligence: An Early Review
In 2019, the entire world is facing a situation of health emergency due to a newly emerged coronavirus (COVID-19). Almost 196 countries are affected by covid-19, while USA, Italy, China, Spain, Iran, and France have the maximum active cases of COVID-19. The issues, medical and healthcare departments are facing in delay of detecting the COVID-19. Several artificial intelligence based system are designed for the automatic detection of COVID-19 using chest x-rays. In this article we will discuss the different approaches used for the detection of COVID-19 and the challenges we are facing. It is mandatory to develop an automatic detection system to prevent the transfer of the virus through contact. Several deep learning architecture are deployed for the detection of COVID-19 such as ResNet, Inception, Googlenet etc. All these approaches are detecting the subjects suffering with pneumonia while its hard to decide whether the pneumonia is caused by COVID-19 or due to any other bacterial or fungal attack.
s3q6l9hv
s3q6l9hv
2020-04-11
2
The aetiology of SARS: Koch's postulates fulfilled.
Proof that a newly identified coronavirus, severe acute respiratory syndrome coronavirus (SARS-CoV) is the primary cause of severe acute respiratory syndrome (SARS) came from a series of studies on experimentally infected cynomolgus macaques (Macaca fascicularis). SARS-CoV-infected macaques developed a disease comparable to SARS in humans; the virus was re-isolated from these animals and they developed SARS-CoV-specific antibodies. This completed the fulfilment of Koch's postulates, as modified by Rivers for viral diseases, for SARS-CoV as the aetiological agent of SARS. Besides the macaque model, a ferret and a cat model for SARS-CoV were also developed. These animal models allow comparative pathogenesis studies for SARS-CoV infections and testing of different intervention strategies. The first of these studies has shown that pegylated interferon-alpha, a drug approved for human use, limits SARS-CoV replication and lung damage in experimentally infected macaques. Finally, we argue that, given the worldwide nature of the socio-economic changes that have predisposed for the emergence of SARS and avian influenza in Southeast Asia, such changes herald the beginning of a global trend for which we are ill prepared.
s4aisy2z
s4aisy2z
2004
1
ElaD, a Deubiquitinating Protease Expressed by E. coli
BACKGROUND: Ubiquitin and ubiquitin-like proteins (Ubl) are designed to modify polypeptides in eukaryotes. Covalent binding of ubiquitin or Ubls to substrate proteins can be reversed by specific hydrolases. One particular set of cysteine proteases, the CE clan, which targets ubiquitin and Ubls, has homologs in eukaryotes, prokaryotes, and viruses. FINDINGS: We have cloned and analyzed the E. coli protein elaD, which is distantly related to eukaryotic CE clan members of the ULP/SENP protease family that are specific for SUMO and Nedd8. Previously misannotated as a putative sulfatase/phosphatase, elaD is an efficient and specific deubiquitinating enzyme in vitro. Interestingly, elaD is present in all intestinal pathogenic E. coli strains, but conspicuously absent from extraintestinal pathogenic strains (ExPECs). Further homologs of this protease can be found in Acanthamoeba Polyphaga Mimivirus, and in Alpha-, Beta-and Gammaproteobacteria. CONCLUSION: The expression of ULP/SENP-related hydrolases in bacteria therefore extends to plant pathogens and medically relevant strains of Escherichia coli, Legionella pneumophila, Rickettsiae, Chlamydiae, and Salmonellae, in which the elaD ortholog sseL has recently been identified as a virulence factor with deubiquitinating activity. As a counterpoint, our phylogenetic and functional examination reveals that ancient eukaryotic ULP/SENP proteases also have the potential of ubiquitin-specific hydrolysis, suggesting an early common origin of this peptidase clan.
s4y6uxsb
s4y6uxsb
2007-04-18
10.1371/journal.pone.0000381
4
Towards an Effective and Efficient Deep Learning Model for COVID-19 Patterns Detection in X-ray Images
Confronting the pandemic of COVID-19, is nowadays one of the most prominent challenges of the human species. A key factor in slowing down the virus propagation is the rapid diagnosis and isolation of infected patients. The standard method for COVID-19 identification, the Reverse transcription polymerase chain reaction method, is time-consuming and in short supply due to the pandemic. Thus, researchers have been looking for alternative screening methods and deep learning applied to chest X-rays of patients has been showing promising results. Despite their success, the computational cost of these methods remains high, which imposes difficulties to their accessibility and availability. Thus, the main goal of this work is to propose an accurate yet efficient method in terms of memory and processing time for the problem of COVID-19 screening in chest X-rays. Methods: To achieve the defined objective we exploit and extend the EfficientNet family of deep artificial neural networks which are known for their high accuracy and low footprints in other applications. We also exploit the underlying taxonomy of the problem with a hierarchical classifier. A dataset of 13,569 X-ray images divided into healthy, non-COVID-19 pneumonia, and COVID-19 patients is used to train the proposed approaches and other 5 competing architectures. Finally, 231 images of the three classes were used to assess the quality of the methods. Results: The results show that the proposed approach was able to produce a high-quality model, with an overall accuracy of 93.9%, COVID-19, sensitivity of 96.8% and positive prediction of 100%, while having from 5 to 30 times fewer parameters than other than the other tested architectures. Larger and more heterogeneous databases are still needed for validation before claiming that deep learning can assist physicians in the task of detecting COVID-19 in X-ray images.
s6wmq3mz
s6wmq3mz
2020-04-12
2
Virtual Screening of Natural Products against Type II Transmembrane Serine Protease (TMPRSS2), the Priming Agent of Coronavirus 2 (SARS-CoV-2)
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused about 2 million infections and is responsible for more than 100,000 deaths worldwide. To date, there is no specific drug registered to combat the disease it causes, named coronavirus disease 2019 (COVID-19). In the current study, we used an in silico approach to screen natural compounds to find potent inhibitors of the host enzyme transmembrane protease serine 2 (TMPRSS2). This enzyme facilitates viral particle entry into host cells, and its inhibition blocks virus fusion with angiotensin-converting enzyme 2 (ACE2). This, in turn, restricts SARS-CoV-2 pathogenesis. A three-dimensional structure of TMPRSS2 was built using SWISS-MODEL and validated by RAMPAGE. The natural compounds library Natural Product Activity and Species Source (NPASS), containing 30,927 compounds, was screened against the target protein. Two techniques were used in the Molecular Operating Environment (MOE) for this purpose, i.e., a ligand-based pharmacophore approach and a molecular docking-based screening. In total, 2140 compounds with pharmacophoric features were retained using the first approach. Using the second approach, 85 compounds with molecular docking comparable to or greater than that of the standard inhibitor (camostat mesylate) were identified. The top 12 compounds with the most favorable structural features were studied for physicochemical and ADMET (absorption, distribution, metabolism, excretion, toxicity) properties. The low-molecular-weight compound NPC306344 showed significant interaction with the active site residues of TMPRSS2, with a binding energy score of −14.69. Further in vitro and in vivo validation is needed to study and develop an anti-COVID-19 drug based on the structures of the most promising compounds identified in this study.
s71naf96
s71naf96
2020-05-12
10.3390/molecules25102271
4.5
Forecasting of COVID-19 Cases and Deaths Using ARIMA Models
After the outbreak of severe acute respiratory syndrome (SARS-2002/2003) and middle east respiratory syndrome (MERS-2012/2014) in the world, new public health crisis, called new coronavirus disease (COVID-19), started in China in December 2019 and has spread all over countries. COVID-19 coronavirus has been global threat of the disease and infected humans rapidly. Control of the pandemi is urgently essential, and science community have continued to research treatment agents. Support therapy and intensive care units in hospitals are also efective to overcome of COVID-19. Statistic forecasting models could aid to healthcare system in preventation of COVID-19. This study aimed to compose of forecasting model that could be practical to predict the spread of COVID-19 in Italy, Spain and Turkey. For this purpose, we performed Auto Regressive Integrated Moving Average (ARIMA) model on the European Centre for Disease Prevention and Control COVID-19 data to predict the number of cases and deaths in COVID-19. According to the our results, while number of cases in Italy and Spain is expected to decrease as of July, in Turkey is expected to decline as of September. The number of deaths in Italy and Spain is expected to be the lowest in July. In Turkey, this number is expected to reach the highest in July. In addition, it is thought that if studies in which the sensitivity and validity of this method are tested with more cases, they will contribute to researchers working in this field. KEYWORDS: COVID-19, pandemi, ARIMA, time series analysis
s7fzex7v
s7fzex7v
2020-04-22
10.1101/2020.04.17.20069237
2
A Call to Arms, Not to Disarm: The Importance of Psychiatric Care in the Acute Medical Setting During the COVID 19 Pandemic
s7k8ldrj
s7k8ldrj
2020-04-03
10.1016/j.psym.2020.03.008
3.5
StralSV: assessment of sequence variability within similar 3D structures and application to polio RNA-dependent RNA polymerase
BACKGROUND: Most of the currently used methods for protein function prediction rely on sequence-based comparisons between a query protein and those for which a functional annotation is provided. A serious limitation of sequence similarity-based approaches for identifying residue conservation among proteins is the low confidence in assigning residue-residue correspondences among proteins when the level of sequence identity between the compared proteins is poor. Multiple sequence alignment methods are more satisfactory--still, they cannot provide reliable results at low levels of sequence identity. Our goal in the current work was to develop an algorithm that could help overcome these difficulties by facilitating the identification of structurally (and possibly functionally) relevant residue-residue correspondences between compared protein structures. RESULTS: Here we present StralSV (structure-alignment sequence variability), a new algorithm for detecting closely related structure fragments and quantifying residue frequency from tight local structure alignments. We apply StralSV in a study of the RNA-dependent RNA polymerase of poliovirus, and we demonstrate that the algorithm can be used to determine regions of the protein that are relatively unique, or that share structural similarity with proteins that would be considered distantly related. By quantifying residue frequencies among many residue-residue pairs extracted from local structural alignments, one can infer potential structural or functional importance of specific residues that are determined to be highly conserved or that deviate from a consensus. We further demonstrate that considerable detailed structural and phylogenetic information can be derived from StralSV analyses. CONCLUSIONS: StralSV is a new structure-based algorithm for identifying and aligning structure fragments that have similarity to a reference protein. StralSV analysis can be used to quantify residue-residue correspondences and identify residues that may be of particular structural or functional importance, as well as unusual or unexpected residues at a given sequence position. StralSV is provided as a web service at http://proteinmodel.org/AS2TS/STRALSV/.
s7kzp795
s7kzp795
2011-06-02
10.1186/1471-2105-12-226
1
Rapid colorimetric detection of COVID-19 coronavirus using a reverse tran-scriptional loop-mediated isothermal amplification (RT-LAMP) diagnostic plat-form: iLACO
The recent outbreak of a novel coronavirus SARS-CoV-2 (also known as 2019-nCoV) threatens global health, given serious cause for concern. SARS-CoV-2 is a human-to-human pathogen that caused fever, severe respiratory disease and pneumonia (known as COVID-19). By press time, more than 70,000 infected people had been confirmed worldwide. SARS-CoV-2 is very similar to the severe acute respiratory syndrome (SARS) coronavirus broke out 17 years ago. However, it has increased transmissibility as compared with the SARS-CoV, e.g. very often infected individuals without any symptoms could still transfer the virus to others. It is thus urgent to develop a rapid, accurate and onsite diagnosis methods in order to effectively identify these early infects, treat them on time and control the disease spreading. Here we developed an isothermal LAMP based method-iLACO (isothermal LAMP based method for COVID-19) to amplify a fragment of the ORF1ab gene using 6 primers. We assured the species-specificity of iLACO by comparing the sequences of 11 related viruses by BLAST (including 7 similar coronaviruses, 2 influenza viruses and 2 normal coronaviruses). The sensitivity is comparable to Taqman based qPCR detection method, detecting synthesized RNA equivalent to 10 copies of 2019-nCoV virus. Reaction time varied from 15-40 minutes, depending on the loading of virus in the collected samples. The accuracy, simplicity and versatility of the new developed method suggests that iLACO assays can be conveniently applied with for 2019-nCoV threat control, even in those cases where specialized molecular biology equipment is not available.
s7uqawbd
s7uqawbd
2020-02-24
10.1101/2020.02.20.20025874
1.5
Emodin is a novel alkaline nuclease inhibitor that suppresses herpes simplex virus type 1 yields in cell cultures
BACKGROUND AND PURPOSE: Most antiviral therapies directed against herpes simplex virus (HSV) infections are limited to a small group of nucleoside analogues that target the viral polymerase. Extensive clinical use of these drugs has led to the emergence of resistant viral strains, mainly in immunocompromised patients. This highlights the need for the development of new anti-herpesviral drugs with novel targets. Herein the effects of a plant anthraquinone, emodin, on the HSV-1 alkaline nuclease activity and virus yields were investigated. EXPERIMENTAL APPROACH: HSV-1 alkaline nuclease activity was examined by nuclease activity assay. Inhibition of virus yields was measured by plaque reduction assay and immunohistochemical staining. Interaction between emodin and alkaline nuclease was analysed by docking technology. KEY RESULTS: Emodin specifically inhibited the nuclease activity of HSV-1 UL12 alkaline nuclease in a biochemical assay. Plaque reduction assay revealed that emodin reduced the plaque formation with an EC(50) of 21.5±4.4 μM. Immunohistochemical staining using the anti-nucleocapsid protein antibody demonstrated that emodin induced the accumulation of viral nucleocapsids in the nucleus in a dose-dependent manner. Docking analysis further suggested that the inhibitory effect of emodin on the UL12 activity may result from the interaction between emodin and critical catalytic amino acid residues of UL12. CONCLUSIONS AND IMPLICATIONS: Our findings suggest that emodin is a potent anti-HSV agent that inhibits the yields of HSV-1 via the suppression of a novel target, UL12.
s7w70kqy
s7w70kqy
2009-01-29
10.1038/bjp.2008.242
3.5
Computational studies of drug repurposing and synergism of lopinavir, oseltamivir and ritonavir binding with SARS-CoV-2 Protease against COVID-19.
A novel coronavirus (SARS-CoV-2) has caused a major outbreak in humans all over the world, and it is the latest pandemic in the series of other infectious diseases. The concept of drug repurposing has been used successfully for many years for known diseases. Considering the emergency and urgency, drug repurposing concept is being explored for coronavirus disease (COVID-19) as well. Recently, the combination of three known drugs, lopinavir, oseltamivir and ritonavir has been proposed to control the virulence to a great extent in COVID-19 affected patients within 48 hours. Hence, we tried to understand the effect of synergism of these drugs against the SARS-CoV-2 protease using sequential docking studies. As a result, combination of three drugs showed a better binding energy than that of individual drugs. Further, the complex was subjected to molecular dynamics simulations to get insights into the stability of the complex, considering the simultaneous interactions between three drugs and the protein. The protein complexed with three drugs remained stable during the simulations. Hence, these drugs can be explored further for drug repurposing against the successful inhibition of COVID-19.
s953j62y
s953j62y
2020-04-06
10.1080/07391102.2020.1752802
3.5
Mining association rules with multiple minimum supports: a new mining algorithm and a support tuning mechanism
Abstract Mining association rules with multiple minimum supports is an important generalization of the association-rule-mining problem, which was recently proposed by Liu et al. Instead of setting a single minimum support threshold for all items, they allow users to specify multiple minimum supports to reflect the natures of the items, and an Apriori-based algorithm, named MSapriori, is developed to mine all frequent itemsets. In this paper, we study the same problem but with two additional improvements. First, we propose a FP-tree-like structure, MIS-tree, to store the crucial information about frequent patterns. Accordingly, an efficient MIS-tree-based algorithm, called the CFP-growth algorithm, is developed for mining all frequent itemsets. Second, since each item can have its own minimum support, it is very difficult for users to set the appropriate thresholds for all items at a time. In practice, users need to tune items' supports and run the mining algorithm repeatedly until a satisfactory end is reached. To speed up this time-consuming tuning process, an efficient algorithm which can maintain the MIS-tree structure without rescanning database is proposed. Experiments on both synthetic and real-life datasets show that our algorithms are much more efficient and scalable than the previous algorithm.
s96d3ust
s96d3ust
2006-10-31
10.1016/j.dss.2004.09.007
1.5
A New Predictor of Disease Severity in Patients with COVID-19 in Wuhan, China
Background: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) broke out in Wuhan, Hubei, China. This study sought to elucidate a novel predictor of disease severity in patients with coronavirus disease-19 (COVID-19) cased by SARS-CoV-2. Methods: Patients enrolled in this study were all hospitalized with COVID-19 in the Central Hospital of Wuhan, China. Clinical features, chronic comorbidities, demographic data, and laboratory and radiological data were reviewed. The outcomes of patients with severe pneumonia and those with non-severe pneumonia were compared using the Statistical Package for the Social Sciences (IBM Corp., Armonk, NY, USA) to explore clinical characteristics and risk factors. The receiver operating characteristic curve was used to screen optimal predictors from the risk factors and the predictive power was verified by internal validation. Results: A total of 377 patients diagnosed with COVID-19 were enrolled in this study, including 117 with severe pneumonia and 260 with non-severe pneumonia. The independent risk factors for severe pneumonia were age [odds ratio (OR): 1.059, 95% confidence interval (CI): 1.036-1.082; p < 0.001], N/L (OR: 1.322, 95% CI: 1.180-1.481; p < 0.001), CRP (OR: 1.231, 95% CI: 1.129-1.341; p = 0.002), and D-dimer (OR: 1.059, 95% CI: 1.013-1.107; p = 0.011). We identified a product of N/L*CRP*D-dimer as having an important predictive value for the severity of COVID-19. The cutoff value was 5.32. The negative predictive value of less than 5.32 for the N/L*CRP*D-dimer was 93.75%, while the positive predictive value was 46.03% in the test sets. The sensitivity and specificity were 89.47% and 67.42%. In the training sets, the negative and positive predictive values were 93.80% and 41.32%, respectively, with a specificity of 70.76% and a sensitivity of 89.87%. Conclusions: A product of N/L*CRP*D-dimer may be an important predictor of disease severity in patients with COVID-19.
s9vv7rw4
s9vv7rw4
2020-03-27
10.1101/2020.03.24.20042119
1.5
SARS-CoV-2: Camazotz's Curse
The world is currently face to face with a pandemic which is spreading rapidly across the globe caused by SARS-CoV-2, a strain of Coronaviruses (CoVs) belonging to subgenus Sarbecovirus of genus Betacoronavirus. World Health Organisation (WHO) on 11 Feb 20 named this disease caused by SARS-CoV-2 as Covid-19. This pandemic is spreading rapidly and more than 20,00,000 cases have occurred globally. The human Coronaviruses discovered in 1960s were considered potentially harmless endemic viruses with seasonal distribution before late 2002. The CoVs are found in a large number of domestic and wild animals and birds. The first pandemic caused by Coronavirus caused by SARS-CoV was recognized in the late 2002 in Guangdong Province and resulted in widespread morbidity and mortality. This was followed by MERS-CoV which began in 2012 in the Arabian peninsula with multiple outbreaks related to it in various parts of the globe. Various studies have suggested how these viruses made their entry from their natural reservoir bats via intermediate host like civets and camels in case of SARS-CoV and MERS-CoV respectively. The intermediate host of the SARS-CoV-2 still needs to be established. The SARS-CoV-2 has 96.2% similarity to the bat Severe Acute Respiratory Syndrome related-Coronavirus (SARSr-CoV RaTG13). SARS-CoV-2 has been found to be more distant in relation to SARS-CoV (79%) and MERS-CoV (50%). At the whole genome sequence level pangolin CoV and SARSr-CoV RaTG13 show 91.02% and 96.2% similarity with SARS-CoV-2 but the S1 subunit of spike protein of pangolin CoV is more closely related to SARS-CoV-2 than SARSr-CoV RaTG13. The genetic analysis of the currently circulating strains of the pandemic have shown 99.98-100% similarity in their genomes implying a recent shift to humans. The animal source of SARS-CoV-2 needs to be identified to implement control measures in the present pandemic. Also, how the virus moves interspecies will help predict and prevent future pandemics.
sbswy7el
sbswy7el
2020-04-27
10.1016/j.mjafi.2020.04.008
3
Animal Models and Vaccines for SARS-CoV Infection
We summarize findings of SARS-CoV infections in several animal models each of which support viral replication in lungs accompanied by histopathological changes and/or clinical signs of illness to varying degrees. New findings are reported on SARS-CoV replication and associated pathology in two additional strains (C57BL/6 and 129S6) of aged mice. We also provide new comparative data on viral replication and associated pathology following infection of golden Syrian hamsters with various SARS-CoV strains and report the levels of neutralizing antibody titers following these infections and the cross-protective efficacy of infection with these strains in protecting against heterologous challenge. Finally, we summarize findings of a variety of vaccine approaches and discuss the available in vitro and in vivo data addressing the potential for disease enhancement following re-infection in animals previously vaccinated against or infected with SARS-CoV.
sc1m4c07
sc1m4c07
2008-04-01
10.1016/j.virusres.2007.03.025
1
Respiratory Viruses
Abstract This article is an overview of the most clinically important respiratory viruses including the recently emerged highly pathogenic coronaviruses and other viruses that are transmitted via the respiratory tract. In this article, we highlight a description of the agent, its life cycle, epidemiology, pathogenesis, clinical features, diagnosis and management of the infection. The viruses in this article are respiratory syncytial virus, parainfluenza virus, human metapneumovirus, rhinovirus, seasonal and emerging coronaviruses, adenovirus, bocavirus and other viruses associated with the respiratory tract for their life cycle.
scs7hkhr
scs7hkhr
2019-12-31
10.1016/b978-0-12-801238-3.66161-5
2.5
Is the anti-filarial drug diethylcarbamazine useful to treat COVID-19 ?
SARS-CoV-2 virus has resulted in a devastating pandemic of COVID-19. Exploring compounds that could offer a breakthrough in treatment is the need of the hour. Re-positioning cheap, freely available and safe drugs is a priority. The paper proposes evidence for the potential use of diethylcarbamazine (DEC) in the treatment of COVID-19. DEC has inhibitory effects on arachidonic acid metabolism to prostaglandins, little known anti-viral effects on animal retroviruses and demonstrated anti-inflammatory actions in animal models of lung inflammation indicating the need to explore this hypothesis further. We believe this is the first time DEC is being proposed to treat COVID-19.
sdih33mv
sdih33mv
2020-05-18
10.1016/j.mehy.2020.109843
3
In Vitro Antiviral Activity and Projection of Optimized Dosing Design of Hydroxychloroquine for the Treatment of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2)
BACKGROUND: The Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) first broke out in Wuhan (China) and subsequently spread worldwide. Chloroquine has been sporadically used in treating SARS-CoV-2 infection. Hydroxychloroquine shares the same mechanism of action as chloroquine, but its more tolerable safety profile makes it the preferred drug to treat malaria and autoimmune conditions. We propose that the immunomodulatory effect of hydroxychloroquine also may be useful in controlling the cytokine storm that occurs late-phase in critically ill SARS-CoV-2 infected patients. Currently, there is no evidence to support the use of hydroxychloroquine in SARS-CoV-2 infection. METHODS: The pharmacological activity of chloroquine and hydroxychloroquine was tested using SARS-CoV-2 infected Vero cells. Physiologically-based pharmacokinetic models (PBPK) were implemented for both drugs separately by integrating their in vitro data. Using the PBPK models, hydroxychloroquine concentrations in lung fluid were simulated under 5 different dosing regimens to explore the most effective regimen whilst considering the drug’s safety profile. RESULTS: Hydroxychloroquine (EC(50)=0.72 μM) was found to be more potent than chloroquine (EC(50)=5.47 μM) in vitro. Based on PBPK models results, a loading dose of 400 mg twice daily of hydroxychloroquine sulfate given orally, followed by a maintenance dose of 200 mg given twice daily for 4 days is recommended for SARS-CoV-2 infection, as it reached three times the potency of chloroquine phosphate when given 500 mg twice daily 5 days in advance. CONCLUSIONS: Hydroxychloroquine was found to be more potent than chloroquine to inhibit SARS-CoV-2 in vitro.
sdij1d90
sdij1d90
2020-03-09
10.1093/cid/ciaa237
0.5
Identification of potential vaccine candidates against SARS-CoV-2, A step forward to fight novel coronavirus 2019-nCoV: A Reverse Vaccinology Approach
The recent Coronavirus Disease 2019 (COVID-19) causes an immense health crisis to global public health. The World Health Organization (WHO) declared the COVID-19 as a pandemic. The COVID-19 is the etiologic agent of a recently arose disease caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Presently, there is no vaccine available against this emerged viral disease. Therefore, it is indeed a need of the hour to develop an effectual and safe vaccine against this decidedly pandemic disease. In the current study, we collected SARS-CoV-2 genome from Indian geographical origin against human host, further more using reverse vaccinology and immunoinformatics tools here we claim effective vaccine candidates that can be mile stone in battle against COVID19. This novel study divulged two promising antigenic peptide GVYFASTEK and NFRVQPTESIV from surface glycoproteins (protein accession no. – QIA98583.1 and QHS34546.1) of SARS-CoV-2, which were predicated to be interacted with class I and class II MHC alleles and showed up to 90% conservancy and high value of antigenicity. Subsequently, the molecular docking studies were verified molecular interaction of these prime antigenic peptides with the residues of HLA-A*11-01 allele for MHC Class I and HLA DRB1*04-01 allele for MHC class II. After vigorous analysis, these peptides were predicted to be suitable epitopes which are capable to elicit the strong cell-mediated immune response against the SARS-CoV-2. Consequences from the present study could facilitate selecting SARS-CoV-2 epitopes for vaccine production pipelines in the immediate future. This novel research will certainly pave the way for a fast, reliable and virtuous platform to provide timely countermeasure of this dangerous pandemic disease, COVID-19.
sdiwnhs0
sdiwnhs0
2020-04-14
10.1101/2020.04.13.039198
2.5
The Importance of Animal Models in the Development of Vaccines
Efficient translation of basic vaccine research into clinical therapies greatly depends upon the availability of appropriate animal models. Testing novel vaccine candidates in animal models is a critical step in the development of modern vaccines. Animal models are being used to assess the quality and quantity of the immune response, to identify the optimal route of delivery and formulation, to determine protection from infection and disease transmission, and to evaluate the safety and toxicity of the vaccine formulation. Animal models help to make the translation from basic research to clinical application, and they often allow prediction of the vaccine potential, which helps in predicting the financial risks for vaccine manufacturers. Choosing an appropriate animal model has become increasingly important for the field, as each model has its own advantages and disadvantages. In this review, the criteria for selecting the right animal model, the advantages and disadvantages of various animal models, as well as the future needs for animal models are being discussed.
seaa46hz
seaa46hz
2012-03-29
10.1007/978-94-007-4543-8_11
4.5
Sybodies targeting the SARS-CoV-2 receptor-binding domain
The COVID-19 pandemic, caused by the novel coronavirus SARS-CoV-2, has resulted in a global health and economic crisis of unprecedented scale. The high transmissibility of SARS-CoV-2, combined with a lack of population immunity and prevalence of severe clinical outcomes, urges the rapid development of effective therapeutic countermeasures. Here, we report the generation of synthetic nanobodies, known as sybodies, against the receptor-binding domain (RBD) of SARS-CoV-2. In an expeditious process taking only twelve working days, sybodies were selected entirely in vitro from three large combinatorial libraries, using ribosome and phage display. We obtained six strongly enriched sybody pools against the isolated RBD and identified 63 unique anti-RBD sybodies which also interact in the context of the full-length SARS-CoV-2 spike ectodomain. Among the selected sybodies, six were found to bind to the viral spike with double-digit nanomolar affinity, and five of these also showed substantial inhibition of RBD interaction with human angiotensin-converting enzyme 2 (ACE2). Additionally, we identified a pair of anti-RBD sybodies that can simultaneously bind to the RBD. It is anticipated that compact binders such as these sybodies could feasibly be developed into an inhalable drug that can be used as a convenient prophylaxis against COVID-19. Moreover, generation of polyvalent antivirals, via fusion of anti-RBD sybodies to additional small binders recognizing secondary epitopes, could enhance the therapeutic potential and guard against escape mutants. We present full sequence information and detailed protocols for the identified sybodies, as a freely accessible resource.
sgm24q1i
sgm24q1i
2020-05-16
10.1101/2020.04.16.045419
3.5
Improving Coronavirus (COVID-19) Diagnosis using Deep Transfer Learning
Background: Coronavirus disease (COVID-19) is an infectious disease caused by a new virus. Exponential growth is not only threatening lives, but also impacting businesses and disrupting travel around the world. Aim: The aim of this work is to develop an efficient diagnosis of COVID-19 disease by differentiating it from viral pneumonia, bacterial pneumonia and healthy cases using deep learning techniques. Method: In this work, we have used pre-trained knowledge to improve the diagnostic performance using transfer learning techniques and compared the performance different CNN architectures. Results: Evaluation results using K-fold (10) showed that we have achieved state of the art performance with overall accuracy of 98.75% on the perspective of CT and X-ray cases as a whole. Conclusion: Quantitative evaluation showed high accuracy for automatic diagnosis of COVID-19. Pre-trained deep learning models develop in this study could be used early screening of coronavirus, however it calls for extensive need to CT or X-rays dataset to develop a reliable application.
sgy03deg
sgy03deg
2020-04-17
10.1101/2020.04.11.20054643
3.5
Synergistic antiviral effect of hydroxychloroquine and azithromycin in combination against SARS-CoV-2: What molecular dynamics studies of virus-host interactions reveal
The emergence of SARS-coronavirus-2 (SARS-CoV-2) has led to a global pandemic disease referred to as coronavirus disease 19 (COVID-19). Hydroxychloroquine (CLQ-OH)/azithromycin (ATM) combination therapy is currently being tested for the treatment of COVID-19, with promising results. However, the molecular mechanism of action of this combination is not yet established. Using molecular dynamics (MD) simulations, this study shows that the drugs act in synergy to prevent any close contact between the virus and the plasma membrane of host cells. Unexpected molecular similarity is shown between ATM and the sugar moiety of GM1, a lipid raft ganglioside acting as a host attachment cofactor for respiratory viruses. Due to this mimicry, ATM interacts with the ganglioside-binding domain of SARS-CoV-2 spike protein. This binding site shared by ATM and GM1 displays a conserved amino acid triad Q-134/F-135/N-137 located at the tip of the spike protein. CLQ-OH molecules are shown to saturate virus attachment sites on gangliosides in the vicinity of the primary coronavirus receptor, angiotensin-converting enzyme-2 (ACE-2). Taken together, these data show that ATM is directed against the virus, whereas CLQ-OH is directed against cellular attachment cofactors. We conclude that both drugs act as competitive inhibitors of SARS-CoV-2 attachment to the host-cell membrane. This is consistent with a synergistic antiviral mechanism at the plasma membrane level, where therapeutic intervention is likely to be most efficient. This molecular mechanism may explain the beneficial effects of CLQ-OH/ATM combination therapy in patients with COVID-19. Incidentally, the data also indicate that the conserved Q-134/F-135/N-137 triad could be considered as a target for vaccine strategies.
shn22k0s
shn22k0s
2020
5
Antiviral activities of type I interferons to SARS-CoV-2 infection
There is an urgent need to identify antivirals to curtail the COVID-19 pandemic. Herein, we report the sensitivity of SARS-CoV-2 to recombinant human interferons α and β (IFNα/β). Treatment with IFN-α or IFN-β at a concentration of 50 international units (IU) per milliliter reduces viral titers by 3.4 log or over 4 log, respectively, in Vero cells. The EC(50) of IFN-α and IFN-β treatment is 1.35 IU/ml and 0.76 IU/ml, respectively, in Vero cells. These results suggest that SARS-CoV-2 is more sensitive than many other human pathogenic viruses, including SARS-CoV. Overall, our results demonstrate the potential efficacy of human Type I IFN in suppressing SARS-CoV-2 infection, a finding which could inform future treatment options for COVID-19.
si5o2hq0
si5o2hq0
2020-04-29
10.1016/j.antiviral.2020.104811
5
The SARS-Coronavirus-Host Interactome: Identification of Cyclophilins as Target for Pan-Coronavirus Inhibitors
Coronaviruses (CoVs) are important human and animal pathogens that induce fatal respiratory, gastrointestinal and neurological disease. The outbreak of the severe acute respiratory syndrome (SARS) in 2002/2003 has demonstrated human vulnerability to (Coronavirus) CoV epidemics. Neither vaccines nor therapeutics are available against human and animal CoVs. Knowledge of host cell proteins that take part in pivotal virus-host interactions could define broad-spectrum antiviral targets. In this study, we used a systems biology approach employing a genome-wide yeast-two hybrid interaction screen to identify immunopilins (PPIA, PPIB, PPIH, PPIG, FKBP1A, FKBP1B) as interaction partners of the CoV non-structural protein 1 (Nsp1). These molecules modulate the Calcineurin/NFAT pathway that plays an important role in immune cell activation. Overexpression of NSP1 and infection with live SARS-CoV strongly increased signalling through the Calcineurin/NFAT pathway and enhanced the induction of interleukin 2, compatible with late-stage immunopathogenicity and long-term cytokine dysregulation as observed in severe SARS cases. Conversely, inhibition of cyclophilins by cyclosporine A (CspA) blocked the replication of CoVs of all genera, including SARS-CoV, human CoV-229E and -NL-63, feline CoV, as well as avian infectious bronchitis virus. Non-immunosuppressive derivatives of CspA might serve as broad-range CoV inhibitors applicable against emerging CoVs as well as ubiquitous pathogens of humans and livestock.
sibidlrl
sibidlrl
2011-10-27
10.1371/journal.ppat.1002331
0.5
Treatment With Lopinavir/Ritonavir or Interferon-β1b Improves Outcome of MERS-CoV Infection in a Nonhuman Primate Model of Common Marmoset
Middle East respiratory syndrome coronavirus (MERS-CoV) causes severe disease in human with an overall case-fatality rate of >35%. Effective antivirals are crucial for improving the clinical outcome of MERS. Although a number of repurposed drugs, convalescent-phase plasma, antiviral peptides, and neutralizing antibodies exhibit anti-MERS-CoV activity in vitro, most are not readily available or have not been evaluated in nonhuman primates. We assessed 3 repurposed drugs with potent in vitro anti-MERS-CoV activity (mycophenolate mofetil [MMF], lopinavir/ritonavir, and interferon-β1b) in common marmosets with severe disease resembling MERS in humans. The lopinavir/ritonavir-treated and interferon-β1b-treated animals had better outcome than the untreated animals, with improved clinical (mean clinical scores ↓50.9%–95.0% and ↓weight loss than the untreated animals), radiological (minimal pulmonary infiltrates), and pathological (mild bronchointerstitial pneumonia) findings, and lower mean viral loads in necropsied lung (↓0.59–1.06 log(10) copies/glyceraldehyde 3-phosphate dehydrogenase [GAPDH]; P < .050) and extrapulmonary (↓0.11–1.29 log(10) copies/GAPDH; P < .050 in kidney) tissues. In contrast, all MMF-treated animals developed severe and/or fatal disease with higher mean viral loads (↑0.15–0.54 log(10) copies/GAPDH) than the untreated animals. The mortality rate at 36 hours postinoculation was 67% (untreated and MMF-treated) versus 0–33% (lopinavir/ritonavir-treated and interferon-β1b-treated). Lopinavir/ritonavir and interferon-β1b alone or in combination should be evaluated in clinical trials. MMF alone may worsen MERS and should not be used.
six4f3xh
six4f3xh
2015-12-15
10.1093/infdis/jiv392
5
COVID-19: A promising cure for the global panic
Abstract The novel Coronavirus disease 2019 (COVID-19) is caused by SARS-CoV-2, which is the causative agent of a potentially fatal disease that is of great global public health concern. The outbreak of COVID-19 is wreaking havoc worldwide due to inadequate risk assessment regarding the urgency of the situation. The COVID-19 pandemic has entered a dangerous new phase. When compared with SARS and MERS, COVID-19 has spread more rapidly, due to increased globalization and adaptation of the virus in every environment. Slowing the spread of the COVID-19 cases will significantly reduce the strain on the healthcare system of the country by limiting the number of people who are severely sick by COVID-19 and need hospital care. Hence, the recent outburst of COVID-19 highlights an urgent need for therapeutics targeting SARS-CoV-2. Here, we have discussed the structure of virus; varying symptoms among COVID-19, SARS, MERS and common flu; the probable mechanism behind the infection and its immune response. Further, the current treatment options, drugs available, ongoing trials and recent diagnostics for COVID-19 have been discussed. We suggest traditional Indian medicinal plants as possible novel therapeutic approaches, exclusively targeting SARS-CoV-2 and its pathways.
sjyrr2bn
sjyrr2bn
2020-04-04
10.1016/j.scitotenv.2020.138277
1
A drug repurposing screen identifies hepatitis C antivirals as inhibitors of the SARS-CoV-2 main protease
The SARS coronavirus type 2 (SARS-CoV-2) emerged in late 2019 as a zoonotic virus highly transmissible between humans that has caused the COVID-19 pandemic 1,2. This pandemic has the potential to disrupt healthcare globally and has already caused high levels of mortality, especially amongst the elderly. The overall case fatality rate for COVID-19 is estimated to be ∼2.3% overall 3 and 32.3% in hospitalized patients age 70-79 years 4. Therapeutic options for treating the underlying viremia in COVID-19 are presently limited by a lack of effective SARS-CoV-2 antiviral drugs, although steroidal anti-inflammatory treatment can be helpful. A variety of potential antiviral targets for SARS-CoV-2 have been considered including the spike protein and replicase. Based upon previous successful antiviral drug development for HIV-1 and hepatitis C, the SARS-CoV-2 main protease (Mpro) appears an attractive target for drug development. Here we show the existing pharmacopeia contains many drugs with potential for therapeutic repurposing as selective and potent inhibitors of SARS-CoV-2 Mpro. We screened a collection of ∼6,070 drugs with a previous history of use in humans for compounds that inhibit the activity of Mpro in vitro. In our primary screen we found ∼50 compounds with activity against Mpro (overall hit rate <0.75%). Subsequent dose validation studies demonstrated 8 dose responsive hits with an IC50 ≤ 50 μM. Hits from our screen are enriched with hepatitis C NS3/4A protease targeting drugs including Boceprevir (IC50=0.95 μM), Ciluprevir (20.77μM). Narlaprevir (IC50=1.10μM), and Telaprevir (15.25μM). These results demonstrate that some existing approved drugs can inhibit SARS-CoV-2 Mpro and that screen saturation of all approved drugs is both feasible and warranted. Taken together this work suggests previous large-scale commercial drug development initiatives targeting hepatitis C NS3/4A viral protease should be revisited because some previous lead compounds may be more potent against SARS-CoV-2 Mpro than Boceprevir and suitable for rapid repurposing.
slouuryl
slouuryl
2020-07-10
10.1101/2020.07.10.197889
5
Identification and characterization of potent small molecule inhibitor of hemorrhagic fever New World arenaviruses
Abstract Category A arenaviruses as defined by the National Institute of Allergy and Infectious Diseases (NIAID) are human pathogens that could be weaponized by bioterrorists. Many of these deadly viruses require biosafety level-4 (BSL-4) containment for all laboratory work, which limits traditional laboratory high-throughput screening (HTS) for identification of small molecule inhibitors. For those reasons, a related BSL-2 New World arenavirus, Tacaribe virus, 67–78% identical to Junín virus at the amino acid level, was used in a HTS campaign where approximately 400,000 small molecule compounds were screened in a Tacaribe virus-induced cytopathic effect (CPE) assay. Compounds identified in this screen showed antiviral activity and specificity against not only Tacaribe virus, but also the Category A New World arenaviruses (Junín, Machupo, and Guanarito). Drug resistant variants were isolated, suggesting that these compounds act through inhibition of a viral protein, the viral glycoprotein (GP2), and not through cellular toxicity mechanisms. A lead compound, ST-294, has been chosen for drug development. This potent and selective compound, with good bioavailability, demonstrated protective anti-viral efficacy in a Tacaribe mouse challenge model. This series of compounds represent a new class of inhibitors that may warrant further development for potential inclusion in a strategic stockpile.
smikf6vx
smikf6vx
2006-02-28
10.1016/j.antiviral.2005.10.008
3.5
Chapter 8 The Middle East Respiratory Syndrome Coronavirus: An Emerging Virus of Global Threat
Abstract Middle East respiratory syndrome (MERS) is a viral respiratory illness caused by a coronavirus (CoV), first identified in Saudi Arabia in 2012. Since then, almost 2000 cases have been reported from 27 countries, with Saudi Arabia being the epicenter. This newly emerging virus is highly pathogenic and has a case mortality rate of 35%. It is similar to the CoV causing severe acute respiratory syndrome CoV (SARS-CoV) in that both belong to the genus beta CoVs that are of zoonotic origin and cause lower respiratory infection. The natural reservoir for MERS-CoV remains unknown. Serological studies indicate that most dromedary camels in the Middle East have been infected with this virus, and they maybe the potential intermediate host. However, the mode of transmission from camels to humans is poorly understood. The majority of confirmed human cases have resulted from human-to-human transmission, most probably via respiratory route. Patients most at risk of developing severe MERS-CoV infection appear to be those with underlying conditions such as diabetes, hypertension, obesity, cardiac diseases, chronic respiratory diseases, and cancer. Unlike SARS-CoV, MERS-CoV is considered an ongoing public health problem, particularly for the Middle East region. In this chapter, we outline the prevailing information regarding the emergence and epidemiology of this virus, its mode of transmission and pathogenicity, its clinical features, and the potential strategies for prevention.
sn7rswab
sn7rswab
2020-12-31
10.1016/b978-0-12-819400-3.00008-9
1
SARS-CoV-2 is well adapted for humans. What does this mean for re-emergence?
In a side-by-side comparison of evolutionary dynamics between the 2019/2020 SARS-CoV-2 and the 2003 SARS-CoV, we were surprised to find that SARS-CoV-2 resembles SARS-CoV in the late phase of the 2003 epidemic after SARS-CoV had developed several advantageous adaptations for human transmission. Our observations suggest that by the time SARS-CoV-2 was first detected in late 2019, it was already pre-adapted to human transmission to an extent similar to late epidemic SARS-CoV. However, no precursors or branches of evolution stemming from a less human-adapted SARS-CoV-2-like virus have been detected. The sudden appearance of a highly infectious SARS-CoV-2 presents a major cause for concern that should motivate stronger international efforts to identify the source and prevent near future re-emergence. Any existing pools of SARS-CoV-2 progenitors would be particularly dangerous if similarly well adapted for human transmission. To look for clues regarding intermediate hosts, we analyze recent key findings relating to how SARS-CoV-2 could have evolved and adapted for human transmission, and examine the environmental samples from the Wuhan Huanan seafood market. Importantly, the market samples are genetically identical to human SARS-CoV-2 isolates and were therefore most likely from human sources. We conclude by describing and advocating for measured and effective approaches implemented in the 2002-2004 SARS outbreaks to identify lingering population(s) of progenitor virus.
sphwclzs
sphwclzs
2020-05-02
10.1101/2020.05.01.073262
4.5
Bulk and single-cell gene expression profiling of SARS-CoV-2 infected human cell lines identifies molecular targets for therapeutic intervention
The coronavirus disease 2019 (COVID-19) pandemic, caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is an ongoing global health threat with more than two million infected people since its emergence in late 2019. Detailed knowledge of the molecular biology of the infection is indispensable for understanding of the viral replication, host responses, and disease progression. We provide gene expression profiles of SARS-CoV and SARS-CoV-2 infections in three human cell lines (H1299, Caco-2 and Calu-3 cells), using bulk and single-cell transcriptomics. Small RNA profiling showed strong expression of the immunity and inflammation-associated microRNA miRNA-155 upon infection with both viruses. SARS-CoV-2 elicited approximately two-fold higher stimulation of the interferon response compared to SARS-CoV in the permissive human epithelial cell line Calu-3, and induction of cytokines such as CXCL10 or IL6. Single cell RNA sequencing data showed that canonical interferon stimulated genes such as IFIT2 or OAS2 were broadly induced, whereas interferon beta (IFNB1) and lambda (IFNL1-4) were expressed only in a subset of infected cells. In addition, temporal resolution of transcriptional responses suggested interferon regulatory factors (IRFs) activities precede that of nuclear factor-κB (NF-κB). Lastly, we identified heat shock protein 90 (HSP90) as a protein relevant for the infection. Inhibition of the HSP90 charperone activity by Tanespimycin/17-N-allylamino-17-demethoxygeldanamycin (17-AAG) resulted in a reduction of viral replication, and of TNF and IL1B mRNA levels. In summary, our study established in vitro cell culture models to study SARS-CoV-2 infection and identified HSP90 protein as potential drug target for therapeutic intervention of SARS-CoV-2 infection.
sq5z686p
sq5z686p
2020-05-05
10.1101/2020.05.05.079194
3
A deadly spillover: SARS-CoV-2 outbreak
sqgjnrwb
sqgjnrwb
2020-04-29
10.1080/13543776.2020.1760838
3
Die Bedeutung von Coronaviren: Das Beispiel SARS
The emergence of the new SARS coronavirus has shown dramatically the high relevance of human coronavirus infections. This overview presents data of both epidemiological and clinical studies of this new virus infection. Moreover, details of research on the pathogenesis, diagnostics, and therapy are given. The recent infections in December 2003 clearly document that SARS will be a major topic also in 2004.
sqxmt699
sqxmt699
2004
10.1007/s00103-004-0868-6
1
Molecular diversity of coronaviruses in bats
Abstract The existence of coronaviruses in bats is unknown until the recent discovery of bat-SARS-CoV in Chinese horseshoe bats and a novel group 1 coronavirus in other bat species. Among 309 bats of 13 species captured from 20 different locations in rural areas of Hong Kong over a 16-month period, coronaviruses were amplified from anal swabs of 37 (12%) bats by RT-PCR. Phylogenetic analysis of RNA-dependent-RNA-polymerase (pol) and helicase genes revealed six novel coronaviruses from six different bat species, in addition to the two previously described coronaviruses. Among the six novel coronaviruses, four were group 1 coronaviruses (bat-CoV HKU2 from Chinese horseshoe bat, bat-CoV HKU6 from rickett's big-footed bat, bat-CoV HKU7 from greater bent-winged bat and bat-CoV HKU8 from lesser bent-winged bat) and two were group 2 coronaviruses (bat-CoV HKU4 from lesser bamboo bats and bat-CoV HKU5 from Japanese pipistrelles). An astonishing diversity of coronaviruses was observed in bats.
ssa59gng
ssa59gng
2006-07-20
10.1016/j.virol.2006.02.041
2
Apps Gone Rogue: Maintaining Personal Privacy in an Epidemic
Containment, the key strategy in quickly halting an epidemic, requires rapid identification and quarantine of the infected individuals, determination of whom they have had close contact with in the previous days and weeks, and decontamination of locations the infected individual has visited. Achieving containment demands accurate and timely collection of the infected individual's location and contact history. Traditionally, this process is labor intensive, susceptible to memory errors, and fraught with privacy concerns. With the recent almost ubiquitous availability of smart phones, many people carry a tool which can be utilized to quickly identify an infected individual's contacts during an epidemic, such as the current 2019 novel Coronavirus crisis. Unfortunately, the very same first-generation contact tracing tools have been used to expand mass surveillance, limit individual freedoms and expose the most private details about individuals. We seek to outline the different technological approaches to mobile-phone based contact-tracing to date and elaborate on the opportunities and the risks that these technologies pose to individuals and societies. We describe advanced security enhancing approaches that can mitigate these risks and describe trade-offs one must make when developing and deploying any mass contact-tracing technology. With this paper, our aim is to continue to grow the conversation regarding contact-tracing for epidemic and pandemic containment and discuss opportunities to advance this space. We invite feedback and discussion.
st2ebdah
st2ebdah
2020-03-19
2
Current status of treatment for 2019 novel coronavirus pneumonia/ 中华微生物学和免疫学杂志
2019 novel coronavirus (2019-nCoV) is a new member of coronavirus family that can cause serious respiratory diseases after the emergence of severe acute respiratory syndrome-coronavirus (SARS-CoV) and middle east respiratory syndrome-coronavirus (MERS-CoV). At present, there is no specific antiviral drug targeting 2019-nCoV. In facing of the increasingly serious epidemic of 2019 novel coronavirus pneumonia and the urgent needs in drug treatment strategies, this paper reviewed the current research situation and progress in antiviral treatment for the newly identified disease.
stnjl8f8
stnjl8f8
2020
1.5
Current advancements and potential strategies in the development of MERS-CoV vaccines
Middle East respiratory syndrome (MERS) is a newly emerging infectious disease caused by a novel coronavirus, MERS-coronavirus (MERS-CoV), a new member in the lineage C of β-coronavirus (β-CoV). The increased human cases and high mortality rate of MERS-CoV infection make it essential to develop safe and effective vaccines. In this review, the current advancements and potential strategies in the development of MERS vaccines, particularly subunit vaccines based on MERS-CoV spike (S) protein and its receptor-binding domain (RBD), are discussed. How to improve the efficacy of subunit vaccines through novel adjuvant formulations and routes of administration as well as currently available animal models for evaluating the in vivo efficacy of MERS-CoV vaccines are also addressed. Overall, these strategies may have important implications for the development of effective and safe vaccines for MERS-CoV in the future.
strhszpd
strhszpd
2014-04-26
10.1586/14760584.2014.912134
1.5
Ultra-sensitive nanozyme-based chemiluminescence paper test for rapid diagnosis of SARS-CoV-2 infection
The recently emerged coronavirus disease COVID-19 has now evolved into a global pandemic. Early detection is crucial for its effective control. Nucleic acid testing for viral pathogen and serological testing for host antibodies are playing important roles in current COVID-19 diagnosis. However, while nucleic acid testing is complicated, facility-restricted and time-consuming, antibody testing may result in high rates of false-negative diagnoses, especially during the early stages of viral infection. Thus, a more rapid and reliable test for both early COVID-19 diagnosis and whole-population screening is urgently needed. Here, we developed a novel nanozyme-based chemiluminescence paper assay for rapid and high-sensitive testing of SARS-CoV-2 spike antigen. Our paper test uses a newly established peroxidase-mimic Co-Fe@hemin nanozyme instead of natural HRP that catalytically amplifies the chemiluminescent signal, allowing for target concentrations to be as low as 0.1 ng/ml. Furthermore, our nanozyme-based chemiluminescence test exhibits a linear range that is 32-fold wider compared to ELISA tests. Importantly, testing is completed in less than 16 min, compared to 1-2 h required for ELISA or nucleic acid tests. Critically, signal detection is feasible using a smartphone camera. Ingredients for our test are simple and readily available, rendering overall cost considerably lower than those used in current diagnoses. In conclusion, our novel test provides a high-sensitive, point-of-care testing (POCT) approach for SARS-CoV-2 antigen detection, which should greatly increase current early screening capacities for suspected infections, and considerably lower demand for national healthcare resources.
sw23wf4b
sw23wf4b
2020-06-05
10.1101/2020.06.05.131748
5
An immunosuppressed Syrian golden hamster model for SARS-CoV infection
Several small animal models have been developed for the study of severe acute respiratory syndrome coronavirus (SARS-CoV) replication and pathogenesis. Syrian golden hamsters are among the best small animal models, though little clinical illness and no mortality are observed after virus infection. Cyclophosphamide was used to immunosuppress hamsters leading to a prolonged disease course and higher mortality after SARS-CoV infection. In addition, there was a significant weight loss, expanded tissue tropism, and increased viral pathology in the lung, heart, kidney, and nasal turbinate tissues. Infection with recombinant SARS-CoV viruses bearing disruptions in the gene 7 coding region showed no significant change in replication kinetics, tissue tropism, morbidity, or mortality suggesting that the ORF7a (7a) and ORF7b (7b) proteins are not required for virus replication in immunosuppressed hamsters. This modified hamster model may provide a useful tool for SARS-CoV pathogenesis studies, evaluation of antiviral therapy, and analysis of additional SARS-CoV mutants.
sxznxse5
sxznxse5
2008-10-01
10.1016/j.virol.2008.07.026
1
SARS-CoV-2 spike protein predicted to form complexes with host receptor protein orthologues from a broad range of mammals
SARS-CoV-2 has a zoonotic origin and was transmitted to humans via an undetermined intermediate host, leading to infections in humans and other mammals. To enter host cells, the viral spike protein (S-protein) binds to its receptor, ACE2, and is then processed by TMPRSS2. Whilst receptor binding contributes to the viral host range, S-protein:ACE2 complexes from other animals have not been investigated widely. To predict infection risks, we modelled S-protein:ACE2 complexes from 215 vertebrate species, calculated changes in the energy of the complex caused by mutations in each species, relative to human ACE2, and correlated these changes with COVID-19 infection data. We also analysed structural interactions to better understand the key residues contributing to affinity. We predict that mutations are more detrimental in ACE2 than TMPRSS2. Finally, we demonstrate phylogenetically that human SARS-CoV-2 strains have been isolated in animals. Our results suggest that SARS-CoV-2 can infect a broad range of mammals, but few fish, birds or reptiles. Susceptible animals could serve as reservoirs of the virus, necessitating careful ongoing animal management and surveillance.
sygnmiun
sygnmiun
2020-06-12
10.1101/2020.05.01.072371
3
The deadly coronaviruses: The 2003 SARS pandemic and the 2020 novel coronavirus epidemic in China
Abstract The 2019-nCoV is officially called SARS-CoV-2 and the disease is named COVID-19. This viral epidemic in China has led to the deaths of over 1800 people, mostly elderly or those with an underlying chronic disease or immunosuppressed state. This is the third serious Coronavirus outbreak in less than 20 years, following SARS in 2002–2003 and MERS in 2012. While human strains of Coronavirus are associated with about 15% of cases of the common cold, the SARS-CoV-2 may present with varying degrees of severity, from flu-like symptoms to death. It is currently believed that this deadly Coronavirus strain originated from wild animals at the Huanan market in Wuhan, a city in Hubei province. Bats, snakes and pangolins have been cited as potential carriers based on the sequence homology of CoV isolated from these animals and the viral nucleic acids of the virus isolated from SARS-CoV-2 infected patients. Extreme quarantine measures, including sealing off large cities, closing borders and confining people to their homes, were instituted in January 2020 to prevent spread of the virus, but by that time much of the damage had been done, as human-human transmission became evident. While these quarantine measures are necessary and have prevented a historical disaster along the lines of the Spanish flu, earlier recognition and earlier implementation of quarantine measures may have been even more effective. Lessons learned from SARS resulted in faster determination of the nucleic acid sequence and a more robust quarantine strategy. However, it is clear that finding an effective antiviral and developing a vaccine are still significant challenges. The costs of the epidemic are not limited to medical aspects, as the virus has led to significant sociological, psychological and economic effects globally. Unfortunately, emergence of SARS-CoV-2 has led to numerous reports of Asians being subjected to racist behavior and hate crimes across the world.
szsb1oan
szsb1oan
2020-03-03
10.1016/j.jaut.2020.102434
0.5
Numerical study of SARS epidemic model with the inclusion of diffusion in the system
Abstract This paper deals with the numerical study of population model based on the epidemics of Severe Acute Respiratory Syndrome (SARS). SEIJR (susceptible, exposed, infected, diagnosed, recovered) model of SARS epidemic is considered with net in flow of individuals into a region. Transmission of disease is analyzed by solving the system of differential equations using numerical methods with different initial population distributions. The effect of diffusion on the spread of disease is examined. Stability is established for the numerical solutions. Effects of interventions (medical and non medical) are also analyzed.
t0oqk88n
t0oqk88n
2014-02-25
10.1016/j.amc.2013.12.062
1.5
A brief review of antiviral drugs evaluated in registered clinical trials for COVID-19
Background: Although a number of antiviral agents have been evaluated for coronaviruses there are no approved drugs available. To provide an overview of the landscape of therapeutic research for COVID-19, we conducted a review of registered clinical trials. Methods: A review of currently registered clinical trials was performed on registries, including the Chinese (chictr.org.cn) and US (clinicaltrials.gov) databases to identify relevant studies up to March, 7th 2020. The search was conducted using the search terms “2019-nCoV”, “COVID-19”, “SARS-CoV-2”, “Hcov-19”, “new coronavirus”, “novel coronavirus”. We included interventional clinical trials focusing on patients with COVID-19 and assessing antiviral drugs or agents. Findings: Out of the 353 studies identified, 115 clinical trials were selected for data extraction. Phase IV trials were the most commonly reported study type (n=27, 23%). However, 62 trials (54%) did not describe the phase of the study. Eighty percent (n=92) of the trials were randomized with parallel assignment and the median number of planned inclusions was 63 (IQR, 36-120). Open-label studies were the most frequent (46%) followed by double-blind (13%) and single blind studies (10%). The most frequently assessed therapies were: stem cells therapy (n=23 trials), lopinavir/ritonavir (n=15), chloroquine (n=11), umifenovir (n=9), hydroxychloroquine (n=7), plasma treatment (n=7), favipiravir (n=7), methylprednisolone (n=5), and remdesivir (n=5). Remdesivir was tested in 5 trials with a median of 400 (IQR, 394-453) planned inclusions per trial, while stem cells therapy was tested in 23 trials, but had a median of 40 (IQR, 23-60) planned inclusions per trial. Lopinavir/ritonavir was associated with the highest total number of planned inclusions (2606) followed by remdesivir (2155). Only 52% of the clinical trials reported the treatment dose (n=60) and only 34% (n=39) the duration. The primary outcome was clinical in 76 studies (66%), virological in 27 (23%); radiological in 9 (8%) or immunological in three studies (3%). Interpretation: Numerous clinical trials have been registered since the beginning of the COVID-19 outbreak, however, a number of information regarding drugs or trial design were lacking. Funding: None
t1wpujpm
t1wpujpm
2020-03-20
10.1101/2020.03.18.20038190
0.5
Genome based Evolutionary study of SARS-CoV-2 towards the Prediction of Epitope Based Chimeric Vaccine
SARS-CoV-2 is known to infect the neurological, respiratory, enteric, and hepatic systems of human and has already become an unprecedented threat to global healthcare system. COVID-19, the most serious public condition caused by SARS-CoV-2 leads the world to an uncertainty alongside thousands of regular death scenes. Unavailability of specific therapeutics or approved vaccine has made the recovery of COVI-19 more troublesome and challenging. The present in silico study aimed to predict a novel chimeric vaccines by simultaneously targeting four major structural proteins via the establishment of ancestral relationship among different strains of coronaviruses. Conserved regions from the homologous protein sets of spike glycoprotein (S), membrane protein (M), envelope protein and nucleocapsid protein (N) were identified through multiple sequence alignment. The phylogeny analyses of whole genome stated that four proteins (S, E, M and N) reflected the close ancestral relation of SARS-CoV-2 to SARS-COV-1 and bat coronavirus. Numerous immunogenic epitopes (both T cell and B cell) were generated from the common fragments which were further ranked on the basis of antigenicity, transmembrane topology, conservancy level, toxicity and allergenicity pattern and population coverage analysis. Top putative epitopes were combined with appropriate adjuvants and linkers to construct a novel multiepitope subunit vaccine against COVID-19. The designed constructs were characterized based on physicochemical properties, allergenicity, antigenicity and solubility which revealed the superiority of construct V3 in terms safety and efficacy. Essential molecular dynamics and Normal Mode analysis confirmed minimal deformability of the refined model at molecular level. In addition, disulfide engineering was investigated to accelerate the stability of the protein. Molecular docking study ensured high binding affinity between construct V3 and HLA cells, as well as with different host receptors. Microbial expression and translational efficacy of the constructs were checked using pET28a(+) vector of E. coli strain K12. The development of preventive measures to combat COVID-19 infections might be aided the present study. However, the in vivo and in vitro validation might be ensured with wet lab trials using model animals for the implementation of the presented data.
t1xjy12y
t1xjy12y
2020-04-15
10.1101/2020.04.15.036285
2.5
Tabagisme et maladie à coronavirus 2019 (COVID-19)
t20huil6
t20huil6
2020-04-08
10.1016/j.rmr.2020.04.001
1
Ivermectin, a new candidate therapeutic against SARS-CoV-2/COVID-19
t36xnh12
t36xnh12
2020-05-30
10.1186/s12941-020-00368-w
4
Utility of the aged BALB/c mouse model to demonstrate prevention and control strategies for Severe Acute Respiratory Syndrome coronavirus (SARS-CoV)
The causative agent of Severe Acute Respiratory Syndrome (SARS) was identified as a coronavirus (CoV) following the outbreak of 2002–2003. There are currently no licensed vaccines or treatments for SARS-CoV infections. Potential prevention and control strategies that show promise in vitro must be evaluated in animal models. The aged BALB/c mouse model for SARS supports a high level of viral replication in association with clinical illness and disease that mimics SARS in the elderly. We tested two preventive strategies, vaccination and passive transfer of serum antibody, to determine the extent of protection achieved against SARS-CoV challenge in this model. These approaches were able to achieve or induce antibody titers sufficient to reduce viral load, protect from weight loss, and reduce or eliminate histopathologic changes in the lungs of aged mice. This study validates the utility of the aged BALB/c mouse model for evaluation of the efficacy of vaccines and immunoprophylaxis.
t4v5zunk
t4v5zunk
2007-03-01
10.1016/j.vaccine.2006.11.055
1
An orally bioavailable broad-spectrum antiviral inhibits SARS-CoV-2 and multiple endemic, epidemic and bat coronavirus
Coronaviruses (CoVs) traffic frequently between species resulting in novel disease outbreaks, most recently exemplified by the newly emerged SARS-CoV-2. Herein, we show that the ribonucleoside analog β-D-N4-hydroxycytidine (NHC, EIDD-1931) has broad spectrum antiviral activity against SARS-CoV 2, MERS-CoV, SARS-CoV, and related zoonotic group 2b or 2c Bat-CoVs, as well as increased potency against a coronavirus bearing resistance mutations to another nucleoside analog inhibitor. In mice infected with SARS-CoV or MERS-CoV, both prophylactic and therapeutic administration of EIDD-2801, an orally bioavailable NHC-prodrug (b-D-N4-hydroxycytidine-5’-isopropyl ester), improved pulmonary function, and reduced virus titer and body weight loss. Decreased MERS-CoV yields in vitro and in vivo were associated with increased transition mutation frequency in viral but not host cell RNA, supporting a mechanism of lethal mutagenesis. The potency of NHC/EIDD-2801 against multiple coronaviruses, its therapeutic efficacy, and oral bioavailability in vivo, all highlight its potential utility as an effective antiviral against SARS-CoV-2 and other future zoonotic coronaviruses.
t5iz3vdz
t5iz3vdz
2020-03-20
10.1101/2020.03.19.997890
2
COVID-19 Docking Server: An interactive server for docking small molecules, peptides and antibodies against potential targets of COVID-19
The coronavirus disease 2019 (COVID-19) caused by a new type of coronavirus has been emerging from China and led to thousands of death globally since December 2019. Despite many groups have engaged in studying the newly emerged virus and searching for the treatment of COVID-19, the understanding of the COVID-19 target -ligand interactions represents a key challenge. Herein, we introduce COVID-19 Docking Server, a web server that predicts the binding modes between COVID-19 targets and the ligands including small molecules, peptide and antibody. Structures of proteins involved in the virus life cycle were collected or constructed based on the homologs of coronavirus, and prepared ready for docking. The platform provides a free and interactive tool for the prediction of COVID-19 target-ligand interactions and following drug discovery for COVID-19.
t6fdr2pa
t6fdr2pa
2020-02-29
2.5
Teicoplanin inhibits Ebola pseudovirus infection in cell culture
Abstract There is currently no approved antiviral therapy for treatment of Ebola virus disease. To discover readily available approved drugs that can be rapidly repurposed for treatment of Ebola virus infections, we screened 1280 FDA-approved drugs and identified glycopeptide antibiotic teicoplanin inhibiting Ebola pseudovirus infection by blocking virus entry in the low micromolar range. Teicoplanin could be evaluated further and incorporated into ongoing clinical studies.
t6ogxz7n
t6ogxz7n
2016-01-31
10.1016/j.antiviral.2015.11.003
5
A simple procedure for the derivation of electron density based surfaces of drug-receptor complexes from a combination of X-ray data and theoretical calculations
Abstract To contribute to an understanding of biological recognition and interaction, an easy-to-use procedure was developed to generate and display molecular surfaces and selected electron density based surface properties. To overcome the present limitations to derive electron densities of macromolecules, the considered systems were reduced to appropriate substructures around the active centers. The combination of experimental X-ray structural information and aspherical atomic electron density data from theoretical calculations resulted in properties like the electrostatic potential and the Hirshfeld surface which allowed a study of electronic complementarity and the identification of sites and strengths of drug-receptor interactions. Applications were examined for three examples. The anilinoquinazoline gefitinib (Iressa®) belongs to a new class of anticancer drugs that inhibit the tyrosine kinase activity of the epidermal growth factor receptor (EGFR). In the second example, the interaction of epoxide inhibitors with the main protease of the SARS coronavirus was investigated. Furthermore, the progesterone receptor complex was examined. The quantitative analysis of hydrogen bonding in the chosen substructure systems follows a progression elaborated earlier on the basis of accurate small molecule crystal structures. This finding and results from modified substructures suggest that also the surface properties seem robust enough to provide stable information about the recognition of interacting biomolecular species although they are obtained from medium molecular weighted subfragments of macromolecular complexes, which consist of no more than ∼40 residues.
t6rnpnfc
t6rnpnfc
2010-08-15
10.1016/j.bmc.2010.06.080
1.5
The Novel Coronavirus – A Snapshot of Current Knowledge
Another animal to human transmission of a coronavirus occurred in December 2019 on a live animal market in the Chinese city of Wuhan causing an epidemic in China, reaching now different continents. This minireview summarizes the research literature on the virological, clinical and epidemiological aspects of this epidemic published until end of February 2020.
t6zf5k99
t6zf5k99
2020-03-06
10.1111/1751-7915.13557
2
COVID-19: what has been learned and to be learned about the novel coronavirus disease
The outbreak of Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome (SARS) coronavirus 2 (SARS-CoV-2), has thus far killed over 3,000 people and infected over 80,000 in China and elsewhere in the world, resulting in catastrophe for humans. Similar to its homologous virus, SARS-CoV, which caused SARS in thousands of people in 2003, SARS-CoV-2 might also be transmitted from the bats and causes similar symptoms through a similar mechanism. However, COVID-19 has lower severity and mortality than SARS but is much more transmissive and affects more elderly individuals than youth and more men than women. In response to the rapidly increasing number of publications on the emerging disease, this article attempts to provide a timely and comprehensive review of the swiftly developing research subject. We will cover the basics about the epidemiology, etiology, virology, diagnosis, treatment, prognosis, and prevention of the disease. Although many questions still require answers, we hope that this review helps in the understanding and eradication of the threatening disease.
t8azymo7
t8azymo7
2020-03-15
10.7150/ijbs.45134
0.5
Return of the Coronavirus: 2019-nCoV
The emergence of a novel coronavirus (2019-nCoV) has awakened the echoes of SARS-CoV from nearly two decades ago. Yet, with technological advances and important lessons gained from previous outbreaks, perhaps the world is better equipped to deal with the most recent emergent group 2B coronavirus.
t8s4s0wo
t8s4s0wo
2020-01-24
10.3390/v12020135
2.5
Coronavirus (COVID-19): ARIMA based time-series analysis to forecast near future
COVID-19, a novel coronavirus, is currently a major worldwide threat. It has infected more than a million people globally leading to hundred-thousands of deaths. In such grave circumstances, it is very important to predict the future infected cases to support prevention of the disease and aid in the healthcare service preparation. Following that notion, we have developed a model and then employed it for forecasting future COVID-19 cases in India. The study indicates an ascending trend for the cases in the coming days. A time series analysis also presents an exponential increase in the number of cases. It is supposed that the present prediction models will assist the government and medical personnel to be prepared for the upcoming conditions and have more readiness in healthcare systems.
t8s52emf
t8s52emf
2020-04-16
2.5
Spiking Pandemic Potential: Structural and Immunological aspects of SARS-CoV-2
SUMMARY SARS-Coronavirus-2 (SARS-CoV-2) causes Coronavirus disease 2019 (COVID-19), an infectious respiratory disease causing thousands of deaths and overwhelming public health systems. The international spread of SARS-CoV-2 is associated with the ease of global travel, and societal dynamics, immunologic naiveté of the host population, and muted innate immune responses. Based on these factors and the expanding geographic scale of the disease, the WHO declared the COVID-19 outbreak a pandemic–the first caused by a coronavirus. In this review, we summarize the current epidemiological status of COVID-19 and consider the virological and immunological lessons, animal models, and tools developed in response to prior SARS-CoV and MERS-CoV outbreaks that can serve as resources for development of SARS-CoV-2 therapeutics and vaccines. In particular, we discuss structural insights into the SARS-CoV-2 spike protein, a major determinant of transmissibility, and discuss key molecular aspects that will aid in understanding and fighting this new global threat.
tcc7e6ls
tcc7e6ls
2020-05-20
10.1016/j.tim.2020.05.012
4.5
Transmission Cycle of SARS-CoV and SARS-CoV-2
Severe acute respiratory syndrome (SARS) is a pandemic that has shocked the world twice over the last two decades caused by a highly transmissible and pathogenic coronavirus (CoV). It causes disease in the lower respiratory tract in humans that was first reported in late 2002 in Guangdong province, China, and later on in December 2019 in Wuhan, China. The two viruses designated as SARS-CoV and SARS-CoV-2, respectively, originated probably from the bat and infected humans via carrier animals. The constant recombination and evolution in the CoV genome may have facilitated their cross-species transmission resulting in recurrent emergence as a pandemic. This chapter intends to accumulate recent findings related to CoV transmission and tentative molecular mechanisms governing the process.
tcrxm7jy
tcrxm7jy
2020-04-30
10.1007/978-981-15-4814-7_4
3.5
Pharmacologic Treatments for Coronavirus Disease 2019 (COVID-19): A Review
Importance: The pandemic of coronavirus disease 2019 (COVID-19) caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) presents an unprecedented challenge to identify effective drugs for prevention and treatment. Given the rapid pace of scientific discovery and clinical data generated by the large number of people rapidly infected by SARS-CoV-2, clinicians need accurate evidence regarding effective medical treatments for this infection. Observations: No proven effective therapies for this virus currently exist. The rapidly expanding knowledge regarding SARS-CoV-2 virology provides a significant number of potential drug targets. The most promising therapy is remdesivir. Remdesivir has potent in vitro activity against SARS-CoV-2, but it is not US Food and Drug Administration approved and currently is being tested in ongoing randomized trials. Oseltamivir has not been shown to have efficacy, and corticosteroids are currently not recommended. Current clinical evidence does not support stopping angiotensin-converting enzyme inhibitors or angiotensin receptor blockers in patients with COVID-19. Conclusions and Relevance: The COVID-19 pandemic represents the greatest global public health crisis of this generation and, potentially, since the pandemic influenza outbreak of 1918. The speed and volume of clinical trials launched to investigate potential therapies for COVID-19 highlight both the need and capability to produce high-quality evidence even in the middle of a pandemic. No therapies have been shown effective to date.
tdqtikbh
tdqtikbh
2020
4.5
Coalition: Advocacy for prospective clinical trials to test the post-exposure potential of hydroxychloroquine against COVID-19
Abstract Our coalition of public health experts, doctors, and scientists worldwide want to draw attention to the need for high-quality evaluation protocols of the potential beneficial effect of hydroxychloroquine (HCQ) as a post-exposure drug for exposed people, meaning people with close contact with positive tested patients, including home and medical caregivers. We have reviewed the mechanisms of antiviral effect of HCQ, the risk-benefit ratio taking into consideration the PK/PD of HCQ and the thresholds of efficacy. We have studied its use as an antimalarial, an antiviral, and an immunomodulating drug and concluded that the use of HCQ at does matching that of the standard treatment of Systemic Lupus erythematous, which has proven safety and efficacy in terms of HCQ blood and tissue concentration adapted to bodyweight (2,3), at 6 mg/kg/day 1 (loading dose) followed by 5 mg/kg/day, with a maximum limit of 600 mg/day in all cases should swiftly be clinically evaluated as a post-exposure drug for exposed people.
tedurmyb
tedurmyb
2020-04-04
10.1016/j.onehlt.2020.100131
2
Why are pregnant women susceptible to COVID-19? An immunological viewpoint
Abstract The 2019 novel coronavirus disease (COVID-19) was first detected in December 2019 and became epidemic in Wuhan, Hubei Province, China. COVID-19 has been rapidly spreading out in China and all over the world. The virus causing COVID-19, SARS-CoV-2 has been known to be genetically similar to severe acute respiratory syndrome coronavirus (SARS-CoV) but distinct from it. Clinical manifestation of COVID-19 can be characterized by mild upper respiratory tract infection, lower respiratory tract infection involving non-life threatening pneumonia, and life-threatening pneumonia with acute respiratory distress syndrome. It affects all age groups, including newborns, to the elders. Particularly, pregnant women may be more susceptible to COVID-19 since pregnant women, in general, are vulnerable to respiratory infection. In pregnant women with COVID-19, there is no evidence for vertical transmission of the virus, but an increased prevalence of preterm deliveries has been noticed. The COVID-19 may alter immune responses at the maternal-fetal interface, and affect the well-being of mothers and infants. In this review, we focused on the reason why pregnant women are more susceptible to COVID-19 and the potential maternal and fetal complications from an immunological viewpoint.
tfkhptdg
tfkhptdg
2020-06-30
10.1016/j.jri.2020.103122
1.5
Linkages between animal and human health sentinel data
INTRODUCTION: In order to identify priorities for building integrated surveillance systems that effectively model and predict human risk of zoonotic diseases, there is a need for improved understanding of the practical options for linking surveillance data of animals and humans. We conducted an analysis of the literature and characterized the linkage between animal and human health data. We discuss the findings in relation to zoonotic surveillance and the linkage of human and animal data. METHODS: The Canary Database, an online bibliographic database of animal-sentinel studies was searched and articles were classified according to four linkage categories. RESULTS: 465 studies were identified and assigned to linkage categories involving: descriptive, analytic, molecular, or no human outcomes of human and animal health. Descriptive linkage was the most common, whereby both animal and human health outcomes were presented, but without quantitative linkage between the two. Rarely, analytic linkage was utilized in which animal data was used to quantitatively predict human risk. The other two categories included molecular linkage, and no human outcomes, which present health outcomes in animals but not humans. DISCUSSION: We found limited use of animal data to quantitatively predict human risk and listed the methods from the literature that performed analytic linkage. The lack of analytic linkage in the literature might not be solely related to technological barriers including access to electronic database, statistical software packages, and Geographical Information System (GIS). Rather, the problem might be from a lack of understanding by researchers of the importance of animal data as a 'sentinel' for human health. Researchers performing zoonotic surveillance should be aware of the value of animal-sentinel approaches for predicting human risk and consider analytic methods for linking animal and human data. Qualitative work needs to be done in order to examine researchers' decisions in linkage strategies between animal and human data.
tfw4zqiy
tfw4zqiy
2009-04-23
10.1186/1746-6148-5-15
4.5
Synthetic peptides outside the spike protein heptad repeat regions as potent inhibitors of SARS-associated coronavirus.
A novel severe acute respiratory syndrome (SARS)-associated coronavirus (SARS-CoV) has been identified as the aetiological agent of SARS. We previously isolated and characterized SARS-CoV and SARS-CoV-like viruses from human and animals, respectively, suggesting that SARS could be transmitted from wild/farmed animals to humans. Comparison of the viral genomes indicated that sequence variation between animal and human isolates existed mainly in the spike (S) gene. We hypothesized that these variations may underlie a change of binding specificity of the S protein to the host cells, permitting viral transmission from animals to humans. Here we report that four 20-mer synthetic peptides (S protein fragments), designed to span these sequence variation hotspots, exhibited significant antiviral activities in a cell line. SARS-CoV infectivity was reduced over 10 000-fold through pre-incubation with two of these peptides, while it was completely inhibited in the presence of three peptides. Molecular modelling of the SARS-CoV peplomer suggests that three of these antiviral peptides map to the interfaces between the three monomers of the trimeric peplomer rather than the heptad repeat region from which short peptides are known to inhibit viral entry. Our results revealed novel regions in the spike protein that can be targeted to inhibit viral infection. The peptides identified in this study could be further developed into antiviral drugs.
tfxarku1
tfxarku1
2005
3
Receptor Recognition by the Novel Coronavirus from Wuhan: an Analysis Based on Decade-Long Structural Studies of SARS Coronavirus
Recently, a novel coronavirus (2019-nCoV) has emerged from Wuhan, China, causing symptoms in humans similar to those caused by severe acute respiratory syndrome coronavirus (SARS-CoV). Since the SARS-CoV outbreak in 2002, extensive structural analyses have revealed key atomic-level interactions between the SARS-CoV spike protein receptor-binding domain (RBD) and its host receptor angiotensin-converting enzyme 2 (ACE2), which regulate both the cross-species and human-to-human transmissions of SARS-CoV. Here, we analyzed the potential receptor usage by 2019-nCoV, based on the rich knowledge about SARS-CoV and the newly released sequence of 2019-nCoV. First, the sequence of 2019-nCoV RBD, including its receptor-binding motif (RBM) that directly contacts ACE2, is similar to that of SARS-CoV, strongly suggesting that 2019-nCoV uses ACE2 as its receptor. Second, several critical residues in 2019-nCoV RBM (particularly Gln493) provide favorable interactions with human ACE2, consistent with 2019-nCoV's capacity for human cell infection. Third, several other critical residues in 2019-nCoV RBM (particularly Asn501) are compatible with, but not ideal for, binding human ACE2, suggesting that 2019-nCoV has acquired some capacity for human-to-human transmission. Last, while phylogenetic analysis indicates a bat origin of 2019-nCoV, 2019-nCoV also potentially recognizes ACE2 from a diversity of animal species (except mice and rats), implicating these animal species as possible intermediate hosts or animal models for 2019-nCoV infections. These analyses provide insights into the receptor usage, cell entry, host cell infectivity and animal origin of 2019-nCoV and may help epidemic surveillance and preventive measures against 2019-nCoV.IMPORTANCE The recent emergence of Wuhan coronavirus (2019-nCoV) puts the world on alert. 2019-nCoV is reminiscent of the SARS-CoV outbreak in 2002 to 2003. Our decade-long structural studies on the receptor recognition by SARS-CoV have identified key interactions between SARS-CoV spike protein and its host receptor angiotensin-converting enzyme 2 (ACE2), which regulate both the cross-species and human-to-human transmissions of SARS-CoV. One of the goals of SARS-CoV research was to build an atomic-level iterative framework of virus-receptor interactions to facilitate epidemic surveillance, predict species-specific receptor usage, and identify potential animal hosts and animal models of viruses. Based on the sequence of 2019-nCoV spike protein, we apply this predictive framework to provide novel insights into the receptor usage and likely host range of 2019-nCoV. This study provides a robust test of this reiterative framework, providing the basic, translational, and public health research communities with predictive insights that may help study and battle this novel 2019-nCoV.
tfz6f32q
tfz6f32q
2020
5
A Bayesian reanalysis of the effects of hydroxychloroquine and azithromycin on viral carriage in patients with COVID-19
Gautret and colleagues reported results of a non-randomised open-label case series which examined the effects of hydroxychloroquine and azithromycin on viral load in the upper respiratory tract of Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) patients. The authors report that hydroxychloroquine (HCQ) had significant virus reducing effects, and that dual treatment of both HCQ and azithromycin further enhanced virus reduction. This data has triggered speculation whether these drugs should be considered as candidates for the treatment of severe COVID-19. However, questions have been raised regarding the study's data integrity, statistical analyses, and experimental design. We therefore reanalysed the original data to interrogate the main claims of the paper. Here we apply Bayesian statistics to assess the robustness of the original papers claims by testing four variants of the data: 1) The original data; 2) Data including patients who deteriorated; 3) Data including patients who deteriorated with exclusion of untested patients in the comparison group; 4) Data that includes patients who deteriorated with the assumption that untested patients were negative. To ask if HCQ monotherapy is effective, we performed an A/B test for a model which assumes a positive effect, compared to a model of no effect. We find that the statistical evidence is highly sensitive to these data variants. Statistical evidence for the positive effect model ranged from strong for the original data (BF ~11), to moderate when including patients who deteriorated (BF ~4.35), to anecdotal when excluding untested patients (BF ~2), and to anecdotal negative evidence if untested patients were assumed positive (BF ~0.6). To assess whether HCQ is more effective when combined with AZ, we performed the same tests, and found only anecdotal evidence for the positive effect model for the original data (BF ~2.8), and moderate evidence for all other variants of the data (BF ~5.6). Our analyses only explore the effects of different assumptions about excluded and untested patients. These assumptions are not adequately reported, nor are they justified in the original paper, and we find that varying them causes substantive changes to the evidential support for the main claims of the original paper. This statistical uncertainty is exacerbated by the fact that the treatments were not randomised, and subject to several confounding variables including the patients' consent to treatment, different care centres, and clinical decision-making. Furthermore, while the viral load measurements were noisy, showing multiple reversals between test outcomes, there is greater certainty around other clinical outcomes such as the 4 patients who seriously deteriorated. The fact that all of these belonged to the HCQ monotherapy group should be assigned greater weight when evaluating the potential clinical efficacy of HCQ. Randomised controlled trials are currently underway, and will be critical in resolving this uncertainty as to whether HCQ and AZ are effective as a treatment for COVID-19.
tg8kfiot
tg8kfiot
2020-04-03
10.1101/2020.03.31.20048777
1
Is low dose radiation therapy a potential treatment for COVID-19 pneumonia?
tg8yqzrt
tg8yqzrt
2020-04-06
10.1016/j.radonc.2020.04.004
4
Inhibitory effects of epigallocatechin gallate on the propagation of bovine coronavirus in Madin‐Darby bovine kidney cells
Epigallocatechin gallate (EGCg) is the main active component of tea polyphenol and shows several biological activities, such as antimicrobial, antitumor‐promoting, anti‐inflammatory and anti‐oxidative activities. In the present study, the inhibitory effect of EGCg on bovine coronavirus (BCV) propagation in Madin‐Darby bovine kidney (MDBK) cells was investigated. EGCg at concentrations of less than 10 µg/mL did not show any cytotoxicity to MDBK cells. BCV propagation was significantly inhibited by pretreatment of the virus with EGCg (0.5–10 µg/mL) before virus inoculation in dose‐dependent, incubation time‐dependent and temperature‐dependent manners. The antiviral effect of pretreating MDBK cells with EGCg on BCV propagation was much weaker than that of pretreating BCV with EGCg. The hemagglutination activity of BCV was also reduced by EGCg in a dose‐dependent manner. These results demonstrate that EGCg possesses a distinct anti‐BCV activity and strongly suggest that EGCg interferes with the adsorption of BCV to MDBK cells by the interaction of EGCg with BCV particles. EGCg may therefore be a useful candidate for controlling BCV infection more effectively.
tgimcej6
tgimcej6
2005-09-19
10.1111/j.1740-0929.2005.00297.x
5
MERS coronavirus outbreak: Implications for emerging viral infections
Abstract In September 2012, a novel coronavirus was isolated from a patient who died in Saudi Arabia after presenting with acute respiratory distress and acute kidney injury. Analysis revealed the disease to be due to a novel virus which was named Middle East Respiratory Coronavirus (MERS-CoV). There have been several MERS-CoV hospital outbreaks in KSA, continuing to the present day, and the disease has a mortality rate in excess of 35%. Since 2012, the World Health Organization has been informed of 2220 laboratory-confirmed cases resulting in at least 790 deaths. Cases have since arisen in 27 countries, including an outbreak in the Republic of Korea in 2015 in which 36 people died, but more than 80% of cases have occurred in Saudi Arabia.. Human-to-human transmission of MERS-CoV, particularly in healthcare settings, initially caused a ‘media panic’, however human-to-human transmission appears to require close contact and thus far the virus has not achieved epidemic potential. Zoonotic transmission is of significant importance and evidence is growing implicating the dromedary camel as the major animal host in spread of disease to humans. MERS-CoV is now included on the WHO list of priority blueprint diseases for which there which is an urgent need for accelerated research and development as they have the potential to cause a public health emergency while there is an absence of efficacious drugs and/or vaccines. In this review we highlight epidemiological, clinical, and infection control aspects of MERS-CoV as informed by the Saudi experience. Attention is given to recommended treatments and progress towards vaccine development.
thnj9c8f
thnj9c8f
2019-03-31
10.1016/j.diagmicrobio.2018.10.011
2.5
Perspectives on the development of neutralizing antibodies against SARS-CoV-2
SARS-CoV-2 gains entry to human cells through its spike (S) protein binding to angiotensin-converting enzyme 2 (ACE2). Therefore, the receptor binding domain (RBD) of the S protein is the primary target for neutralizing antibodies. Selection of broad-neutralizing antibodies against SARS-CoV-2 and SARS-CoV is attractive and might be useful for treating not only COVID-19 but also future SARS-related CoV infections. Broad-neutralizing antibodies, such as 47D11, S309, and VHH-72, have been reported to target a conserved region in the RBD of the S1 subunit. The S2 subunit required for viral membrane fusion might be another target. Due to their small size and high stability, single-domain antibodies might have the ability to be administered by an inhaler making them potentially attractive therapeutics for respiratory infections. A cocktail strategy combining two (or more) antibodies that recognize different parts of the viral surface that interact with human cells might be the most effective.
tj4m01s4
tj4m01s4
2020-05-20
10.1093/abt/tbaa009
5
Coronaviruses: Molecular Biology
Coronaviruses (CoVs) are enveloped, positive-strand RNA viruses with characteristic spike glycoproteins that project outward like the rays of the sun (corona – Latin for ‘crown’), when visualized by electron microscopy. CoV are classified, together with the toroviruses, in the family Coronaviridae and the order Nidovirales. All nidoviruses have a common genome organization and generate a nested set (nido – Latin for ‘nest’) of 3′ co-terminal mRNAs. CoVs have been isolated from a variety of species, including birds, livestock, domestic animals, and humans. CoV infections can cause respiratory, gastrointestinal, and neurologic disease, depending on the strain of the virus and the site of infection. Importantly, CoVs have been shown to cross species barriers and have emerged from animal reservoirs to infect humans and cause severe disease. The CoV responsible for an outbreak of severe acute respiratory disease (SARS-CoV) in 2002–03 likely originated as a bat coronavirus which, during replication in an intermediate host (such as the palm civet), evolved to be able to infect humans efficiently. SARS-CoV infected over 8000 people with approximately 10% mortality rate. The SARS-CoV outbreak was controlled by public health measures alone. However, emergence or re-emergence of CoV from animal reservoirs is a potential concern for public health.
tktqlfgd
tktqlfgd
2008-12-31
10.1016/b978-012374410-4.00769-x
0.5
Treatment and Outcome of a Patient With Lung Cancer Infected With Severe Acute Respiratory Syndrome Coronavirus-2
tl67wn1l
tl67wn1l
2020-03-06
10.1016/j.jtho.2020.02.025
1
Reply to “Statins may decrease the Fatality Rate of MERS Infection”
tle5jvak
tle5jvak
2015-09-29
10.1128/mbio.01303-15
1.5
Coronavirus COVID-19 impacts to dentistry and potential salivary diagnosis
tlfj4szl
tlfj4szl
2020-02-20
10.1007/s00784-020-03248-x
4
A COVID-19 epidemic model with latency period
At the beginning of a COVID-19 infection, there is a period of time known as the exposed or latency period, before an infected person is capable of transmitting the infection to another person. We develop two differential equations models to account for this period. The first is a model that incorporates infected persons in the exposed class, before transmission is possible. The second is a model that incorporates a time delay in infected persons, before transmission is possible. We apply both models to the COVID-19 epidemic in China. We estimate the epidemiological parameters in the models, such as the transmission rate and the basic reproductive number, using data of reported cases. We thus evaluate the role of the exposed or latency period in the dynamics of a COVID-19 epidemic.
tm9h5kdu
tm9h5kdu
2020-04-28
10.1016/j.idm.2020.03.003
2
Susceptibility of selected domestic animals to COVID-19
tmio2p2r
tmio2p2r
2020-07-07
10.1016/j.asams.2020.07.004
5
Zinc Sulfate in Narrow Range as an In Vitro Anti-HSV-1 Assay
This report explains the employing of a combination test of traditional cell culture with a quantitative real-time PCR for assessment of the antiviral effect of zinc sulfate (ZnSO(4)) on herpes simplex virus (HSV)-infected Vero cells. Our evidence showed that the treatment with 0.3 mM ZnSO(4) strongly inhibited the replication of virus progeny (MOI 0.001) at least 68-fold less. On the other hand, the IC50 demonstrated that the highest activity of ZnSO(4) was at the 0.23 mM concentration.
tmkfju93
tmkfju93
2019-04-26
10.1007/s12011-019-01728-0
1.5
Recomendaciones sobre el manejo clínico de la infección por el «nuevo coronavirus» SARS-CoV2. Grupo de trabajo de la Asociación Española de Pediatría (AEP)
Resumen El 31 de diciembre de 2019, la Comisión Municipal de Salud y Sanidad de Wuhan (provincia de Hubei, China) informó sobre la existencia de 27 casos de neumonía de etiología desconocida con inicio de síntomas el 8 de diciembre, incluyendo 7 casos graves, con exposición común a un mercado de marisco, pescado y animales vivos en la ciudad de Wuhan. El 7 de enero de 2020, las autoridades chinas identificaron como agente causante del brote un nuevo tipo de virus de la familia Coronaviridae, denominado temporalmente «nuevo coronavirus», 2019-nCoV. El 30 de enero de 2020 la Organización Mundial de la Salud (OMS) declara el brote una Emergencia Internacional. El día 11 de febrero la OMS le asigna el nombre de SARS-CoV2 e infección COVID-19 (Coronavirus Infectious Disease). El Ministerio de Sanidad convoca a las Sociedades de Especialidades para la elaboración de un protocolo clínico de manejo de la infección. La Asociación Española de Pediatría nombra un grupo de trabajo de las Sociedades de Infectología Pediátrica y Cuidados Intensivos Pediátricos que se encargan de elaborar las presentes recomendaciones con la evidencia disponible en el momento de su realización. Abstract On 31 December 2019, the Wuhan Municipal Committee of Health and Healthcare (Hubei Province, China) reported that there were 27 cases of pneumonia of unknown origin with symptoms starting on the 8 December. There were 7 serious cases with common exposure in market with shellfish, fish, and live animals, in the city of Wuhan. On 7 January 2020, the Chinese authorities identified that the agent causing the outbreak was a new type of virus of the Coronaviridae family, temporarily called «new coronavirus», 2019-nCoV. On January 30th, 2020, the World Health Organisation (WHO) declared the outbreak an International Emergency. On 11 February 2020 the WHO assigned it the name of SARS-CoV2 and COVID-19 (SARS-CoV2 and COVID-19). The Ministry of Health summoned the Specialties Societies to prepare a clinical protocol for the management of COVID-19. The Spanish Paediatric Association appointed a Working Group of the Societies of Paediatric Infectious Diseases and Paediatric Intensive Care to prepare the present recommendations with the evidence available at the time of preparing them.
tnctqc1a
tnctqc1a
2020-03-12
10.1016/j.anpedi.2020.02.001
1
5-Fluorouracil in combination with deoxyribonucleosides and deoxyribose as possible therapeutic options for the Coronavirus, COVID-19 infection
Abstract The recent global pandemic created by the Coronavirus SARS-CoV-2, started in Wuhan, China in December 2019, has generated panic, both in term of human death (4-5% of infected patients identified through testing) and the global economy. Human sufferings seem to be continuing, and it is not clear how long this will continue and how much more destruction it is going to cause until complete control is achieved. One of the most disturbing issues is Covid-19 treatment; although a large number of medications, previously used successfully with other viruses (including Chinese herbal medicines and anti-malaria drugs), are under consideration, there remain questions as to whether they can play a satisfactory role for this disease. Global attempts are ongoing to find the drugs for the treatment of this virus but none of the antiviral drugs used for treatment of other human viral infection is working and hence attempts to find new drugs are continuing. Here the author is proposing that 5-Fluorouracil (5-FU) which when used on its own is failing as an antiviral agent due to the removal of this compound by proof reading ability exceptionally found in Coronaviruses. The author here is proposing to test 5-FU in combination with a number of deoxynucleosides on animal models infected with this Covid-19. Should encouraging results ensue, therapies could then be tried on patients.
tnh0szvz
tnh0szvz
2020-04-22
10.1016/j.mehy.2020.109754
3
Serum neopterin for early assessment of severity of severe acute respiratory syndrome
Abstract Neopterin and C-reactive protein (CRP) concentrations were determined in serum samples from 129 severe acute respiratory syndrome (SARS) patients and 156 healthy blood donors. In the patients with confirmed SARS, an early neopterin elevation was detected already at the day of onset of symptoms and rose to a maximum level of 45.0 nmol/L 3 days after the onset. All SARS patients had elevated neopterin concentrations (>10 nmol/L) within 9 days after the onset. The mean neopterin concentrations were 34.2 nmol/L in acute sera of SARS patients, 5.1 nmol/L in convalescent sera, and 6.7 nmol/L in healthy controls. In contrast, the mean CRP concentrations in both acute and convalescent sera of SARS patients were in the normal range (<10 mg/L). Serum neopterin level in SARS patients was associated with fever period and thus the clinical progression of the disease, while there was no significant correlation between the CRP level and the fever period. Serum neopterin may allow early assessment of the severity of SARS. The decrease of neopterin level was found after steroid treatment, which indicates that blood samples should be collected before steroid treatment for the neopterin measurement.
to3wn7yj
to3wn7yj
2005-07-31
10.1016/j.clim.2005.03.009
1.5
Proteomics of SARS-CoV-2-infected host cells reveals therapy targets.
A novel coronavirus was recently discovered and termed SARS-CoV-2. Human infection can cause coronavirus disease 2019 (COVID-19), which has been rapidly spreading around the globe1,2. SARS-CoV-2 shows some similarities to other coronaviruses. However, treatment options and a cellular understanding of SARS-CoV-2 infection are lacking. Here we identify the host cell pathways modulated by SARS-CoV-2 infection and show that inhibition of these pathways prevent viral replication in human cells. We established a human cell culture model for infection with SARS-CoV-2 clinical isolate. Employing this system, we determined the SARS-CoV-2 infection profile by translatome3 and proteome proteomics at different times after infection. These analyses revealed that SARS-CoV-2 reshapes central cellular pathways, such as translation, splicing, carbon metabolism and nucleic acid metabolism. Small molecule inhibitors targeting these pathways prevented viral replication in cells. Our results reveal the cellular infection profile of SARS-CoV-2 and led to the identification of drugs inhibiting viral replication. We anticipate our results to guide efforts to understand the molecular mechanisms underlying host cell modulation upon SARS-CoV-2 infection. Furthermore, our findings provide insight for the development of therapy options for COVID-19.
to6b17cb
to6b17cb
2020-05-14
10.1038/s41586-020-2332-7
4.5
Corona Epidemic in Indian context: Predictive Mathematical Modelling
The novel Coronavirus pathogen Covid-19 is a cause of concern across the world as the human-to-human infection caused by it is spreading at a fast pace. The virus that first manifested in Wuhan, China has travelled across continents. The increase in number of deaths in Italy, Iran, USA, and other countries has alarmed both the developed and developing countries. Scientists are working hard to develop a vaccine against the virus, but until now no breakthrough has been achieved. India, the second most populated country in the world, is working hard in all dimensions to stop the spread of community infection. Health care facilities are being updated; medical and paramedical staffs are getting trained, and many agencies are raising awareness on the issues related to this virus and its transmission. The administration is leaving no stone unturned to prepare the country to mitigate the adverse effects. However, as the number of infected patients, and those getting cured is changing differently in different states everyday it is difficult to predict the spread of the virus and its fate in Indian context. Different states have adopted measures to stop the community spread. Considering the vast size of the country, the population size and other socio-economic conditions of the states, a single uniform policy may not work to contain the disease. In this paper, we discuss a predictive mathematical model that can give us some idea of the fate of the virus, an indicative data and future projections to understand the further course this pandemic can take. The data can be used by the health care agencies, the Government Organizations and the Planning Commission to make suitable arrangements to fight the pandemic. Though the model is preliminary, it can be used at regional level to manage the health care system in the present scenario. The recommendations can be made, and advisories prepared based on the predictive results that can be implemented at regional levels.
tohbzenc
tohbzenc
2020-04-07
10.1101/2020.04.03.20047175
2.5
Recent progress in understanding 2019 novel coronavirus (SARS-CoV-2) associated with human respiratory disease: detection, mechanisms and treatment
ABSTRACT Viral respiratory diseases such as severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS) always pose a severe threat to people. First identified in late December 2019, a novel coronavirus (2019-nCoV; SARS-CoV-2) has affected many provinces in China and multiple countries worldwide. The viral outbreak has aroused panic and a public-health emergency around the world, and the number of infections continues to rise. However, the causes and consequences of the pneumonia remain unknown. To effectively implement epidemic prevention, early identification and diagnosis are critical to disease control. Here we scrutinise a series of available studies by global scientists on the clinical manifestations, detection methods and treatment options for the disease caused by SARS-CoV-2, named coronavirus disease 2019 (COVID-19), and also propose potential strategies for preventing the infection.
tomsdx3z
tomsdx3z
2020-03-29
10.1016/j.ijantimicag.2020.105950
1
Diacerein: A potential multi-target therapeutic drug for COVID-19
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which causes coronavirus disease 19 (COVID-19), was declared pandemic by the World Health Organization in March 2020. SARS-CoV-2 binds its host cell receptor, angiotensin-converting enzyme 2 (ACE2), through the viral spike (S) protein. The mortality related to severe acute respiratory distress syndrome (ARDS) and multi-organ failure in COVID-19 patients has been suggested to be connected with cytokine storm syndrome (CSS), an excessive immune response that severely damages healthy lung tissue. In addition, cardiac symptoms, including fulminant myocarditis, are frequent in patients in a severe state of illness. Diacerein (DAR) is an anthraquinone derivative drug whose active metabolite is rhein. Different studies have shown that this compound inhibits the IL-1, IL-2, IL-6, IL-8, IL-12, IL-18, TNF-&#945;, NF-&#954;B and NALP3 inflammasome pathways. The antiviral activity of rhein has also been documented. This metabolite prevents hepatitis B virus (HBV) replication and influenza A virus (IAV) adsorption and replication through mechanisms involving regulation of oxidative stress and alterations of the TLR4, Akt, MAPK, and NF-&#954;B signalling pathways. Importantly, rhein inhibits the interaction between the SARS-CoV S protein and ACE2 in a dose-dependent manner, suggesting rhein as a potential therapeutic agent for the treatment of SARS-CoV infection. Based on these findings, we hypothesize that DAR is a multi-target drug useful for COVID-19 treatment. This anthraquinone may control hyperinflammatory conditions by multi-faceted cytokine inhibition and by reducing viral infection.
totc93f4
totc93f4
2020
4.5
Reversal of the Progression of Fatal Coronavirus Infection in Cats by a Broad-Spectrum Coronavirus Protease Inhibitor
Coronaviruses infect animals and humans causing a wide range of diseases. The diversity of coronaviruses in many mammalian species is contributed by relatively high mutation and recombination rates during replication. This dynamic nature of coronaviruses may facilitate cross-species transmission and shifts in tissue or cell tropism in a host, resulting in substantial change in virulence. Feline enteric coronavirus (FECV) causes inapparent or mild enteritis in cats, but a highly fatal disease, called feline infectious peritonitis (FIP), can arise through mutation of FECV to FIP virus (FIPV). The pathogenesis of FIP is intimately associated with immune responses and involves depletion of T cells, features shared by some other coronaviruses like Severe Acute Respiratory Syndrome Coronavirus. The increasing risks of highly virulent coronavirus infections in humans or animals call for effective antiviral drugs, but no such measures are yet available. Previously, we have reported the inhibitors that target 3C-like protease (3CLpro) with broad-spectrum activity against important human and animal coronaviruses. Here, we evaluated the therapeutic efficacy of our 3CLpro inhibitor in laboratory cats with FIP. Experimental FIP is 100% fatal once certain clinical and laboratory signs become apparent. We found that antiviral treatment led to full recovery of cats when treatment was started at a stage of disease that would be otherwise fatal if left untreated. Antiviral treatment was associated with a rapid improvement in fever, ascites, lymphopenia and gross signs of illness and cats returned to normal health within 20 days or less of treatment. Significant reduction in viral titers was also observed in cats. These results indicate that continuous virus replication is required for progression of immune-mediated inflammatory disease of FIP. These findings may provide important insights into devising therapeutic strategies and selection of antiviral compounds for further development for important coronaviruses in animals and humans.
tph5n7ak
tph5n7ak
2016-03-30
10.1371/journal.ppat.1005531
2
Structure, Function, and Antigenicity of the SARS-CoV-2 Spike Glycoprotein
The emergence of SARS-CoV-2 has resulted in >90,000 infections and >3,000 deaths. Coronavirus spike (S) glycoproteins promote entry into cells and are the main target of antibodies. We show that SARS-CoV-2 S uses ACE2 to enter cells and that the receptor-binding domains of SARS-CoV-2 S and SARS-CoV S bind with similar affinities to human ACE2, correlating with the efficient spread of SARS-CoV-2 among humans. We found that the SARS-CoV-2 S glycoprotein harbors a furin cleavage site at the boundary between the S(1)/S(2) subunits, which is processed during biogenesis and sets this virus apart from SARS-CoV and SARS-related CoVs. We determined cryo-EM structures of the SARS-CoV-2 S ectodomain trimer, providing a blueprint for the design of vaccines and inhibitors of viral entry. Finally, we demonstrate that SARS-CoV S murine polyclonal antibodies potently inhibited SARS-CoV-2 S mediated entry into cells, indicating that cross-neutralizing antibodies targeting conserved S epitopes can be elicited upon vaccination.
trlni6iq
trlni6iq
2020-03-09
10.1016/j.cell.2020.02.058
3
Full Issue PDF
tsootrxz
tsootrxz
2020-05-31
10.1016/s2452-302x(20)30205-9
4.5
Interferon-a2b treatment for COVID-19
Summary Background The global pandemic of COVID-19 cases caused by infection with SARS-CoV-2 is ongoing. We describe here the clinical course of COVID-19 in a cohort of confirmed cases in Wuhan, China, treated with the repurposed potential experimental therapeutics IFN-α2b, arbidol or a combination of IFN-α2b plus arbidol. Methods 77 adults with confirmed COVID-19 were treated with either nebulized IFN-α2b (5mU,b.i.d.), arbidol (200mg dispersible tablet, t.i.d.) or a combination of IFN-α2b plus arbidol. Serial SARS-CoV-2 testing along with hematological measurements, including cell counts and blood biochemistry, serum cytokine levels, temperature and blood oxygen saturation levels were recorded for each patient during their hospital stay. Findings Treatment with IFN-α2b with or without arbidol significantly reduced the duration of detectable virus in the upper respiratory tract and in parallel reduced duration of elevated blood levels for the inflammatory markers IL-6 and CRP. Interpretation IFN-α2b should be investigated as therapy in COVID-19 cases.
ttdzvw1s
ttdzvw1s
2020-04-10
10.1101/2020.04.06.20042580
2.5
Fast Identification of Possible Drug Treatment of Coronavirus Disease-19 (COVID-19) through Computational Drug Repurposing Study
The recent outbreak of novel coronavirus disease-19 (COVID-19) calls for and welcomes possible treatment strategies using drugs on the market. It is very efficient to apply computer-aided drug design techniques to quickly identify promising drug repurposing candidates, especially after the detailed 3D structures of key viral proteins are resolved. The virus causing COVID-19 is SARS-CoV-2. Taking advantage of a recently released crystal structure of SARS-CoV-2 main protease in complex with a covalently bonded inhibitor, N3 (Liu et al., 10.2210/pdb6LU7/pdb), I conducted virtual docking screening of approved drugs and drug candidates in clinical trials. For the top docking hits, I then performed molecular dynamics simulations followed by binding free energy calculations using an end point method called MM-PBSA-WSAS (molecular mechanics/Poisson-Boltzmann surface area/weighted solvent-accessible surface area; Wang, Chem. Rev. 2019, 119, 9478; Wang, Curr. Comput.-Aided Drug Des. 2006, 2, 287; Wang; ; Hou J. Chem. Inf. Model., 2012, 52, 1199). Several promising known drugs stand out as potential inhibitors of SARS-CoV-2 main protease, including carfilzomib, eravacycline, valrubicin, lopinavir, and elbasvir. Carfilzomib, an approved anticancer drug acting as a proteasome inhibitor, has the best MM-PBSA-WSAS binding free energy, -13.8 kcal/mol. The second-best repurposing drug candidate, eravacycline, is synthetic halogenated tetracycline class antibiotic. Streptomycin, another antibiotic and a charged molecule, also demonstrates some inhibitory effect, even though the predicted binding free energy of the charged form (-3.8 kcal/mol) is not nearly as low as that of the neutral form (-7.9 kcal/mol). One bioactive, PubChem 23727975, has a binding free energy of -12.9 kcal/mol. Detailed receptor-ligand interactions were analyzed and hot spots for the receptor-ligand binding were identified. I found that one hot spot residue, His41, is a conserved residue across many viruses including SARS-CoV, SARS-CoV-2, MERS-CoV, and hepatitis C virus (HCV). The findings of this study can facilitate rational drug design targeting the SARS-CoV-2 main protease.
ttl1f9dd
ttl1f9dd
2020
3.5
First Reported Cases of SARS-CoV-2 Infection in Companion Animals — New York, March–April 2020
On April 22, CDC and the U.S. Department of Agriculture (USDA) reported cases of two domestic cats with confirmed infection with SARS-CoV-2, the virus that causes coronavirus disease 2019 (COVID-19). These are the first reported companion animals (including pets and service animals) with SARS-CoV-2 infection in the United States, and among the first findings of SARS-CoV-2 symptomatic companion animals reported worldwide. These feline cases originated from separate households and were epidemiologically linked to suspected or confirmed human COVID-19 cases in their respective households. Notification of presumptive positive animal test results triggered a One Health* investigation by state and federal partners, who determined that no further transmission events to other animals or persons had occurred. Both cats fully recovered. Although there is currently no evidence that animals play a substantial role in spreading COVID-19, CDC advises persons with suspected or confirmed COVID-19 to restrict contact with animals during their illness and to monitor any animals with confirmed SARS-CoV-2 infection and separate them from other persons and animals at home (1).
tu1vevx9
tu1vevx9
2020-06-12
10.15585/mmwr.mm6923e3
5
Functional Immune Deficiency Syndrome via Intestinal Infection in COVID-19
Using a Systems Biology approach, we integrated genomic, transcriptomic, proteomic, and molecular structure information to provide a holistic understanding of the COVID-19 pandemic. The expression data analysis of the Renin Angiotensin System indicates mild nasal, oral or throat infections are likely and that the gastrointestinal tissues are a common primary target of SARS-CoV-2. Extreme symptoms in the lower respiratory system likely result from a secondary-infection possibly by a comorbidity-driven upregulation of ACE2 in the lung. The remarkable differences in expression of other RAS elements, the elimination of macrophages and the activation of cytokines in COVID-19 bronchoalveolar samples suggest that a functional immune deficiency is a critical outcome of COVID-19. We posit that using a non-respiratory system as a major pathway of infection is likely determining the unprecedented global spread of this coronavirus. One Sentence Summary A Systems Approach Indicates Non-respiratory Pathways of Infection as Key for the COVID-19 Pandemic
tug2t7dm
tug2t7dm
2020-04-11
10.1101/2020.04.06.028712
2.5
A Cascaded Learning Strategy for Robust COVID-19 Pneumonia Chest X-Ray Screening
We introduce a comprehensive screening platform for the COVID-19 (a.k.a., SARS-CoV-2) pneumonia. The proposed AI-based system works on chest x-ray (CXR) images to predict whether a patient is infected with the COVID-19 disease. Although the recent international joint effort on making the availability of all sorts of open data, the public collection of CXR images is still relatively small for reliably training a deep neural network (DNN) to carry out COVID-19 prediction. To better address such inefficiency, we design a cascaded learning strategy to improve both the sensitivity and the specificity of the resulting DNN classification model. Our approach leverages a large CXR image dataset of non-COVID-19 pneumonia to generalize the original well-trained classification model via a cascaded learning scheme. The resulting screening system is shown to achieve good classification performance on the expanded dataset, including those newly added COVID-19 CXR images.
tupom7fb
tupom7fb
2020-04-24
3.5
Mass Spectrometric Identification of SARS-CoV-2 Proteins from Gargle Solution Samples of COVID-19 Patients
Mass spectrometry (MS) can deliver valuable diagnostic data that complements genomic information and allows us to increase our current knowledge of the COVID-19 disease caused by the SARS-CoV-2 virus. We developed a simple, MS-based method to specifically detect SARS-CoV-2 proteins from gargle solution samples of COVID-19 patients. Our protocol consists of an acetone precipitation and tryptic digestion of proteins contained within the gargle solution, followed by a targeted MS analysis. Our methodology identifies unique peptides originating from SARS-CoV-2 nucleoprotein. Building on these promising initial results, faster MS protocols can now be developed as routine diagnostic tools for COVID-19 patients. Graphical Abstract Image credit (left): Gerd Altmann, Pixabay License, https://pixabay.com/illustrations/corona-coronavirus-virus-covid-19-4959447
tvv73r7h
tvv73r7h
2020-04-19
10.1101/2020.04.18.047878
2
Advanced bioinformatics rapidly identifies existing therapeutics for patients with coronavirus disease-2019 (COVID-19)
BACKGROUND: The recent global pandemic has placed a high priority on identifying drugs to prevent or lessen clinical infection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), caused by Coronavirus disease-2019 (COVID-19). METHODS: We applied two computational approaches to identify potential therapeutics. First, we sought to identify existing FDA approved drugs that could block coronaviruses from entering cells by binding to ACE2 or TMPRSS2 using a high-throughput AI-based binding affinity prediction platform. Second, we sought to identify FDA approved drugs that could attenuate the gene expression patterns induced by coronaviruses, using our Disease Cancelling Technology (DCT) platform. RESULTS: Top results for ACE2 binding iincluded several ACE inhibitors, a beta-lactam antibiotic, two antiviral agents (Fosamprenavir and Emricasan) and glutathione. The platform also assessed specificity for ACE2 over ACE1, important for avoiding counterregulatory effects. Further studies are needed to weigh the benefit of blocking virus entry against potential counterregulatory effects and possible protective effects of ACE2. However, the data herein suggest readily available drugs that warrant experimental evaluation to assess potential benefit. DCT was run on an animal model of SARS-CoV, and ranked compounds by their ability to induce gene expression signals that counteract disease-associated signals. Top hits included Vitamin E, ruxolitinib, and glutamine. Glutathione and its precursor glutamine were highly ranked by two independent methods, suggesting both warrant further investigation for potential benefit against SARS-CoV-2. CONCLUSIONS: While these findings are not yet ready for clinical translation, this report highlights the potential use of two bioinformatics technologies to rapidly discover existing therapeutic agents that warrant further investigation for established and emerging disease processes.
tw727gir
tw727gir
2020-06-25
10.1186/s12967-020-02430-9
5
Nucleosides for the treatment of respiratory RNA virus infections
Influenza virus, respiratory syncytial virus, human metapneumovirus, parainfluenza virus, coronaviruses, and rhinoviruses are among the most common viruses causing mild seasonal colds. These RNA viruses can also cause lower respiratory tract infections leading to bronchiolitis and pneumonia. Young children, the elderly, and patients with compromised cardiac, pulmonary, or immune systems are at greatest risk for serious disease associated with these RNA virus respiratory infections. In addition, swine and avian influenza viruses, together with severe acute respiratory syndrome-associated and Middle Eastern respiratory syndrome coronaviruses, represent significant pandemic threats to the general population. In this review, we describe the current medical need resulting from respiratory infections caused by RNA viruses, which justifies drug discovery efforts to identify new therapeutic agents. The RNA polymerase of respiratory viruses represents an attractive target for nucleoside and nucleotide analogs acting as inhibitors of RNA chain synthesis. Here, we present the molecular, biochemical, and structural fundamentals of the polymerase of the four major families of RNA respiratory viruses: Orthomyxoviridae, Pneumoviridae/Paramyxoviridae, Coronaviridae, and Picornaviridae. We summarize past and current efforts to develop nucleoside and nucleotide analogs as antiviral agents against respiratory virus infections. This includes molecules with very broad antiviral spectrum such as ribavirin and T-705 (favipiravir), and others targeting more specifically one or a few virus families. Recent advances in our understanding of the structure(s) and function(s) of respiratory virus polymerases will likely support the discovery and development of novel nucleoside analogs.
txaoz7oh
txaoz7oh
2018-03-21
10.1177/2040206618764483
0.5
The evidence of porcine hemagglutinating encephalomyelitis virus induced nonsuppurative encephalitis as the cause of death in piglets
An acute outbreak of porcine hemagglutinating encephalomyelitis virus (PHEV) infection in piglets, characterized with neurological symptoms, vomiting, diarrhea, and wasting, occurred in China. Coronavirus-like particles were observed in the homogenized tissue suspensions of the brain of dead piglets by electron microscopy, and a wild PHEV strain was isolated, characterized, and designated as PHEV-CC14. Histopathologic examinations of the dead piglets showed characteristics of non-suppurative encephalitis, and some neurons in the cerebral cortex were degenerated and necrotic, and neuronophagia. Similarly, mice inoculated with PHEV-CC14 were found to have central nervous system (CNS) dysfunction, with symptoms of depression, arched waists, standing and vellicating front claws. Furthmore, PHEV-positive labeling of neurons in cortices of dead piglets and infected mice supported the viral infections of the nervous system. Then, the major structural genes of PHEV-CC14 were sequenced and phylogenetically analyzed, and the strain shared 95%–99.2% nt identity with the other PHEV strains available in GenBank. Phylogenetic analysis clearly proved that the wild strain clustered into a subclass with a HEV-JT06 strain. These findings suggested that the virus had a strong tropism for CNS, in this way, inducing nonsuppurative encephalitis as the cause of death in piglets. Simultaneously, the predicted risk of widespread transmission showed a certain variation among the PHEV strains currently circulating around the world. Above all, the information presented in this study can not only provide good reference for the experimental diagnosis of PHEV infection for pig breeding, but also promote its new effective vaccine development.
txk1qic1
txk1qic1
2016-09-15
10.7717/peerj.2443
3
A Novel Triage Tool of Artificial Intelligence Assisted Diagnosis Aid System for Suspected COVID-19 pneumonia In Fever Clinics
Currently, the prevention and control of COVID-19 outside Hubei province in China, and other countries has become more and more critically serious. We developed and validated a diagnosis aid model without CT images for early identification of suspected COVID-19 pneumonia (S-COVID-19-P) on admission in adult fever patients and made the validated model available via an online triage calculator. Patients admitted from Jan 14 to Feb 26, 2020 with the epidemiological history of exposure to COVID-19 were included [Model development (n = 132) and validation (n = 32)]. Candidate features included clinical symptoms, routine laboratory tests and other clinical information on admission. Features selection and model development were based on Lasso regression. The primary outcome is the development and validation of a diagnosis aid model for S-COVID-19-P early identification on admission. The development cohort contains 26 S-COVID-19-P and 7 confirmed COVID-19 pneumonia cases. The model performance in held-out testing set and validation cohort resulted in AUCs of 0.841 and 0.938, F-1 score of 0.571 and 0.667, recall of 1.000 and 1.000, specificity of 0.727 and 0.778, and the precision of 0.400 and 0.500. Based on this model, an optimized strategy for S-COVID-19-P early identification in fever clinics has also been designed. S-COVID-19-P could be identified early by a machine-learning model only used collected clinical information without CT images on admission in fever clinics with 100% recall score. The well performed and validated model has been deployed as an online triage tool, which is available at: https://intensivecare.shinyapps.io/COVID19/.
txt4jiy8
txt4jiy8
2020-03-20
10.1101/2020.03.19.20039099
1.5
Broad-Spectrum Host-Based Antivirals Targeting the Interferon and Lipogenesis Pathways as Potential Treatment Options for the Pandemic Coronavirus Disease 2019 (COVID-19).
The ongoing Coronavirus Disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) signals an urgent need for an expansion in treatment options. In this study, we investigated the anti-SARS-CoV-2 activities of 22 antiviral agents with known broad-spectrum antiviral activities against coronaviruses and/or other viruses. They were first evaluated in our primary screening in VeroE6 cells and then the most potent anti-SARS-CoV-2 antiviral agents were further evaluated using viral antigen expression, viral load reduction, and plaque reduction assays. In addition to remdesivir, lopinavir, and chloroquine, our primary screening additionally identified types I and II recombinant interferons, 25-hydroxycholesterol, and AM580 as the most potent anti-SARS-CoV-2 agents among the 22 antiviral agents. Betaferon (interferon-β1b) exhibited the most potent anti-SARS-CoV-2 activity in viral antigen expression, viral load reduction, and plaque reduction assays among the recombinant interferons. The lipogenesis modulators 25-hydroxycholesterol and AM580 exhibited EC50 at low micromolar levels and selectivity indices of >10.0. Combinational use of these host-based antiviral agents with virus-based antivirals to target different processes of the SARS-CoV-2 replication cycle should be evaluated in animal models and/or clinical trials.
tzmev77c
tzmev77c
2020-06-10
10.3390/v12060628
4
Sensitivity of SARS/MERS CoV to interferons and other drugs based on achievable serum concentrations in humans.
A novel coronavirus (MERS-CoV) related to SARS-CoV recently emerged in the Middle East causing more than 400 deaths with a mortality rate of about 30%, much higher than SARS-CoV. Both viruses target epithelial cells in the respiratory tract, although utilizing different cellular receptors. Because of the sporadic nature of the MERS outbreak and difficulty in collecting randomized, controlled clinical data, the objective of this review was to focus on published in vitro and in vivo drug sensitivity data using both cell lines and available animal models of SARS/MERS CoV infection. Determination of drug activity was based on achievable serum levels in humans relative to in vitro IC50 (50% inhibitory concentration) or EC50 (50% effective concentration) drug concentrations. The most active drugs against SARS/MERS CoV at clinically achievable serum levels were type I interferons and a TLR3 agonist, interferon inducer/activator.
u0kyyyb7
u0kyyyb7
2014
3
Is the anti-filarial drug diethylcarbamazine useful to treat COVID-19?
The SARS-CoV-2 virus has resulted in a devastating pandemic of COVID-19. Exploring compounds that could offer a breakthrough in treatment is the need of the hour. Re-positioning cheap, freely available and safe drugs is a priority. The paper proposes evidence for the potential use of diethylcarbamazine (DEC) in the treatment of COVID-19. DEC has inhibitory effects on arachidonic acid metabolism to prostaglandins, little known anti-viral effects on animal retroviruses and demonstrated anti-inflammatory actions in animal models of lung inflammation indicating the need to explore this hypothesis further. We believe this is the first time DEC is being proposed to treat COVID-19.
u3n60qjw
u3n60qjw
2020-04-18
2
Broad-Spectrum Host-Based Antivirals Targeting the Interferon and Lipogenesis Pathways as Potential Treatment Options for the Pandemic Coronavirus Disease 2019 (COVID-19)
The ongoing Coronavirus Disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) signals an urgent need for an expansion in treatment options. In this study, we investigated the anti-SARS-CoV-2 activities of 22 antiviral agents with known broad-spectrum antiviral activities against coronaviruses and/or other viruses. They were first evaluated in our primary screening in VeroE6 cells and then the most potent anti-SARS-CoV-2 antiviral agents were further evaluated using viral antigen expression, viral load reduction, and plaque reduction assays. In addition to remdesivir, lopinavir, and chloroquine, our primary screening additionally identified types I and II recombinant interferons, 25-hydroxycholesterol, and AM580 as the most potent anti-SARS-CoV-2 agents among the 22 antiviral agents. Betaferon (interferon-ß1b) exhibited the most potent anti-SARS-CoV-2 activity in viral antigen expression, viral load reduction, and plaque reduction assays among the recombinant interferons. The lipogenesis modulators 25-hydroxycholesterol and AM580 exhibited EC50 at low micromolar levels and selectivity indices of >10.0. Combinational use of these host-based antiviral agents with virus-based antivirals to target different processes of the SARS-CoV-2 replication cycle should be evaluated in animal models and/or clinical trials.
u3ow62fn
u3ow62fn
2020
4
Comparative computational analysis of SARS-CoV-2 nucleocapsid protein epitopes in taxonomically related coronaviruses
Abstract Several research lines are currently ongoing to address the multitude of facets of the pandemic COVID-19. In line with the One-Health concept, extending the target of the studies to the animals which humans are continuously interacting with may favor a better understanding of the SARS-CoV-2 biology and pathogenetic mechanisms; thus, helping to adopt the most suitable containment measures. The last two decades have already faced severe manifestations of the coronavirus infection in both humans and animals, thus, circulating epitopes from previous outbreaks might confer partial protection from SARS-CoV-2 infections. In the present study, we provide an in-silico survey of the major nucleocapsid protein epitopes and compare them with the homologues of taxonomically-related coronaviruses with tropism for animal species that are closely inter-related with the human beings population all over the world. Protein sequence alignment provides evidence of high sequence homology for some of the investigated proteins. Moreover, structural epitope mapping by homology modelling revealed a potential immunogenic value also for specific sequences scoring a lower identity with SARS-CoV-2 nucleocapsid proteins. These evidence provide a molecular structural rationale for a potential role in conferring protection from SARS-CoV-2 infection and identifying potential candidates for the development of diagnostic tools and prophylactic-oriented strategies.
u4bgqwlw
u4bgqwlw
2020-04-14
10.1016/j.micinf.2020.04.002
2.5
Non-animal replacement methods for veterinary vaccine potency testing: state of the science and future directions
Abstract NICEATM and ICCVAM convened an international workshop to review the state of the science of human and veterinary vaccine potency and safety testing methods and to identify opportunities to advance new and improved methods that can further reduce, refine, and replace animal use. Six topics were addressed in detail by speakers and workshop participants and are reported in a series of six reports. This workshop report, the second in the series, provides recommendations for current and future use of non-animal methods and strategies for veterinary vaccine potency testing. Workshop participants recommended that future efforts to replace animal use give priority to vaccines (1) that use large numbers of animals per test and for which many serials are produced annually, (2) that involve significant animal pain and distress during procedures, (3) for which the functional protective antigen has been identified, (4) that involve foreign animal/zoonotic organisms that are dangerous to humans, and (5) that involve pathogens that can be easily spread to wildlife populations. Vaccines identified as the highest priorities were those for rabies, Leptospira spp., Clostridium spp., Erysipelas, foreign animal diseases (FAD), poultry diseases, and fish diseases. Further research on the identification, purification, and characterization of vaccine protective antigens in veterinary vaccines was also identified as a priority. Workshop participants recommended priority research, development, and validation activities to address critical knowledge and data gaps, including opportunities to apply new science and technology. Recommendations included (1) investigations into the relative impact of various adjuvants on antigen quantification assays, (2) investigations into extraction methods that could be used for vaccines containing adjuvants that can interfere with antigen assays, and (3) review of the current status of rabies and tetanus human vaccine in vitro potency methods for their potential application to the corresponding veterinary vaccines. Workshop participants recommended enhanced international harmonization and cooperation and closer collaborations between human and veterinary researchers to expedite progress. Implementation of the workshop recommendations is expected to advance alternative in vitro methods for veterinary vaccine potency testing that will benefit animal welfare and replace animal use while ensuring continued protection of human and animal health.
u55ibep9
u55ibep9
2011-12-31
10.1016/j.provac.2011.10.005
4.5
Decoding SARS-CoV-2 transmission, evolution and ramification on COVID-19 diagnosis, vaccine, and medicine
Tremendous effort has been given to the development of diagnostic tests, preventive vaccines, and therapeutic medicines for coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Much of this development has been based on the reference genome collected on January 5, 2020. Based on the genotyping of 6156 genome samples collected up to April 24, 2020, we report that SARS-CoV-2 has had 4459 alarmingly mutations which can be clustered into five subtypes. We introduce mutation ratio and mutation $h$-index to characterize the protein conservativeness and unveil that SARS-CoV-2 envelope protein, main protease, and endoribonuclease protein are relatively conservative, while SARS-CoV-2 nucleocapsid protein, spike protein, and papain-like protease are relatively non-conservative. In particular, the nucleocapsid protein has more than half its genes changed in the past few months, signaling devastating impacts on the ongoing development of COVID-19 diagnosis, vaccines, and drugs.
u6ewlh16
u6ewlh16
2020-04-29
2.5
Diabetes mellitus is associated with increased mortality and severity of disease in COVID-19 pneumonia – A systematic review, meta-analysis, and meta-regression
Abstract Background and aims Diabetes Mellitus (DM) is chronic conditions with devastating multi-systemic complication and may be associated with severe form of Coronavirus Disease 2019 (COVID-19). We conducted a systematic review and meta-analysis in order to investigate the association between DM and poor outcome in patients with COVID-19 pneumonia. Methods Systematic literature search was performed from several electronic databases on subjects that assess DM and outcome in COVID-19 pneumonia. The outcome of interest was composite poor outcome, including mortality, severe COVID-19, acute respiratory distress syndrome (ARDS), need for intensive care unit (ICU) care, and disease progression. Results There were a total of 6452 patients from 30 studies. Meta-analysis showed that DM was associated with composite poor outcome (RR 2.38 [1.88, 3.03], p < 0.001; I2: 62%) and its subgroup which comprised of mortality (RR 2.12 [1.44, 3.11], p < 0.001; I2: 72%), severe COVID-19 (RR 2.45 [1.79, 3.35], p < 0.001; I2: 45%), ARDS (RR 4.64 [1.86, 11.58], p = 0.001; I2: 9%), and disease progression (RR 3.31 [1.08, 10.14], p = 0.04; I2: 0%). Meta-regression showed that the association with composite poor outcome was influenced by age (p = 0.003) and hypertension (p < 0.001). Subgroup analysis showed that the association was weaker in studies with median age ≥55 years-old (RR 1.92) compared to <55 years-old (RR 3.48), and in prevalence of hypertension ≥25% (RR 1.93) compared to <25% (RR 3.06). Subgroup analysis on median age <55 years-old and prevalence of hypertension <25% showed strong association (RR 3.33) Conclusion DM was associated with mortality, severe COVID-19, ARDS, and disease progression in patients with COVID-19.
u6uqroi0
u6uqroi0
2020-04-17
10.1016/j.dsx.2020.04.018
2
COVID-19 Outbreak: An Overview
BACKGROUND: In late December 2019, Chinese health authorities reported an outbreak of pneumonia of unknown origin in Wuhan, Hubei Province. SUMMARY: A few days later, the genome of a novel coronavirus was released (http://virological.org/t/novel-2019-coronavirus-genome/319; Wuhan-Hu-1, GenBank accession No. MN908947) and made publicly available to the scientific community. This novel coronavirus was provisionally named 2019-nCoV, now SARS-CoV-2 according to the Coronavirus Study Group of the International Committee on Taxonomy of Viruses. SARS-CoV-2 belongs to the Coronaviridae family, Betacoronavirus genus, subgenus Sarbecovirus. Since its discovery, the virus has spread globally, causing thousands of deaths and having an enormous impact on our health systems and economies. In this review, we summarize the current knowledge about the epidemiology, phylogenesis, homology modeling, and molecular diagnostics of SARS-CoV-2. KEY MESSAGES: Phylogenetic analysis is essential to understand viral evolution, whereas homology modeling is important for vaccine strategies and therapies. Highly sensitive and specific diagnostic assays are key to case identification, contact tracing, identification of the animal source, and implementation of control measures.
u7tz6xzz
u7tz6xzz
2020-04-07
10.1159/000507423
3
The epidemiology, diagnosis and treatment of COVID-19
Abstract In December 2019, the outbreak of the novel coronavirus disease (COVID-19) in China spread worldwide, becoming an emergency of major international concern. SARS-CoV-2 infection causes clusters of severe respiratory illness similar to severe acute respiratory syndrome coronavirus. Human-to-human transmission via droplets, contaminated hands or surfaces has been described, with incubation times of 2-14 days. Early diagnosis, quarantine, and supportive treatments are essential to cure patients. This paper reviews the literature on all available information about the epidemiology, diagnosis, isolation and treatments of COVID-19. Treatments, including antiviral agents, chloroquine and hydroxychloroquine, corticosteroids, antibodies, convalescent plasma transfusion and vaccines, are discussed in this article. In addition, registered trials investigating treatment options for COVID-19 infection are listed.
u7zxlgxz
u7zxlgxz
2020-03-28
10.1016/j.ijantimicag.2020.105955
1
Primum non nocere – Are chloroquine and hydroxychloroquine safe prophylactic/treatment options for SARS-CoV-2 (covid-19)?
Chloroquine (CQ) and its analog hydroxychloroquine (HCQ) were recently included in several clinical trials as potential prophylactic and therapeutic options for SARS-COV-2 infection/covid-19. However, drug effectiveness in preventing, treating, or slowing the progression of the disease is still unknown. Despite some initial promising in vitro results, rigorous pre-clinical animal studies and randomized clinical trials have not been performed yet. On the other hand, while the potential effectiveness of CQ/HCQ is, at best, hypothetical, their side effects are factual and most worrisome, particularly when considering vulnerable groups of patients being treated with these drugs. in this comment, we briefly explain the possible mechanisms of action of CQ/HCQ for treating other diseases, possible actions against covid-19, and their potent side effects, in order to reinforce the necessity of evaluating the benefit-risk balance when widely prescribing these drugs for SARS-COV-2 infection/covid-19. We conclude by strongly recommending against their indiscriminate use.
u87lx38h
u87lx38h
2020-06-26
10.11606/s1518-8787.2020054002631
5
Experimental models of demyelination and remyelination
Abstract Introduction Experimental animal models constitute a useful tool to deepen our knowledge of central nervous system disorders. In the case of multiple sclerosis, however, there is no such specific model able to provide an overview of the disease; multiple models covering the different pathophysiological features of the disease are therefore necessary. Development We reviewed the different in vitro and in vivo experimental models used in multiple sclerosis research. Concerning in vitro models, we analysed cell cultures and slice models. As for in vivo models, we examined such models of autoimmunity and inflammation as experimental allergic encephalitis in different animals and virus-induced demyelinating diseases. Furthermore, we analysed models of demyelination and remyelination, including chemical lesions caused by cuprizone, lysolecithin, and ethidium bromide; zebrafish; and transgenic models. Conclusions Experimental models provide a deeper understanding of the different pathogenic mechanisms involved in multiple sclerosis. Choosing one model or another depends on the specific aims of the study.
uak8xgos
uak8xgos
2020-02-29
10.1016/j.nrleng.2019.03.007
1
Hyperglycemia, hydroxychloroquine, and the COVID‐19 pandemic
Coronavirus disease‐2019 (COVID‐19) infection and its severity can be explained by the concentration of glycosylated severe acute respiratory syndrome‐coronavirus 2 (SARS‐CoV‐2) viral particles in the lung epithelium, the concentration of glycosylated angiotensin‐converting enzyme receptor 2 (ACE2) in the lung epithelium, and the degree and control of the pulmonary immune response to the SARS‐CoV‐2 spike protein at approximately day 8 to 10 after symptom onset, which may be related to both. Binding of ACE2 by SARS‐CoV‐2 in COVID‐19 also suggests that prolonged uncontrolled hyperglycemia, and not just a history of diabetes mellitus, may be important in the pathogenesis of the disease. It is tempting to consider that the same mechanism acts in COVID‐19 as in SARS, where an overactive macrophage M1 inflammatory response, as neutralizing antibodies to the SARS‐CoV‐2 spike protein form at day 7 to 10, results in acute respiratory distress syndrome (ARDS) in susceptible patients. It also allows consideration of agents, such as hydroxychloroquine, which may interfere with this overly brisk macrophage inflammatory response and perhaps influence the course of the disease, in particular, those that blunt but do not completely abrogate the M1 to M2 balance in macrophage polarization, as well as viral load, which in SARS appears to be temporally related to the onset of ARDS.
ub7s6yz6
ub7s6yz6
2020-04-27
10.1002/jmv.25887
3
COVID-19: Learning from Lessons To Guide Treatment and Prevention Interventions
Coronavirus disease 2019 (COVID-19) is caused by the novel coronavirus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and first emerged in December 2019 in Wuhan, Hubei province, China. Since then, the virus has rapidly spread to many countries. While the outbreak in China appears to be in decline, the disease has spread across the world, with a daily increase in the number of confirmed cases and infection-related deaths. Here, we highlight (i) the lessons that have been learnt so far and how they will benefit reducing the impact of COVID-19 disease and (ii) an update on the status of drug treatment and vaccine development to prevent COVID-19 and potential future related pandemics. Although the mortality rate is clearly higher than for influenza, the rate does seem to vary from country to country, possibly reflecting differences in how rapidly local health authorities respond to isolate and effectively care for the affected population. Drugs are urgently needed for both prophylaxis and the treatment of severely ill patients; however, no proven effective therapies for SARS-CoV-2 currently exist. A number of drugs that have been approved for other diseases are being tested for the treatment of COVID-19 patients, but there is an absence of data from appropriately designed clinical trials showing that these drugs, either alone or in combination, will prove effective. There is also a global urgency to develop a vaccine against COVID-19, but development and appropriate testing will take at least a year before such a vaccine will be globally available. This review summarizes the lessons learnt so far from the COVID-19 pandemic, examines the evidence regarding the drugs that are being tested for the treatment of COVID19, and describes the progress made in efforts to develop an effective vaccine.
ucipq8uk
ucipq8uk
2020-05-13
10.1128/msphere.00317-20
4.5
Potential antiviral options against SARS-CoV-2 infection
As of June 2020, the number of people infected with severe acute respiratory coronavirus 2 (SARS-CoV-2) continues to skyrocket, with more than 6,5 million cases worldwide. Both the World Health Organization (WHO) and United Nations (UN) has highlighted the need for better control of SARS-CoV-2 infections. However, developing novel virus-specific vaccines, monoclonal antibodies and antiviral drugs against SARS-CoV-2 can be time-consuming and costly. Convalescent sera and safe-in-man broad-spectrum antivirals (BSAAs) are readily available treatment options. Here we developed a neutralization assay using SARS-CoV-2 strain and Vero-E6 cells. We identified most potent sera from recovered patients for treatment of SARS-CoV-2-infected patients. We also screened 136 safe-in-man broad-spectrum antivirals against SARS-CoV-2 infection in Vero-E6 cells and identified nelfinavir, salinomycin, amodiaquine, obatoclax, emetine and homoharringtonine. We found that combinations of virus-directed nelfinavir along with host-directed amodiaquine exhibited the highest synergy. Finally, we developed a website to disseminate the knowledge on available and emerging treatments of COVID-19.
ucqago27
ucqago27
2020-06-04
10.1101/2020.05.12.091165
3
From a single host to global spread. The global mobility based modelling of the COVID-19 pandemic implies higher infection and lower detection rates than current estimates.
Background: Since the outbreak of the COVID-19 pandemic, multiple efforts of modelling of the geo-temporal transmissibility of the virus have been undertaken, but none succeeded in describing the pandemic at the global level. We propose a set of parameters for the first COVID-19 Global Epidemic and Mobility Model (GLEaM). The simulation starting with just a single pre-symptomatic, yet infectious, case in Wuhan, China, results in an accurate prediction of the number of diagnosed cases after 125 days in multiple countries across three continents. Methods: We have built a modified SIR model and parameterized it analytically, according to the literature and by fitting the missing parameters to the observed dynamics of the virus spread. We compared our results with the number of diagnosed cases in sixeight selected countries which provide reliable statistics but differ substantially in terms of strength and speed of undertaken precautions. The obtained 95% confidence intervals for the predictions fit well to the empirical data. Findings: The parameters that successfully model the pandemic are: the basic reproduction number R0, ~4.4; a latent non-infectious period of 1.1. days followed by 4.6 days of the presymptomatic infectious period; the probability of developing severe symptoms, 0.01; the probability of being diagnosed when presenting severe symptoms of 0.6; the probability of diagnosis for cases with mild symptoms or asymptomatic, 0.001. Also, the higher the testing rate per country, the lower the discrepancy between data (diagnosed cases) and model. Interpretation: Parameters that successfully reproduce the observed number of cases indicate that both R0 and the prevalence of the virus might be underestimated. This is in concordance with the newest research on undocumented COVID-19 cases. Consequently, the actual mortality rate is putatively lower than estimated. Confirmation of the pandemic characteristic by further refinement of the model and screening tests is crucial for developing an effective strategy for the global epidemiological crisis.
udtj0lom
udtj0lom
2020-03-23
10.1101/2020.03.21.20040444
1.5
Inactivated SARS-CoV vaccine elicits high titers of spike protein-specific antibodies that block receptor binding and virus entry
Abstract The only severe acute respiratory syndrome (SARS) vaccine currently being tested in clinical trial consists of inactivated severe acute respiratory syndrome-associate coronavirus (SARS-CoV). However, limited information is available about host immune responses induced by the inactivated SARS vaccine. In this study, we demonstrated that SARS-CoV inactivated by β-propiolactone elicited high titers of antibodies in the immunized mice and rabbits that recognize the spike (S) protein, especially the receptor-binding domain (RBD) in the S1 region. The antisera from the immunized animals efficiently bound to the RBD and blocked binding of RBD to angiotensin-converting enzyme 2, the functional receptor on the susceptible cells for SARS-CoV. With a sensitive and quantitative single-cycle infection assay using pseudovirus bearing the SARS-CoV S protein, we demonstrated that mouse and rabbit antisera significantly inhibited S protein-mediated virus entry with mean 50% inhibitory titers of 1:7393 and 1:2060, respectively. These data suggest that the RBD of S protein is a major neutralization determinant in the inactivated SARS vaccine which can induce potent neutralizing antibodies to block SARS-CoV entry. However, caution should be taken in using the inactivated SARS-CoV as a vaccine since it may also cause harmful immune and/or inflammatory responses.
ue7v0yab
ue7v0yab
2004-12-10
10.1016/j.bbrc.2004.10.052
1
High-Throughput Screening and Identification of Potent Broad-Spectrum Inhibitors of Coronaviruses
Coronaviruses (CoVs) act as cross-species viruses and have the potential to spread rapidly into new host species and cause epidemic diseases. Despite the severe public health threat of severe acute respiratory syndrome coronavirus and Middle East respiratory syndrome CoV (MERS-CoV), there are currently no drugs available for their treatment; therefore, broad-spectrum inhibitors of emerging and endemic CoVs are urgently needed. To search for effective inhibitory agents, we performed high-throughput screening (HTS) of a 2,000-compound library of approved drugs and pharmacologically active compounds using the established genetically engineered human CoV OC43 (HCoV-OC43) strain expressing Renilla luciferase (rOC43-ns2Del-Rluc) and validated the inhibitors using multiple genetically distinct CoVs in vitro. We screened 56 hits from the HTS data and validated 36 compounds in vitro using wild-type HCoV-OC43. Furthermore, we identified seven compounds (lycorine, emetine, monensin sodium, mycophenolate mofetil, mycophenolic acid, phenazopyridine, and pyrvinium pamoate) as broad-spectrum inhibitors according to their strong inhibition of replication by four CoVs in vitro at low-micromolar concentrations. Additionally, we found that emetine blocked MERS-CoV entry according to pseudovirus entry assays and that lycorine protected BALB/c mice against HCoV-OC43-induced lethality by decreasing viral load in the central nervous system. This represents the first demonstration of in vivo real-time bioluminescence imaging to monitor the effect of lycorine on the spread and distribution of HCoV-OC43 in a mouse model. These results offer critical information supporting the development of an effective therapeutic strategy against CoV infection. IMPORTANCE Currently, there is no approved therapy to treat coronavirus infection; therefore, broad-spectrum inhibitors of emerging and endemic CoVs are needed. Based on our high-throughput screening assay using a compound library, we identified seven compounds with broad-spectrum efficacy against the replication of four CoVs in vitro. Additionally, one compound (lycorine) was found to protect BALB/c mice against HCoV-OC43-induced lethality by decreasing viral load in the central nervous system. This inhibitor might offer promising therapeutic possibilities for combatting novel CoV infections in the future.
ueaoipgl
ueaoipgl
2019-03-27
10.1128/jvi.00023-19
2
Potent human monoclonal antibodies against SARS CoV, Nipah and Hendra viruses.
BACKGROUND Recently, several potently neutralizing fully human monoclonal antibodies (hmAbs) targeting the severe acute respiratory syndrome-associated coronavirus (SARS CoV) S glycoprotein, and the G glycoprotein of the paramyxoviruses Hendra virus (HeV) and Nipah virus (NiV) have been discovered [corrected]. OBJECTIVE To examine, compare and contrast the functional characteristics of hmAbs with the potential for prophylaxis and treatment of diseases caused by SARS CoV, HeV and NiV. METHODS A review of relevant literature. RESULTS/CONCLUSIONS Structural, functional and biochemical analyses [corrected] have provided insights into the molecular mechanisms of receptor recognition and antibody neutralization, and suggested that these antibodies alone or in combination could fight the viruses' heterogeneity and mutability, which is a major problem in the development of effective therapeutic agents against viruses, including therapeutic antibodies.
uemu8zd8
uemu8zd8
2009
10.1517/14712590902763755
3
SARS — beginning to understand a new virus
The 114-day epidemic of the severe acute respiratory syndrome (SARS) swept 29 countries, affected a reported 8,098 people, left 774 patients dead and almost paralysed the Asian economy. Aggressive quarantine measures, possibly aided by rising summer temperatures, successfully terminated the first eruption of SARS and provided at least a temporal break, which allows us to consolidate what we have learned so far and plan for the future. Here, we review the genomics of the SARS coronavirus (SARS-CoV), its phylogeny, antigenic structure, immune response and potential therapeutic interventions should the SARS epidemic flare up again.
ueqlhgn0
ueqlhgn0
2003
10.1038/nrmicro775
0.5
ChAdOx1 nCoV-19 vaccination prevents SARS-CoV-2 pneumonia in rhesus macaques
Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) emerged in December 20191,2 and is responsible for the COVID-19 pandemic3. Vaccines are an essential countermeasure urgently needed to control the pandemic4. Here, we show that the adenovirus-vectored vaccine ChAdOx1 nCoV-19, encoding the spike protein of SARS-CoV-2, is immunogenic in mice, eliciting a robust humoral and cell-mediated response. This response was not Th2 dominated, as demonstrated by IgG subclass and cytokine expression profiling. A single vaccination with ChAdOx1 nCoV-19 induced a humoral and cellular immune response in rhesus macaques. We observed a significantly reduced viral load in bronchoalveolar lavage fluid and respiratory tract tissue of vaccinated animals challenged with SARS-CoV-2 compared with control animals, and no pneumonia was observed in vaccinated rhesus macaques. Importantly, no evidence of immune-enhanced disease following viral challenge in vaccinated animals was observed. ChAdOx1 nCoV-19 is currently under investigation in a phase I clinical trial. Safety, immunogenicity and efficacy against symptomatic PCR-positive COVID-19 disease will now be assessed in randomised controlled human clinical trials.
uexahhdr
uexahhdr
2020-05-13
10.1101/2020.05.13.093195
3.5
COVID_MTNet: COVID-19 Detection with Multi-Task Deep Learning Approaches
COVID-19 is currently one the most life-threatening problems around the world. The fast and accurate detection of the COVID-19 infection is essential to identify, take better decisions and ensure treatment for the patients which will help save their lives. In this paper, we propose a fast and efficient way to identify COVID-19 patients with multi-task deep learning (DL) methods. Both X-ray and CT scan images are considered to evaluate the proposed technique. We employ our Inception Residual Recurrent Convolutional Neural Network with Transfer Learning (TL) approach for COVID-19 detection and our NABLA-N network model for segmenting the regions infected by COVID-19. The detection model shows around 84.67% testing accuracy from X-ray images and 98.78% accuracy in CT-images. A novel quantitative analysis strategy is also proposed in this paper to determine the percentage of infected regions in X-ray and CT images. The qualitative and quantitative results demonstrate promising results for COVID-19 detection and infected region localization.
uez654q2
uez654q2
2020-04-07
2
Bird Flu, SARS and Beyond
In the politically sensitive year of 1997, Hong Kong experienced an outbreak of avian flu when the deadly H5N1 virus unprecedentedly jumped the species barrier from chickens and infected human beings. Hong Kong decided to slaughter over a million chickens, and the virus was stopped in its tracks. In 2003, Hong Kong was the epicenter of the SARS pandemic, which originated in Guangdong province. The Faculty of Medicine played key roles in both instances, with its Microbiology Department successfully identifying a novel coronavirus as being responsible for SARS. Hong Kong learned from its experience and took action to combat the emergence of new infectious diseases. Such vigilance paid off in 2009, when swine flu swept the world, and in 2013, when a novel avian flu H7N9 emerged in China.
ugc7ce21
ugc7ce21
2018-03-15
10.1007/978-981-10-6316-9_14
2.5
Interferon-γ and interleukin-4 downregulate expression of the SARS coronavirus receptor ACE2 in Vero E6 cells
Abstract Interferons (IFNs) inhibit severe acute respiratory syndrome coronavirus (SARS-CoV) replication and might be valuable for SARS treatment. In this study, we demonstrate that treatment of Vero E6 cells with interleukin-4 (IL-4) decreased the susceptibility of these cells to SARS-CoV infection. In contrast to IFNs, IL-4 did not show antiviral activity when administered immediately after SARS-CoV infection, suggesting that IL-4 acts early during the SARS-CoV replication cycle. Indeed, binding of recombinant SARS-CoV spike protein to Vero E6 cells was diminished on cells treated with IL-4, but also on cells exposed to IFN-γ. Consistent with these observations, IL-4 and IFN-γ downregulated cell surface expression of angiotensin-converting enzyme 2 (ACE2), the SARS-CoV receptor. Besides diminished ACE2 cell surface expression, ACE2 mRNA levels were also decreased after treatment with these cytokines. These findings suggest that IL-4 and IFN-γ inhibit SARS-CoV replication partly through downregulation of ACE2.
uhwg608l
uhwg608l
2006-09-30
10.1016/j.virol.2006.06.011
2
Neutralizing antibody responses to SARS-CoV-2 in a COVID-19 recovered patient cohort and their implications
Background The COVID-19 pandemic caused by SARS-CoV-2 coronavirus threatens global public health. Currently, neutralizing antibodies (NAbs) versus this virus are expected to correlate with recovery and protection of this disease. However, the characteristics of these antibodies have not been well studied in association with the clinical manifestations in patients. Methods Plasma collected from 175 COVID-19 recovered patients with mild symptoms were screened using a safe and sensitive pseudotyped-lentiviral-vector-based neutralization assay. Spike-binding antibody in plasma were determined by ELISA using RBD, S1, and S2 proteins of SARS-CoV-2. The levels and the time course of SARS-CoV-2-specific NAbs and the spike-binding antibodies were monitored at the same time. Findings SARS-CoV-2 NAbs were unable to cross-reactive with SARS-CoV virus. SARS-CoV-2-specific NAbs were detected in patients from day 10-15 after the onset of the disease and remained thereafter. The titers of NAb among these patients correlated with the spike-binding antibodies targeting S1, RBD, and S2 regions. The titers of NAbs were variable in different patients. Elderly and middle-age patients had significantly higher plasma NAb titers (P<0.0001) and spike-binding antibodies (P=0.0003) than young patients. Notably, among these patients, there were ten patients whose NAb titers were under the detectable level of our assay (ID50: < 40); while in contrast, two patients, showed very high titers of NAb, with ID50 :15989 and 21567 respectively. The NAb titers were positive correlated with plasma CRP levels but negative correlated with the lymphocyte counts of patients at the time of admission, indicating an association between humoral response and cellular immune response. Interpretation The variations of SARS-CoV-2 specific NAbs in recovered COVID-19 patients may raise the concern about the role of NAbs on disease progression. The correlation of NAb titers with age, lymphocyte counts, and blood CRP levels suggested that the interplay between virus and host immune response in coronavirus infections should be further explored for the development of effective vaccine against SARS-CoV-2 virus. Furthermore, titration of NAb is helpful prior to the use of convalescent plasma for prevention or treatment. Funding Ministry of Science and Technology of China, National Natural Science Foundation of China, Shanghai Municipal Health Commission, and Chinese Academy of Medical Sciences
uifnjio5
uifnjio5
2020-04-06
10.1101/2020.03.30.20047365
1
Overview of lethal human coronaviruses
Coronavirus infections of multiple origins have spread to date worldwide, causing severe respiratory diseases. Seven coronaviruses that infect humans have been identified: HCoV-229E, HCoV-OC43, HCoV-NL63, HCoV-HKU1, SARS-CoV, MERS-CoV, and SARS-CoV-2. Among them, SARS-CoV and MERS-CoV caused outbreaks in 2002 and 2012, respectively. SARS-CoV-2 (COVID-19) is the most recently discovered. It has created a severe worldwide outbreak beginning in late 2019, leading to date to over 4 million cases globally. Viruses are genetically simple, yet highly diverse. However, the recent outbreaks of SARS-CoV and MERS-CoV, and the ongoing outbreak of SARS-CoV-2, indicate that there remains a long way to go to identify and develop specific therapeutic treatments. Only after gaining a better understanding of their pathogenic mechanisms can we minimize viral pandemics. This paper mainly focuses on SARS-CoV, MERS-CoV, and SARS-CoV-2. Here, recent studies are summarized and reviewed, with a focus on virus–host interactions, vaccine-based and drug-targeted therapies, and the development of new approaches for clinical diagnosis and treatment.
ujq9mxk7
ujq9mxk7
2020-06-10
10.1038/s41392-020-0190-2
4
Cross-reactive antibody response between SARS-CoV-2 and SARS-CoV infections
The World Health Organization has recently declared the ongoing outbreak of COVID-19, which is caused by a novel coronavirus SARS-CoV-2, as pandemic. There is currently a lack of knowledge in the antibody response elicited from SARS-CoV-2 infection. One major immunological question is concerning the antigenic differences between SARS-CoV-2 and SARS-CoV. We address this question by using plasma from patients infected by SARS-CoV-2 or SARS-CoV, and plasma obtained from infected or immunized mice. Our results show that while cross-reactivity in antibody binding to the spike protein is common, cross-neutralization of the live viruses is rare, indicating the presence of non-neutralizing antibody response to conserved epitopes in the spike. Whether these non-neutralizing antibody responses will lead to antibody-dependent disease enhancement needs to be addressed in the future. Overall, this study not only addresses a fundamental question regarding the antigenicity differences between SARS-CoV-2 and SARS-CoV, but also has important implications in vaccine
ukz73rp2
ukz73rp2
2020-03-17
10.1101/2020.03.15.993097
3.5
Broad-spectrum coronavirus antiviral drug discovery
Introduction: The highly pathogenic coronaviruses severe acute respiratory syndrome coronavirus (SARS-CoV) and Middle East respiratory syndrome coronavirus (MERS-CoV) are lethal zoonotic viruses that have emerged into human populations these past 15 years. These coronaviruses are associated with novel respiratory syndromes that spread from person-to-person via close contact, resulting in high morbidity and mortality caused by the progression to Acute Respiratory Distress Syndrome (ARDS). Areas covered: The risks of re-emergence of SARS-CoV from bat reservoir hosts, the persistence of MERS-CoV circulation, and the potential for future emergence of novel coronaviruses indicate antiviral drug discovery will require activity against multiple coronaviruses. In this review, approaches that antagonize viral nonstructural proteins, neutralize structural proteins, or modulate essential host elements of viral infection with varying levels of efficacy in models of highly pathogenic coronavirus disease are discussed. Expert opinion: Treatment of SARS and MERS in outbreak settings has focused on therapeutics with general antiviral activity and good safety profiles rather than efficacy data provided by cellular, rodent, or nonhuman primate models of highly pathogenic coronavirus infection. Based on lessons learned from SARS and MERS outbreaks, lack of drugs capable of pan-coronavirus antiviral activity increases the vulnerability of public health systems to a highly pathogenic coronavirus pandemic.
unnrflmr
unnrflmr
2019-03-08
10.1080/17460441.2019.1581171
0.5
Prioritisation of potential anti-SARS-CoV-2 drug repurposing opportunities based on ability to achieve adequate target site concentrations derived from their established human pharmacokinetics
Many papers are emerging that describe the in vitro antiviral activity of drugs that may be repurposed for therapy or chemoprophylaxis against SARS-CoV-2. However, no comprehensive evaluation of these molecules in the context of the achievable plasma pharmacokinetics after administration of approved doses and schedules to humans has been conducted. Moreover, most publications have focussed on 50% maximum effective concentrations (EC50), which may be an insufficiently robust indicator of antiviral activity because of marked differences in the slope of the concentration-response curve between drugs. Accordingly, in vitro anti-SARS-CoV-2 activity data was digitised from all available publications up to 13th April 2020 and used to recalculate an EC90 value for each drug. EC90 values were then expressed as a ratio to the achievable maximum plasma concentrations (Cmax) reported for each drug after administration of the approved dose to humans (Cmax/EC90 ratio). Only 14 of the analysed drugs achieved a Cmax/EC90 ratio above 1 meaning that plasma Cmax concentrations exceeded those necessary to inhibit 90% of SARS-CoV-2 replication. A more in-depth assessment of these drugs demonstrated that only nitazoxanide, nelfinavir, tipranavir (boosted with ritonavir) and sulfadoxine achieved plasma concentrations above their anti-SARS-CoV-2 activity across their entire approved dosing interval at their approved human dose. For all drugs reported, the unbound lung to plasma tissue partition coefficient (KpUlung) was also simulated and used along with reported Cmax and fraction unbound in plasma to derive a lung Cmax/EC50 as a better indicator of potential human efficacy (lung Cmax/EC90 ratio was also calculable for a limited number of drugs). Using this parameter hydroxychloroquine, chloroquine, mefloquine, atazanavir (boosted with ritonavir), tipranavir (boosted with ritonavir), ivermectin, azithromycin and lopinavir (boosted with ritonavir) were all predicted to achieve lung concentrations over 10-fold higher than their reported EC50. This analysis was not possible for nelfinavir because insufficient data were available to calculate KpUlung but nitozoxanide and sulfadoxine were also predicted to exceed their reported EC50 by 3.1- and 1.5-fold in lung, respectively. The antiviral activity data reported to date is of variable quality and conducted under different conditions by different investigators. However, this analysis has prioritised candidates with the best chance for success in therapy or chemoprevention of Covid-19 based upon the currently available in vitro activity and human plasma pharmacokinetic data. Future studies should focus on EC90 values and discuss findings in the context of achievable exposures in humans, especially within target compartments such as the lung, in order to maximise the potential for success of proposed human clinical trials.
untuy1e6
untuy1e6
2020-04-22
10.1101/2020.04.16.20068379
2
Anti-infective immunoadhesins from plants
Immunoadhesins are recombinant proteins that combine the ligand-binding region of a receptor or adhesion molecule with immunoglobulin constant domains. All FDA-approved immunoadhesins are designed to modulate the interaction of a human receptor with its normal ligand, such as Etanercept (Enbrel(®)), which interferes with the binding of tumour necrosis factor (TNF) to the TNF-alpha receptor and is used to treat inflammatory diseases such as rheumatoid arthritis. Like antibodies, immunoadhesins have long circulating half-lives, are readily purified by affinity-based methods and have the avidity advantages conferred by bivalency. Immunoadhesins that incorporate normal cellular receptors for viruses or bacterial toxins hold great, but as yet unrealized, potential for treating infectious disease. As decoy receptors, immunoadhesins have potential advantages over pathogen-targeted monoclonal antibodies. Planet Biotechnology has specialized in developing anti-infective immunoadhesins using plant expression systems. An immunoadhesin incorporating the cellular receptor for anthrax toxin, CMG2, potently blocks toxin activity in vitro and protects animals against inhalational anthrax. An immunoadhesin based on the receptor for human rhinovirus, ICAM-1, potently blocks infection of human cells by one of the major causes of the common cold. An immunoadhesin targeting the MERS coronavirus is in an early stage of development. We describe here the unique challenges involved in designing and developing immunoadhesins targeting infectious diseases in the hope of inspiring further research into this promising class of drugs.
unwxxt8s
unwxxt8s
2015-08-04
10.1111/pbi.12441
3.5
Wildlife trade, consumption and conservation awareness in southwest China
Commercial trade in wildlife is the major cause of species endangerment and a main threat to animal welfare in China and its neighboring countries. Driven by consumptive use for food and traditional medicine, the large volume of both legal and illegal trade in wildlife has caused great destruction to ecosystems and pushed many species to the brink of extinction. Data gathered from trading hubs at ports, boundary markets, city markets and stores, indicates the large amount of wildlife traded in the region of Guangxi, Yunnan and Qinghai provinces, a direct result of the numerous wildlife markets available. In a survey distributed in various trading places, while about half of the respondents agreed that wildlife should be protected, 60% of them had consumed wildlife at some point in the last 2 years. The results also indicated that law and regulation on wildlife trade control is insufficient. Wildlife trade controls are very limited because of bias on the utilization of wildlife as a natural resource to be exploited by the government agencies. The survey also shows that the current situation of wildlife consumption in key cities in China is serious, especially the consumption for food. The main consumption groups in China are male and young people with high education levels and good incomes. The key in public awareness publicity and education is to give them more information on the negative impacts of wildlife consumption and knowledge of protection.
uokqn2u8
uokqn2u8
2008-03-21
10.1007/s10531-008-9358-8
5
Fast Identification of Possible Drug Treatment of Coronavirus Disease-19 (COVID-19) through Computational Drug Repurposing Study
[Image: see text] The recent outbreak of novel coronavirus disease-19 (COVID-19) calls for and welcomes possible treatment strategies using drugs on the market. It is very efficient to apply computer-aided drug design techniques to quickly identify promising drug repurposing candidates, especially after the detailed 3D structures of key viral proteins are resolved. The virus causing COVID-19 is SARS-CoV-2. Taking advantage of a recently released crystal structure of SARS-CoV-2 main protease in complex with a covalently bonded inhibitor, N3 (Liu et al., 10.2210/pdb6LU7/pdb), I conducted virtual docking screening of approved drugs and drug candidates in clinical trials. For the top docking hits, I then performed molecular dynamics simulations followed by binding free energy calculations using an end point method called MM-PBSA-WSAS (molecular mechanics/Poisson–Boltzmann surface area/weighted solvent-accessible surface area; Wang, Chem. Rev.2019, 119, 947831244000; Wang, Curr. Comput.-Aided Drug Des.2006, 2, 287; Wang; HouJ. Chem. Inf. Model., 2012, 52, 119922497310). Several promising known drugs stand out as potential inhibitors of SARS-CoV-2 main protease, including carfilzomib, eravacycline, valrubicin, lopinavir, and elbasvir. Carfilzomib, an approved anticancer drug acting as a proteasome inhibitor, has the best MM-PBSA-WSAS binding free energy, −13.8 kcal/mol. The second-best repurposing drug candidate, eravacycline, is synthetic halogenated tetracycline class antibiotic. Streptomycin, another antibiotic and a charged molecule, also demonstrates some inhibitory effect, even though the predicted binding free energy of the charged form (−3.8 kcal/mol) is not nearly as low as that of the neutral form (−7.9 kcal/mol). One bioactive, PubChem 23727975, has a binding free energy of −12.9 kcal/mol. Detailed receptor–ligand interactions were analyzed and hot spots for the receptor–ligand binding were identified. I found that one hot spot residue, His41, is a conserved residue across many viruses including SARS-CoV, SARS-CoV-2, MERS-CoV, and hepatitis C virus (HCV). The findings of this study can facilitate rational drug design targeting the SARS-CoV-2 main protease.
upcsvjuo
upcsvjuo
2020-04-21
10.1021/acs.jcim.0c00179
4.5
Neutralization of SARS-CoV-2 spike pseudotyped virus by recombinant ACE2-Ig
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged in Wuhan, China, at the end of 2019, and there are currently no specific antiviral treatments or vaccines available. SARS-CoV-2 has been shown to use the same cell entry receptor as SARS-CoV, angiotensin-converting enzyme 2 (ACE2). In this report, we generate a recombinant protein by connecting the extracellular domain of human ACE2 to the Fc region of the human immunoglobulin IgG1. A fusion protein containing an ACE2 mutant with low catalytic activity is also used in this study. The fusion proteins are then characterized. Both fusion proteins have a high binding affinity for the receptor-binding domains of SARS-CoV and SARS-CoV-2 and exhibit desirable pharmacological properties in mice. Moreover, the fusion proteins neutralize virus pseudotyped with SARS-CoV or SARS-CoV-2 spike proteins in vitro. As these fusion proteins exhibit cross-reactivity against coronaviruses, they have potential applications in the diagnosis, prophylaxis, and treatment of SARS-CoV-2.
uqwtq4vx
uqwtq4vx
2020-04-24
10.1038/s41467-020-16048-4
5
CLINICAL VIGNETTES
urk7fe34
urk7fe34
2004-04-16
10.1111/j.1525-1497.2004.s1006_1.x
4.5
Ribavirin, Remdesivir, Sofosbuvir, Galidesivir, and Tenofovir against SARS-CoV-2 RNA dependent RNA polymerase (RdRp): A molecular docking study
AIMS: A new human coronavirus (HCoV), which has been designated SARS-CoV-2, began spreading in December 2019 in Wuhan City, China causing pneumonia called COVID-19. The spread of SARS-CoV-2 has been faster than any other coronaviruses that have succeeded in crossing the animal-human barrier. There is concern that this new virus will spread around the world as did the previous two HCoVs-Severe Acute Respiratory Syndrome (SARS) and Middle East Respiratory Syndrome (MERS)-each of which caused approximately 800 deaths in the years 2002 and 2012, respectively. Thus far, 11,268 deaths have been reported from the 258,842 confirmed infections in 168 countries. MAIN METHODS: In this study, the RNA-dependent RNA polymerase (RdRp) of the newly emerged coronavirus is modeled, validated, and then targeted using different anti-polymerase drugs currently on the market that have been approved for use against various viruses. KEY FINDINGS: The results suggest the effectiveness of Ribavirin, Remdesivir, Sofosbuvir, Galidesivir, and Tenofovir as potent drugs against SARS-CoV-2 since they tightly bind to its RdRp. In addition, the results suggest guanosine derivative (IDX-184), Setrobuvir, and YAK as top seeds for antiviral treatments with high potential to fight the SARS-CoV-2 strain specifically. SIGNIFICANCE: The availability of FDA-approved anti-RdRp drugs can help treat patients and reduce the danger of the mysterious new viral infection COVID-19. The drugs mentioned above can tightly bind to the RdRp of the SARS-CoV-2 strain and thus may be used to treat the disease. No toxicity measurements are required for these drugs since they were previously tested prior to their approval by the FDA.
urpianz6
urpianz6
2020
4
Emergency and Urgent Orthopaedic Surgeries in non covid patients during the COVID 19 pandemic: Perspective from India
OBJECTIVES: To Evaluate the results and the protocols of our Institution for 18 Emergency and Urgent Non Covid Surgeries during the Covid 19 Pandemic METHODS: 18 patients underwent Emergency and Urgent Orthopaedic Surgeries at institution. The Protocol was Screening, Segregation, Selection, Isolation, theatre modification, and Online Follow. RESULTS: Two adverse events including, one death and one intensive care admission due to underlying morbidity were recorded. Average Hospital stay was 2.5 days with no patients becoming covid positive at follow up. CONCLUSION: Strict Surgical protocols need to be followed for surgery during the Covid19 pandemic.
urr9oqfc
urr9oqfc
2020-05-12
10.1016/j.jor.2020.05.012
3.5
Docking study of chloroquine and hydroxychloroquine interaction with RNA binding domain of nucleocapsid phospho-protein - an in silico insight into the comparative efficacy of repurposing antiviral drugs
Recent outbreak of novel Coronavirus disease () pandemic around the world is associated with severe acute respiratory syndrome. The death toll associated with the pandemic is increasing day by day. SARS-CoV-2 is an enveloped virus and its N terminal domain (NTD) of Nucleocapsid protein (N protein) binds to the viral (+) sense RNA and results in virus ribonucleoprotien complex, essential for the virus replication. The N protein is composed of a serine-rich linker region sandwiched between NTD and C terminal (CTD). These terminals play a role in viral entry and its processing post entry. The NTD of SARS-CoV-2 N protein forms orthorhombic crystals and binds to the viral genome. Therefore, there is always a quest to target RNA binding domain of nucleocapsid phosphoprotein (NTD-N-protein which in turn may help in controlling diseases caused by SARS-CoV-2 in humans. The role of Chloroquine and Hydroxychloroquine as potential treatments for is still under debate globally because of some side effects associated with it. This study involves the In silico interactions of Chloroquine and Hydroxychloroquine with the NTD-N-protein of SARS-CoV-2. With the help of various computational methods, we have explored the potential role of both of these antiviral drugs for the treatment of patients by comparing the efficacy of both of the drugs to bind to NTD-N-protein. In our research Hydroxychloroquine exhibited potential inhibitory effects of NTD-N-protein with binding energy -7.28 kcal/mol than Chloroquine (-6.30 kcal/mol) at SARS-CoV-2 receptor recognition of susceptible cells. The outcomes of this research strongly appeal for in vivo trials of Hydroxychloroquine for the patients infected with . Furthermore, the recommended doses of Hydroxychloroquine may reduce the chances of catching to the healthcare workers and staff who are in contact with or delivering direct care to coronavirus patients as long as they have not been diagnosed with . We further hypothesize that the comparative NTD-N-protein -drug docking interactions may help to understand the comparative efficacy of other candidate repurposing drugs until discovery of a proper vaccine.Communicated by Ramaswamy H. Sarma.
us0qpw0m
us0qpw0m
2020
4
Is there an ideal animal model for SARS?
The outbreak of severe acute respiratory syndrome (SARS) in 2003 was controlled by public health measures at a time when specific interventions such as antiviral drugs, vaccines and immunotherapy were not available. Since then, several animal models have been developed for the study of SARS and, although no model replicates the human disease in all aspects, the use of animal models for SARS has led to the establishment of several important principles for vaccine and immunotherapy. Consistency and reproducibility of findings in a given model must be demonstrated to establish the superiority of one model over others. Here, we suggest aspects of an ideal animal model for studies of SARS pathogenesis and vaccine development and present our assessment of the strengths and limitations of the current animal models for SARS.
uurvoa1o
uurvoa1o
2006-07-31
10.1016/j.tim.2006.05.007
0.5
Rapid isolation of potent SARS-CoV-2 neutralizing antibodies and protection in a small animal model
The development of countermeasures to prevent and treat COVID-19 is a global health priority. In under 7 weeks, we enrolled a cohort of SARS-CoV-2-recovered participants, developed neutralization assays to interrogate serum and monoclonal antibody responses, adapted our high throughput antibody isolation, production and characterization pipeline to rapidly screen over 1000 antigen-specific antibodies, and established an animal model to test protection. We report multiple highly potent neutralizing antibodies (nAbs) and show that passive transfer of a nAb provides protection against high-dose SARS-CoV-2 challenge in Syrian hamsters. The study suggests a role for nAbs in prophylaxis, and potentially therapy, of COVID-19. The nAbs define protective epitopes to guide vaccine design.
uuwvmltw
uuwvmltw
2020-05-15
10.1101/2020.05.11.088674
3.5
Noninvasive ventilation in acute respiratory failure due to H1N1 influenza: A word of caution
uvv06b4n
uvv06b4n
2011
10.4103/0970-2113.80340
4
Connecting hydroxychloroquine in vitro antiviral activity to in vivo concentration for prediction of antiviral effect: a critical step in treating COVID-19 patients
Translation of in vitro antiviral activity to the in vivo setting is crucial to identify potentially effective dosing regimens of hydroxychloroquine. In vitro EC50/EC90 values for hydroxychloroquine should be compared to the in vivo free extracellular tissue concentration, which is similar to the free plasma hydroxychloroquine concentration.
uwa3ylgn
uwa3ylgn
2020-05-21
10.1093/cid/ciaa623
5
Data-mining to build a knowledge representation store for clinical decision support. Studies on curation and validation based on machine performance in multiple choice medical licensing examinations
Abstract Extracting medical knowledge by structured data mining of many medical records and from unstructured data mining of natural language source text on the Internet will become increasingly important for clinical decision support. Output from these sources can be transformed into large numbers of elements of knowledge in a Knowledge Representation Store (KRS), here using the notation and to some extent the algebraic principles of the Q-UEL Web-based universal exchange and inference language described previously, rooted in Dirac notation from quantum mechanics and linguistic theory. In a KRS, semantic structures or statements about the world of interest to medicine are analogous to natural language sentences seen as formed from noun phrases separated by verbs, prepositions and other descriptions of relationships. A convenient method of testing and better curating these elements of knowledge is by having the computer use them to take the test of a multiple choice medical licensing examination. It is a venture which perhaps tells us almost as much about the reasoning of students and examiners as it does about the requirements for Artificial Intelligence as employed in clinical decision making. It emphasizes the role of context and of contextual probabilities as opposed to the more familiar intrinsic probabilities, and of a preliminary form of logic that we call presyllogistic reasoning.
uwbmox8a
uwbmox8a
2016-06-01
10.1016/j.compbiomed.2016.02.010
1
Review of Viral Testing (Polymerase Chain Reaction) and Antibody/Serology Testing for Severe Acute Respiratory Syndrome-Coronavirus-2 for the Intensivist
OBJECTIVE: As the severe acute respiratory syndrome-coronavirus-2 pandemic develops, assays to detect the virus and infection caused by it are needed for diagnosis and management. To describe to clinicians how each assay is performed, what each assay detects, and the benefits and limitations of each assay. DATA SOURCES: Published literature and internet. STUDY SELECTION: As well done, relevant and recent as possible. DATA EXTRACTION: Sources were read to extract data from them. DATA SYNTHESIS: Was synthesized by all coauthors. CONCLUSIONS: Available assays test for current or previous severe acute respiratory syndrome-coronavirus-2 infection. Nucleic acid assays such as quantitative, or real-time, polymerase chain reaction and loop-mediated isothermal amplification are ideal for acute diagnosis with polymerase chain reaction testing remaining the “gold standard” to diagnose acute infection by severe acute respiratory syndrome-coronavirus-2, specifically the presence of viral RNA. Assays that detect serum antibodies can theoretically diagnose both acute and remote infection but require time for the patient to develop immunity and may detect nonspecific antibodies. Antibody assays that quantitatively measure neutralizing antibodies are needed to test efficacy of convalescent plasma therapy but are more specialized.
uxeaaski
uxeaaski
2020-06-15
10.1097/cce.0000000000000154
5
Perspectives on advancing preventative medicine through vaccinology at the comparative veterinary, human and conservation medicine interface: Not missing the opportunities
Vaccination has historically and remains one of the most cost-effective and safest forms of medicine today. Along with basic understanding of germ theory and sanitation, vaccination, over the past 50 years, has transformed lives and economies in both rich and poor countries by its direct impact on human and animal life—resulting in the eradication of small pox, huge reductions in the burden of previously common human and animal diseases such as polio, typhoid, measles in human medicine and contagious bovine pleuropneumonia, foot-and-mouth disease, screwworm and hog cholera and the verge of eradicating brucellosis, tuberculosis, and pseudorabies in veterinary medicine. In addition vaccination along with other animal production changes has provided the ability to produce otherwise unaffordable animal protein and animal health worldwide. The landscape however on which vaccinology was discovered and applied over the past 200 years, even in the past 10 years has and is undergoing continuous change. For vaccination as a public health tool to have its greatest impacts in human and veterinary medicine, these great medical sciences will have to come together, policy-relevant science for sustainable conservation in developing and developed countries needs to become the norm and address poverty (including lack of basic health care) in communities affected by conservation, and to consider costs and benefits (perceived or not) affecting the well-being of all stakeholders, from the local to the multinational. The need to return to and/or develop new education-based models for turning the tide from the heavily return-on-investment therapeutic era of the last century into one where the investment into the preventative sciences and medicine lead to sustainable cultural and cost-effective public health and economic changes of the future is never more evident than today. The new complex problems of the new millennium will require new educational models that train para- and professional people for thinking and solving complex inter-related biological, ecological, public-, political/economic problems. The single profession that is best positioned to impact vaccinology is Veterinary Medicine. It’s melding with human medicine and their role in future comparative and conservation-based programs will be critical to the successful application of vaccines into the 21st century.
uy0f7f2o
uy0f7f2o
2008-11-18
10.1016/j.vaccine.2008.07.094
1.5
Can Bioactive Lipids Inactivate Coronavirus (COVID-19)?
SARS-CoV-2, SARS and MERS are all enveloped viruses that can cause acute respiratory syndrome. Arachidonic acid (AA) and other unsaturated fatty acids (especially eicosapentaenoic acd, EPA and docosahexaenoic acid DHA) are known to inactivate enveloped viruses and inhibit proliferation of various microbial organisms. The pro-inflammatory metabolites of AA and EPA such as prostaglandins, leukotrienes and thromboxanes induce inflammation whereas lipoxins, resolvins, protectins and maresins derived from AA, EPA and DHA not only suppress inflammation but also enhance would healing and augment phagocytosis of macrophages and other immunocytes and decrease microbial load. In view of these actions, it is suggested that AA and other unsaturated fatty acids and their metabolites may serve as endogenous anti-viral compounds and their deficiency may render humans susceptible to SARS-CoV-2, SARS and MERS and other similar viruses’ infections. Hence, oral or intravenous administration of AA and other unsaturated fatty acids may aid in enhancing resistance and recovery from SARS-CoV-2, SARS and MERS infections.
uyu2buo1
uyu2buo1
2020-03-27
10.1016/j.arcmed.2020.03.004
1.5
Transmission parameters of the A/H1N1 (2009) influenza virus pandemic: a review
Please cite this paper as: Boëlle P‐Y et al. (2011) Transmission parameters of the A/H1N1 (2009) influenza virus pandemic: a review. Influenza and Other Respiratory Viruses 5(5), 306–316. Background The new influenza virus A/H1N1 (2009), identified in mid‐2009, rapidly spread over the world. Estimating the transmissibility of this new virus was a public health priority. Methods We reviewed all studies presenting estimates of the serial interval or generation time and the reproduction number of the A/H1N1 (2009) virus infection. Results Thirteen studies documented the serial interval from household or close‐contact studies, with overall mean 3 days (95% CI: 2·4, 3·6); taking into account tertiary transmission reduced this estimate to 2·6 days. Model‐based estimates were more variable, from 1·9 to 6 days. Twenty‐four studies reported reproduction numbers for community‐based epidemics at the town or country level. The range was 1·2–3·1, with larger estimates reported at the beginning of the pandemic. Accounting for under‐reporting in the early period of the pandemic and limiting variation because of the choice of the generation time interval, the reproduction number was between 1·2 and 2·3 with median 1·5. Discussion The serial interval of A/H1N1 (2009) flu was typically short, with mean value similar to the seasonal flu. The estimates of the reproduction number were more variable. Compared with past influenza pandemics, the median reproduction number was similar (1968) or slightly smaller (1889, 1918, 1957).
uywz5nqw
uywz5nqw
2011-03-31
10.1111/j.1750-2659.2011.00234.x
1
The diagnostic evaluation of Convolutional Neural Network (CNN) for the assessment of chest X-ray of patients infected with COVID-19
Abstract Introduction : The main target of COVID-19 is the lungs where it may cause pneumonia in severely ill patients. Chest X- ray is an important diagnostic test to assess the lung for the damaging effects of COVID-19. Many other microbial pathogens can also cause damage to lungs leading to pneumonia but there are certain radiological features which can favor the diagnosis of pneumonia caused by COVID-19. With the rising number of cases of COVID-19, it would be imperative to develop computer programs which may assist the health professionals in the prevailing scenario. Materials & Methods : A total of two hundred and seventy eight (278) images of chest X-rays have been assessed by applying ResNet-50 convolutional neural network architectures in the present study. The digital images were acquired from the public repositories provided by University of Montreal and National Institutes of Health. These digital images of Chest X-rays were divided into three groups labeled as normal, pneumonia and COVID- 19. The third group contains digital images of chest X-rays of patients diagnosed with COVID-19 infection while the second group contains images of lung with pneumonia caused by other pathogens. Results : The radiological images included in the data set are 89 images of lungs with COVID-19 infection, 93 images of lungs without any radiological abnormality and 96 images of patient with pneumonia caused by other pathogens. In this data set, 80% of the images were employed for training, and 20% for testing. A pre-trained (on ImageNet data set) ResNet-50 architecture was used to diagnose the cases of COVID-19 infections on lung Xray images. The analysis of the data revealed that computer vision based program achieved diagnostic accuracy of 98.18 %, and F1-score of 98.19. Conclusion : The performance of convolutional neural network regarding the differentiation of pulmonary changes caused by COVID-19 from the other type of pneumonias on digital images of the chest X- rays is excellent and it may be an extremely useful adjunct tool for the health professionals. Keywords: COVID-19, Convolutional Neural Network, ResNet-50
v02fs28k
v02fs28k
2020-03-31
10.1101/2020.03.26.20044610
1
Review of Bats and SARS
Bats have been identified as a natural reservoir for an increasing number of emerging zoonotic viruses, including henipaviruses and variants of rabies viruses. Recently, we and another group independently identified several horseshoe bat species (genus Rhinolophus) as the reservoir host for a large number of viruses that have a close genetic relationship with the coronavirus associated with severe acute respiratory syndrome (SARS). Our current research focused on the identification of the reservoir species for the progenitor virus of the SARS coronaviruses responsible for outbreaks during 2002–2003 and 2003–2004. In addition to SARS-like coronaviruses, many other novel bat coronaviruses, which belong to groups 1 and 2 of the 3 existing coronavirus groups, have been detected by PCR. The discovery of bat SARS-like coronaviruses and the great genetic diversity of coronaviruses in bats have shed new light on the origin and transmission of SARS coronaviruses.
v08cs51n
v08cs51n
2006-12-16
10.3201/eid1212.060401
1.5
Inappropriate modeling of chronic and complex disorders: How to reconsider the approach in the context of predictive, preventive and personalized medicine, and translational medicine
Preclinical investigations such as animal modeling make the basis of clinical investigations and subsequently patient care. Predictive, preventive, and personalized medicine (PPPM) not only highlights a patient-tailored approach by choosing the right medication, the right dose at the right time point but it as well essentially requires early identification, by the means of complex and state-of-the-art technologies of unmanifested pathological processes in an individual, in order to deliver targeted prevention early enough to reverse manifestation of a pathology. Such an approach can be achieved by taking into account clinical, pathological, environmental, and psychosocial characteristics of the patients or an individual who has a suboptimal health condition. Inappropriate modeling of chronic and complex disorders, in this context, may diminish the predictive potential and slow down the development of PPPM and consequently modern healthcare. Therefore, it is the common goal of PPPM and translational medicine to find the solution for the problem we present in our review. Both, translational medicine and PPPM in parallel, essentially need accurate surrogates for misleading animal models. This study was therefore undertaken to provide shreds of evidence against the validity of animal models. Limitations of current animal models and drug development strategies based on animal modeling have been systematically discussed. Finally, a variety of potential surrogates have been suggested to change the unfavorable situation in medical research and consequently in healthcare.
v3vxhqi4
v3vxhqi4
2019-07-31
10.1007/s13167-019-00176-z
1.5
Persistence of intestinal SARS-CoV-2 infection in patients with COVID-19 leads to re-admission after pneumonia resolved
Abstract The current reports of COVID-19 focus on the respiratory system, but intestinal infections caused by SARS-CoV-2 are also worthy of attention. Here we report persistence of intestinal SARS-CoV-2 infection in three cases with COVID-19 leads to re-admission after pneumonia resolved.
v4c1lgpd
v4c1lgpd
2020-04-27
10.1016/j.ijid.2020.04.063
3.5
COVID-19: review on latest available drugs and therapies against SARS-CoV-2. Coagulation and inflammation cross-talking
SARS-CoV-2 is the agent responsible for COVID-19. The infection can be dived into three phases: mild infection, the pulmonary phase and the inflammatory phase. Treatment options for the pulmonary phase include: Hydroxychloroquine, Remdesivir, Lopinavir/Ritonavir. The inflammatory phase includes therapeutic options like Tocilizumab, Anakinra, Baricitinib, Eculizumab, Emapalumab and Heparin. Human clinical trials are starting to show some results, in some cases like that of Remdesivir these are controversial. Coagulopathy is a common complication in severe cases, inflammation and coagulation are intertwined and cross-talking between these two responses is known to happen. A possible amplification of this cross-talking is suggested to be implicated in the severe cases that show both a cytokine storm and coagulopathy.
v59dpmuu
v59dpmuu
2020-06-20
10.1016/j.virusres.2020.198070
5
Animal models for SARS and MERS coronaviruses
The emergence of Severe Acute Respiratory Syndrome coronavirus (SARS-CoV) and Middle East Respiratory Syndrome coronavirus (MERS-CoV), two strains of animal coronaviruses that crossed the species barrier to infect and cause severe respiratory infections in humans within the last 12 years, have taught us that coronaviruses represent a global threat that does not recognize international borders. We can expect to see other novel coronaviruses emerge in the future. An ideal animal model should reflect the clinical signs, viral replication and pathology seen in humans. In this review, we present factors to consider in establishing an animal model for the study of novel coronaviruses and compare the different animal models that have been employed to study SARS-CoV and MERS-CoV.
v5sya5to
v5sya5to
2015-08-01
10.1016/j.coviro.2015.06.009
1
In Vitro Antiviral Activity and Projection of Optimized Dosing Design of Hydroxychloroquine for the Treatment of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2)
BACKGROUND: The Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) first broke out in Wuhan (China) and subsequently spread worldwide. Chloroquine has been sporadically used in treating SARS-CoV-2 infection. Hydroxychloroquine shares the same mechanism of action as chloroquine, but its more tolerable safety profile makes it the preferred drug to treat malaria and autoimmune conditions. We propose that the immunomodulatory effect of hydroxychloroquine also may be useful in controlling the cytokine storm that occurs late-phase in critically ill SARS-CoV-2 infected patients. Currently, there is no evidence to support the use of hydroxychloroquine in SARS-CoV-2 infection. METHODS: The pharmacological activity of chloroquine and hydroxychloroquine was tested using SARS-CoV-2 infected Vero cells. Physiologically-based pharmacokinetic models (PBPK) were implemented for both drugs separately by integrating their in vitro data. Using the PBPK models, hydroxychloroquine concentrations in lung fluid were simulated under 5 different dosing regimens to explore the most effective regimen whilst considering the drug's safety profile. RESULTS: Hydroxychloroquine (EC50=0.72 µM) was found to be more potent than chloroquine (EC50=5.47 µM) in vitro. Based on PBPK models results, a loading dose of 400 mg twice daily of hydroxychloroquine sulfate given orally, followed by a maintenance dose of 200 mg given twice daily for 4 days is recommended for SARS-CoV-2 infection, as it reached three times the potency of chloroquine phosphate when given 500 mg twice daily 5 days in advance. CONCLUSIONS: Hydroxychloroquine was found to be more potent than chloroquine to inhibit SARS-CoV-2 in vitro.
v5t5htqz
v5t5htqz
2020
5
Severe acute respiratory syndrome coronavirus 3C-like protease-induced apoptosis
The pathogenesis of severe acute respiratory syndrome-associated coronavirus (SARS-CoV) is an important issue for the treatment and prevention of severe acute respiratory syndrome. Recently, SARS-CoV has been demonstrated to induce cell apoptosis in Vero-E6 cells. The possible role of SARS-CoV 3C-like protease (3CL(pro)) in virus-induced apoptosis is characterized in this study. Growth arrest and apoptosis via caspase-3 and caspase-9 activities were demonstrated in SARS-CoV 3CL(pro)-expressing human promonocyte cells. The fluorescence intensity of dihydrorhodamine 123 staining indicated that cellular reactive oxygen species were markedly increased in SARS-CoV 3CL(pro)-expressing cells. Moreover, in vivo signalling pathway assay indicated that 3CL(pro) increased the activation of the nuclear factor-kappa B-dependent reporter, but inhibited activator protein-1-dependent transcription. This finding is likely to be responsible for virus-induced apoptotic signalling.
v6kw8xsh
v6kw8xsh
2006-04-01
10.1111/j.1574-695x.2006.00045.x
2
Concerns for activated breathing control (ABC) with breast cancer in the era of COVID-19: Maximizing infection control while minimizing heart dose
v6yrr39c
v6yrr39c
2020-04-01
10.1016/j.adro.2020.03.009
1
Mesenchymal Stem Cell Infusion Shows Promise for Combating Coronavirus (COVID-19)- Induced Pneumonia
A new study published by the journal Aging & Disease reported that intravenous administration of clinical-grade human mesenchymal stem cells (MSCs) into patients with coronavirus disease 2019 (COVID-19) resulted in improved functional outcomes (Leng et al., Aging Dis, 11:216-228, 2020). This study demonstrated that intravenous infusion of MSCs is a safe and effective approach for treating patients with COVID-19 pneumonia, including elderly patients displaying severe pneumonia. COVID-19 is a severe acute respiratory illness caused by a new coronavirus named severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Currently, treating COVID-19 patients, particularly those afflicted with severe pneumonia, is challenging as no specific drugs or vaccines against SARS-CoV-2 are available. Therefore, MSC therapy inhibiting the overactivation of the immune system and promoting endogenous repair by improving the lung microenvironment after the SARS-CoV-2 infection found in this study is striking. Additional studies in a larger cohort of patients are needed to validate this therapeutic intervention further, however.
v73bsrwg
v73bsrwg
2020-03-09
10.14336/ad.2020.0301
2.5
The Role of Augmented Intelligence (AI) in Detecting and Preventing the Spread of Novel Coronavirus
v8k2898q
v8k2898q
2020-02-04
10.1007/s10916-020-1536-6
1.5
Controversies of renin–angiotensin system inhibition during the COVID-19 pandemic
The current COVID-19 pandemic is associated with unprecedented morbidity and mortality. Early reports suggested an association between disease severity and hypertension but did not account for sources of confounding. However, the responsible virus — SARS-CoV-2 — gains entry to host cells via angiotensin-converting enzyme 2 (ACE2), highlighting the need to understand the relationship between the virus and the renin–angiotensin system (RAS) and how this might be affected by RAS inhibitors.
va34p27b
va34p27b
2020-04-03
10.1038/s41581-020-0279-4
5
Tropism, replication competence, and innate immune responses of the coronavirus SARS-CoV-2 in human respiratory tract and conjunctiva: an analysis in ex-vivo and in-vitro cultures
BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged in December 2019, causing a respiratory disease (coronavirus disease 2019, COVID-19) of varying severity in Wuhan, China, and subsequently leading to a pandemic. The transmissibility and pathogenesis of SARS-CoV-2 remain poorly understood. We evaluate its tissue and cellular tropism in human respiratory tract, conjunctiva, and innate immune responses in comparison with other coronavirus and influenza virus to provide insights into COVID-19 pathogenesis. METHODS: We isolated SARS-CoV-2 from a patient with confirmed COVID-19, and compared virus tropism and replication competence with SARS-CoV, Middle East respiratory syndrome-associated coronavirus (MERS-CoV), and 2009 pandemic influenza H1N1 (H1N1pdm) in ex-vivo cultures of human bronchus (n=5) and lung (n=4). We assessed extrapulmonary infection using ex-vivo cultures of human conjunctiva (n=3) and in-vitro cultures of human colorectal adenocarcinoma cell lines. Innate immune responses and angiotensin-converting enzyme 2 expression were investigated in human alveolar epithelial cells and macrophages. In-vitro studies included the highly pathogenic avian influenza H5N1 virus (H5N1) and mock-infected cells as controls. FINDINGS: SARS-CoV-2 infected ciliated, mucus-secreting, and club cells of bronchial epithelium, type 1 pneumocytes in the lung, and the conjunctival mucosa. In the bronchus, SARS-CoV-2 replication competence was similar to MERS-CoV, and higher than SARS-CoV, but lower than H1N1pdm. In the lung, SARS-CoV-2 replication was similar to SARS-CoV and H1N1pdm, but was lower than MERS-CoV. In conjunctiva, SARS-CoV-2 replication was greater than SARS-CoV. SARS-CoV-2 was a less potent inducer of proinflammatory cytokines than H5N1, H1N1pdm, or MERS-CoV. INTERPRETATION: The conjunctival epithelium and conducting airways appear to be potential portals of infection for SARS-CoV-2. Both SARS-CoV and SARS-CoV-2 replicated similarly in the alveolar epithelium; SARS-CoV-2 replicated more extensively in the bronchus than SARS-CoV. These findings provide important insights into the transmissibility and pathogenesis of SARS-CoV-2 infection and differences with other respiratory pathogens. FUNDING: US National Institute of Allergy and Infectious Diseases, University Grants Committee of Hong Kong Special Administrative Region, China; Health and Medical Research Fund, Food and Health Bureau, Government of Hong Kong Special Administrative Region, China.
vaeh5z4z
vaeh5z4z
2020-05-07
10.1016/s2213-2600(20)30193-4
4.5
Molecular Modeling Evaluation of the Binding Effect of Ritonavir, Lopinavir and Darunavir to Severe Acute Respiratory Syndrome Coronavirus 2 Proteases
Three anti-HIV drugs, ritonavir, lopinavir and darunavir, might have therapeutic effect on coronavirus disease 2019 (COVID-19). In this study, the structure models of two severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) proteases, coronavirus endopeptidase C30 (CEP_C30) and papain like viral protease (PLVP), were built by homology modeling. Ritonavir, lopinavir and darunavir were then docked to the models, respectively, followed by energy minimization of the protease-drug complexes. In the simulations, ritonavir can bind to CEP_C30 most suitably, and induce significant conformation changes of CEP_C30; lopinavir can also bind to CEP_C30 suitably, and induce significant conformation changes of CEP_C30; darunavir can bind to PLVP suitably with slight conformation changes of PLVP. It is suggested that the therapeutic effect of ritonavir and lopinavir on COVID-19 may be mainly due to their inhibitory effect on CEP_C30, while ritonavir may have stronger efficacy; the inhibitory effect of darunavir on SARS-CoV-2 and its potential therapeutic effect may be mainly due to its inhibitory effect on PLVP.
vbgf50os
vbgf50os
2020-02-18
10.1101/2020.01.31.929695
2
Current and future therapeutical approaches for COVID-19
• COVID-19, an alarming pandemic outbreak of 2020. • Amelioration of the clinical understanding of COVID-19 and its potential targets. • Adapted clinical strategies based on merits and demerits of COVID-19 treatment. • Current clinical manifestations and the proposed prospects against COVID-19. Coronavirus 2019 (COVID-19), the WHO-classified novel coronavirus of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has rapidly become a global pandemic. To tackle both its spread and virulence, research is ongoing worldwide to develop an effective anti-COVID-19 drug or vaccine. In this review, we explore the clinical understanding and severity of COVID-19 emergence across the world, with a focus on China. We also discuss potential therapeutic targets, either host virus based, that could be used to tackle the COVID-19 outbreak.
vd2jptlm
vd2jptlm
2020-06-20
10.1016/j.drudis.2020.06.018
5
Effects of a SARS-associated coronavirus vaccine in monkeys
The causative agent of severe acute respiratory syndrome (SARS) has been identified as a new type of coronavirus. Here, we have investigated the ability of adenoviral delivery of codon-optimised SARS-CoV strain Urbani structural antigens spike protein S1 fragment, membrane protein, and nucleocapsid protein to induce virus-specific broad immunity in rhesus macaques. We immunised rhesus macaques intramuscularly with a combination of the three Ad5-SARS-CoV vectors or a control vector and gave a booster vaccination on day 28. The vaccinated animals all had antibody responses against spike protein S1 fragment and T-cell responses against the nucleocapsid protein. All vaccinated animals showed strong neutralising antibody responses to SARS-CoV infection in vitro. These results show that an adenoviral-based vaccine can induce strong SARS-CoV-specific immune responses in the monkey, and hold promise for development of a protective vaccine against the SARS causal agent.
vduk4asq
vduk4asq
2003-12-06
10.1016/s0140-6736(03)14962-8
3.5
The RBD Of The Spike Protein Of SARS-Group Coronaviruses Is A Highly Specific Target Of SARS-CoV-2 Antibodies But Not Other Pathogenic Human and Animal Coronavirus Antibodies
A new Severe Acute Respiratory Syndrome Coronavirus variant (SARS-CoV-2) that first emerged in late 2019 is responsible for a pandemic of severe respiratory illness. People infected with this highly contagious virus present with clinically inapparent, mild or severe disease. Currently, the presence of the virus in individual patients and at the population level is being monitored by testing symptomatic cases by PCR for the presence of viral RNA. There is an urgent need for SARS-CoV-2 serologic tests to identify all infected individuals, irrespective of clinical symptoms, to conduct surveillance and implement strategies to contain spread. As the receptor binding domain (RBD) of the viral spike (S) protein is poorly conserved between SARS-CoVs and other pathogenic human coronaviruses, the RBD represents a promising antigen for detecting CoV specific antibodies in people. Here we use a large panel of human sera (70 SARS-CoV-2 patients and 71 control subjects) and hyperimmune sera from animals exposed to zoonotic CoVs to evaluate the performance of the RBD as an antigen for accurate detection of SARS-CoV-2-specific antibodies. By day 9 after the onset of symptoms, the recombinant SARS-CoV-2 RBD antigen was highly sensitive (98%) and specific (100%) to antibodies induced by SARS-CoVs. We observed a robust correlation between levels of RBD binding antibodies and SARS-CoV-2 neutralizing antibodies in patients. Our results, which reveal the early kinetics of SARS-CoV-2 antibody responses, strongly support the use of RBD-based antibody assays for population-level surveillance and as a correlate of neutralizing antibody levels in people who have recovered from SARS-CoV-2 infections.
ve4ubnf5
ve4ubnf5
2020-05-10
10.1101/2020.05.06.20093377
3.5
Machine Learning Models Identify Inhibitors of SARS-CoV-2
With the ongoing SARS-CoV-2 pandemic there is an urgent need for the discovery of a treatment for the coronavirus disease (COVID-19). Drug repurposing is one of the most rapid strategies for addressing this need and numerous compounds have been selected for in vitro testing by several groups already. These have led to a growing database of molecules with in vitro activity against the virus. Machine learning models can assist drug discovery through prediction of the best compounds based on previously published data. Herein we have implemented several machine learning methods to develop predictive models from recent SARS-CoV-2 in vitro inhibition data and used them to prioritize additional FDA approved compounds for in vitro testing selected from our in-house compound library. From the compounds predicted with a Bayesian machine learning model, CPI1062 and CPI1155 showed antiviral activity in HeLa-ACE2 cell-based assays and represent potential repurposing opportunities for COVID-19. This approach can be greatly expanded to exhaustively virtually screen available molecules with predicted activity against this virus as well as a prioritization tool for SARS-CoV-2 antiviral drug discovery programs. The very latest model for SARS-CoV-2 is available at www.assaycentral.org.
vfd0su0w
vfd0su0w
2020-06-16
10.1101/2020.06.16.154765
5
Glecaprevir and Maraviroc are high-affinity inhibitors of SARS-CoV-2 main protease: possible implication in COVID-19 therapy
Due to the lack of efficient therapeutic options and clinical trial limitations, the FDA-approved drugs can be a good choice to handle Coronavirus disease (COVID-19). Many reports have enough evidence for the use of FDA-approved drugs which have inhibitory potential against target proteins of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). Here, we utilized a structure-based drug design approach to find possible drug candidates from the existing pool of FDA-approved drugs and checked their effectiveness against the SARS-CoV-2. We performed virtual screening of the FDA-approved drugs against the main protease (Mpro) of SARS-CoV-2, an essential enzyme, and a potential drug target. Using well-defined computational methods, we identified Glecaprevir and Maraviroc (MVC) as the best inhibitors of SARS-CoV-2 Mpro. Both drugs bind to the substrate-binding pocket of SARS-CoV-2 Mpro and form a significant number of non-covalent interactions. Glecaprevir and MVC bind to the conserved residues of substrate-binding pocket of SARS-CoV-2 Mpro. This work provides sufficient evidence for the use of Glecaprevir and MVC for the therapeutic management of COVID-19 after experimental validation and clinical manifestations.
vi6ya49u
vi6ya49u
2020
5
Target Virus or Target Ourselves for COVID-19 Drugs Discovery?-Lessons learned from anti-influenzas virus therapies
Abstract The COVID-19 pandemic, after it was reported in December 2019, is a highly contagious and now spreading to over 190 countries, causing a severe public health burden. Currently, there is no vaccine or specific drug to treat COVID-19, which is caused by a novel coronavirus, SARS-2-CoV. For this emergency, the FDA has approved Remdesivir and Hydroxychloroquine for treatment of COVID-19 as Emergency Use Authorization. However, even after this pandemic, COVID-19 may still have a chance to come back. Therefore, we need to come out with new strategies for drug discovery for combating COVID-19 in the future.
vijzfbyj
vijzfbyj
2020-03-31
10.1016/j.medidd.2020.100037
2
Isolation of SARS-CoV-2-related coronavirus from Malayan pangolins
The current outbreak of COVID-19 poses unprecedented challenges to global health1. The new coronavirus responsible for this outbreak-SARS-CoV-2-shares high sequence identity to SARS-CoV and a bat coronavirus, RaTG132. Although bats may be the reservoir host for a variety of coronaviruses3,4, it remains unknown whether SARS-CoV-2 has additional host species. Here we show that a coronavirus, which we name pangolin-CoV, isolated from a Malayan pangolin has 100%, 98.6%, 97.8% and 90.7% amino acid identity with SARS-CoV-2 in the E, M, N and S proteins, respectively. In particular, the receptor-binding domain of the S protein of pangolin-CoV is almost identical to that of SARS-CoV-2, with one difference in a noncritical amino acid. Our comparative genomic analysis suggests that SARS-CoV-2 may have originated in the recombination of a virus similar to pangolin-CoV with one similar to RaTG13. Pangolin-CoV was detected in 17 out of the 25 Malayan pangolins that we analysed. Infected pangolins showed clinical signs and histological changes, and circulating antibodies against pangolin-CoV reacted with the S protein of SARS-CoV-2. The isolation of a coronavirus from pangolins that is closely related to SARS-CoV-2 suggests that these animals have the potential to act as an intermediate host of SARS-CoV-2. This newly identified coronavirus from pangolins-the most-trafficked mammal in the illegal wildlife trade-could represent a future threat to public health if wildlife trade is not effectively controlled.
vimbhox4
vimbhox4
2020
4.5
Chapter 33 Animal Models of Human Viral Diseases
Abstract As the threat of exposure to emerging and reemerging viruses within a naïve population increases, it is vital that the basic mechanisms of pathogenesis and immune response be thoroughly investigated. Recent outbreaks of Middle East respiratory syndrome corona virus, Ebola virus, Chikungunya virus, and Zika virus illustrate the emerging threats that are encountered. By utilizing animal models in this endeavor, the host response to viruses can be studied in a more complex and integrated context to identify novel drug targets, and assess the efficacy and safety of new products rapidly. This is especially true in the advent and implementation of the FDA animal rule. Although no one animal model is able to recapitulate all aspects of human disease, understanding the current limitations allows for a more targeted experimental design. Important facets to consider prior to an animal study are route of viral exposure, species of animal, biomarkers of disease, and a humane endpoint. This chapter covers the current animal models for medically important human viruses, and demonstrates where the gaps in knowledge exist.
vk4lt83x
vk4lt83x
2017-12-31
10.1016/b978-0-12-809468-6.00033-4
1
The characteristics of hDPP4 transgenic mice subjected to aerosol MERS coronavirus infection via an animal nose‐only exposure device
BACKGROUND: Middle East respiratory syndrome coronavirus (MERS‐CoV), which is not fully understood in regard to certain transmission routes and pathogenesis and lacks specific therapeutics and vaccines, poses a global threat to public health. METHODS: To simulate the clinical aerosol transmission route, hDPP4 transgenic mice were infected with MERS‐CoV by an animal nose‐only exposure device and compared with instillation‐inoculated mice. The challenged mice were observed for 14 consecutive days and necropsied on days 3, 5, 7, and 9 to analyze viral load, histopathology, viral antigen distribution, and cytokines in tissues. RESULTS: MERS‐CoV aerosol‐infected mice with an incubation period of 5‐7 days showed weight loss on days 7‐11, obvious lung lesions on day 7, high viral loads in the lungs on days 3‐9 and in the brain on days 7‐9, and 60% survival. MERS‐CoV instillation‐inoculated mice exhibited clinical signs on day 1, obvious lung lesions on days 3‐5, continuous weight loss, 0% survival by day 5, and high viral loads in the lungs and brain on days 3‐5. Viral antigen and high levels of proinflammatory cytokines and chemokines were detected in the aerosol and instillation groups. Disease, lung lesion, and viral replication progressions were slower in the MERS‐CoV aerosol‐infected mice than in the MERS‐CoV instillation‐inoculated mice. CONCLUSION: hDPP4 transgenic mice were successfully infected with MERS‐CoV aerosols via an animal nose‐only exposure device, and aerosol‐ and instillation‐infected mice simulated the clinical symptoms of moderate diffuse interstitial pneumonia. However, the transgenic mice exposed to aerosol MERS‐CoV developed disease and lung pathology progressions that more closely resembled those observed in humans.
vkjcheaz
vkjcheaz
2019-10-30
10.1002/ame2.12088
1
The FDA- approved gold drug Auranofin inhibits novel coronavirus (SARS-COV-2) replication and attenuates inflammation in human cells
SARS-COV-2 has recently emerged as a new public health threat. Herein, we report that the FDA-approved gold drug, auranofin, inhibits SARS-COV-2 replication in human cells at low micro molar concentration. Treatment of cells with auranofin resulted in a 95% reduction in the viral RNA at 48 hours after infection. Auranofin treatment dramatically reduced the expression of SARS-COV-2-induced cytokines in human cells. These data indicate that auranofin could be a useful drug to limit SARS-CoV-2 infection and associated lung injury due to its anti-viral, anti-inflammatory and anti-ROS properties. Auranofin has a well-known toxicity profile and is considered safe for human use.
vm0k7hfx
vm0k7hfx
2020-04-14
10.1101/2020.04.14.041228
4
Molecular docking and binding mode analysis of selected FDA approved drugs against COVID-19 selected key protein targets: An effort towards drug repurposing to identify the combination therapy to combat COVID-19
The emergence of COVID-19 has severely compromised the arsenal of antiviral and antibiotic drugs. Drug discovery is a multistep process with a high failure rate, high cost and it takes approximately 10-12 years for the development of new molecules into the clinical candidate. On the other side, drug repurposing also called old drugs for new uses, is an attractive alternative approach for a new application of marketed FDA approved or investigational drugs. In the current pandemic situation raised due to COVID-19, repurposing of existing FDA approved drugs are emerging as the first line of the treatment. The causative viral agent of this highly contagious disease and acute respiratory syndrome coronavirus (SARS-CoV) shares high nucleotide similarity. Therefore, many existing viral targets are structurally expected to be similar to SARS-CoV and likely to be inhibited by the same compounds. Here, we selected three viral key proteins based on their vital role in viral life cycle: ACE2 (helps in entry into the human host), viral nonstructural proteins RNA-dependent RNA polymerase (RdRp) NSP12, and NSP16 which helps in replication, and viral latency (invasion from immunity). The FDA approved drugs chloroquine (CQ), hydroxychloroquine (HCQ), remdesivir (RDV) and arbidol (ABD) are emerging as promising agents to combat COVID-19. Our hypothesis behind the docking studies is to determine the binding affinities of these drugs and identify the key amino acid residues playing a key role in their mechanism of action. The docking studies were carried out through Autodock and online COVID-19 docking server. Further studies on a broad range of FDA approved drugs including few more protein targets, molecular dynamics studies, in-vitro and in-vivo biological evaluation are required to identify the combination therapy targeting various stages of the viral life cycle.
vnn7lp8w
vnn7lp8w
2020-04-14
2
Animal Models for the Study of Neuroimmunological Disease
The development and use of numerous animal models of human autoimmune diseases have provided important advances in our understanding of pathogenic mechanisms of disease and provided robust and reliable models to test novel therapeutic strategies. However, few preclinical studies of therapeutic treatments have demonstrated efficacy in the clinic, possibly because of the biological differences between humans and other animals. Although animal models of human disease are imperfect, it is important to understand the differences between the human disease and its animal models and to design experimental studies using animal models appropriately for the questions being asked. This review provides an overview of the currently used animal models of three human neuroimmunological diseases, multiple sclerosis, Guillain-Barré syndrome, and myasthenia gravis, as well as the advantages and disadvantages of each model and how they correlate or differ from their human counterpart.
vobslprh
vobslprh
2016-03-26
10.1007/978-4-431-55594-0_3
1
Systematic review and meta-analysis of predictive symptoms and comorbidities for severe COVID-19 infection
Background/introduction COVID−19, a novel coronavirus outbreak starting in China, is now a rapidly developing public health emergency of international concern. The clinical spectrum of COVID−19 disease is varied, and identifying factors associated with severe disease has been described as an urgent research priority. It has been noted that elderly patients with pre-existing comorbidities are more vulnerable to more severe disease. However, the specific symptoms and comorbidities that most strongly predict disease severity are unclear. We performed a systematic review and meta-analysis to identify the symptoms and comorbidities predictive of COVID−19 severity. Method This study was prospectively registered on PROSPERO. A literature search was performed in three databases (MEDLINE, EMBASE and Global Health) for studies indexed up to 5th March 2020. Two reviewers independently screened the literature and both also completed data extraction. Quality appraisal of studies was performed using the STROBE checklist. Random effects meta-analysis was performed for selected symptoms and comorbidities to identify those most associated with severe COVID−19 infection or ICU admission. Results Of the 2259 studies identified, 42 were selected after title and abstract analysis, and 7 studies (including 1813 COVID−19 patients) were chosen for inclusion. The ICU group were older (62.4 years) compared to the non-ICU group (46 years), with a significantly higher proportion of males (67.2% vs. 57.1%, p=0.04). Dyspnoea was the only significant symptom predictive for both severe disease (pOR 3.70, 95% CI 1.83 − 7.46) and ICU admission (pOR 6.55, 95% CI 4.28 − 10.0). Notwithstanding the low prevalence of COPD in severe disease and ICU-admitted groups (4.5% and 9.7%, respectively), COPD was the most strongly predictive comorbidity for both severe disease (pOR 6.42, 95% CI 2.44 − 16.9) and ICU admission (pOR 17.8, 95% CI 6.56 − 48.2). Cardiovascular disease and hypertension were also strongly predictive for both severe disease and ICU admission. Those with CVD and hypertension were 4.4 (95% CI 2.64 − 7.47) and 3.7 (95% CI 2.22 − 5.99) times more likely to have an ICU admission respectively, compared to patients without the comorbidity. Conclusions Dyspnoea was the only symptom strongly predictive for both severe disease and ICU admission, and could be useful in guiding clinical management decisions early in the course of illness. When looking at ICU-admitted patients, who represent the more severe end of the spectrum of clinical severity, COPD patients are particularly vulnerable, and those with cardiovascular disease and hypertension are also at a high-risk of severe illness. To aid clinical assessment, risk stratification, efficient resource allocation, and targeted public health interventions, future research must aim to further define those at high-risk of severe illness with COVID−19.
vof63qat
vof63qat
2020-03-16
10.1101/2020.03.15.20035360
1
The Brain Retains: Nonhuman Primate Models for Pediatric HIV-1 in the CNS
PURPOSE OF REVIEW: Perinatal HIV-1 infection is associated with an increased risk for neurologic impairments. With limited access to clinical specimens, animal models could advance our understanding of pediatric central nervous system (CNS) disease and viral persistence. Here, we summarize current findings on HIV-1 CNS infection from nonhuman primate (NHP) models and discuss their implications for improving pediatric clinical outcomes. RECENT FINDINGS: SIV/SHIV can be found in the CNS of infant macaques within 48 h of challenge. Recent studies show an impermeable BBB during SIV infection, suggesting neuroinvasion in post-partum infection is likely not wholly attributed to barrier dysfunction. Histopathological findings reveal dramatic reductions in hippocampal neuronal populations and myelination in infected infant macaques, providing a link for cognitive impairments seen in pediatric cases. Evidence from humans and NHPs support the CNS as a functional latent reservoir, harbored in myeloid cells that may require unique eradication strategies. Studies in NHP models are uncovering early events, causes, and therapeutic targets of CNS disease as well as highlighting the importance of age-specific studies that capture the distinct features of pediatric HIV-1 infection.
vogh5eys
vogh5eys
2020
3.5
A live attenuated severe acute respiratory syndrome coronavirus is immunogenic and efficacious in golden Syrian hamsters.
The immunogenicity and protective efficacy of a live attenuated vaccine consisting of a recombinant severe acute respiratory syndrome (SARS) coronavirus lacking the E gene (rSARS-CoV-DeltaE) were studied using hamsters. Hamsters immunized with rSARS-CoV-DeltaE developed high serum-neutralizing antibody titers and were protected from replication of homologous (SARS-CoV Urbani) and heterologous (GD03) SARS-CoV in the upper and lower respiratory tract. rSARS-CoV-DeltaE-immunized hamsters remained active following wild-type virus challenge, while mock-immunized hamsters displayed decreased activity. Despite being attenuated in replication in the respiratory tract, rSARS-CoV-DeltaE is an immunogenic and efficacious vaccine in hamsters.
vogj4jfz
vogj4jfz
2008
10.1128/jvi.00304-08
1
Evidence for RNA editing in the transcriptome of 2019 Novel Coronavirus
The 2019-nCoV outbreak has become a global health risk. Editing by host deaminases is an innate restriction process to counter viruses, and it is not yet known whether it operates against coronaviruses. Here we analyze RNA sequences from bronchoalveolar lavage fluids derived from two Wuhan patients. We identify nucleotide changes that may be signatures of RNA editing: Adenosine-to-Inosine changes from ADAR deaminases and Cytosine-to-Uracil changes from APOBEC ones. A mutational analysis of genomes from different strains of human-hosted Coronaviridae reveals patterns similar to the RNA editing pattern observed in the 2019-nCoV transcriptomes. Our results suggest that both APOBECs and ADARs are involved in Coronavirus genome editing, a process that may shape the fate of both virus and patient.
vorczspu
vorczspu
2020-03-03
10.1101/2020.03.02.973255
1
Crystal structure of Nsp15 endoribonuclease NendoU from SARS-CoV-2
Severe Acute Respiratory Syndrome coronavirus 2 (SARS-CoV-2) is rapidly spreading around the world. There is no existing vaccine or proven drug to prevent infections and stop virus proliferation. Although this virus is similar to human and animal SARS-CoVs and Middle East Respiratory Syndrome coronavirus (MERS-CoVs), the detailed information about SARS-CoV-2 proteins structures and functions is urgently needed to rapidly develop effective vaccines, antibodies, and antivirals. We applied high-throughput protein production and structure determination pipeline at the Center for Structural Genomics of Infectious Diseases to produce SARS-CoV-2 proteins and structures. Here we report two high-resolution crystal structures of endoribonuclease Nsp15/NendoU. We compare these structures with previously reported homologs from SARS and MERS coronaviruses.
vosgahs3
vosgahs3
2020
3.5
Anti-HCV, nucleotide inhibitors, repurposing against COVID-19
AIMS: A newly emerged Human Coronavirus (HCoV) is reported two months ago in Wuhan, China (COVID-19). Until today >2700 deaths from the 80,000 confirmed cases reported mainly in China and 40 other countries. Human to human transmission is confirmed for COVID-19 by China a month ago. Based on the World Health Organization (WHO) reports, SARS HCoV is responsible for >8000 cases with confirmed 774 deaths. Additionally, MERS HCoV is responsible for 858 deaths out of about 2500 reported cases. The current study aims to test anti-HCV drugs against COVID-19 RNA dependent RNA polymerase (RdRp). MATERIALS AND METHODS: In this study, sequence analysis, modeling, and docking are used to build a model for Wuhan COVID-19 RdRp. Additionally, the newly emerged Wuhan HCoV RdRp model is targeted by anti-polymerase drugs, including the approved drugs Sofosbuvir and Ribavirin. KEY FINDINGS: The results suggest the effectiveness of Sofosbuvir, IDX-184, Ribavirin, and Remidisvir as potent drugs against the newly emerged HCoV disease. SIGNIFICANCE: The present study presents a perfect model for COVID-19 RdRp enabling its testing in silico against anti-polymerase drugs. Besides, the study presents some drugs that previously proved its efficiency against the newly emerged viral infection.
vpgvb5s4
vpgvb5s4
2020
5
Molecular mimicry between SARS-CoV-2 and respiratory pacemaker neurons
vq2m4c8q
vq2m4c8q
2020-05-01
10.1016/j.autrev.2020.102556
4.5
Chapter 19 Advantages and Limitations of Commonly Used Nonhuman Primate Species in Research and Development of Biopharmaceuticals
Abstract Nonhuman primates (NHPs) have been used extensively during the past four decades for research and nonclinical development because they are close to humans in terms of genetics, anatomy, physiology, and immunology. They have been widely used in the development of infection models, leading to the generation of vaccines and drugs, as well as in the nonclinical pharmacologic and toxicologic assessment of biopharmaceuticals, especially in the fields of immunotherapy and oncology, despite the constant pressure to move to lower species. In many cases, NHPs are the only species that allows a correct risk assessment for humans. Nevertheless, limitations inherent to each species have to be considered before an investigation. This chapter shines some light on the respective interests and limitations of using cynomolgus monkeys, rhesus monkeys, and marmosets in medical research and nonclinical development, with a specific focus on reproduction and immunology.
vqws942c
vqws942c
2015-12-31
10.1016/b978-0-12-417144-2.00019-6
1.5
How bad will it get?
While the coronavirus death rate may be lower than some estimates, case numbers may be far higher, reports Debora MacKenzie
vskiyqop
vskiyqop
2020-02-15
10.1016/s0262-4079(20)30278-5
2
Focus on Receptors for Coronaviruses with Special Reference to Angiotensin-converting Enzyme 2 as a Potential Drug Target - A Perspective.
Coronaviruses (CoVs) possess an enveloped, single, positive-stranded RNA genome which encodes for four membrane proteins, namely spike (S), envelope (E), membrane (M) and nucleocapsid (N) proteins 3-5 [1]. With regard to pathogenicity, S proteins are essential for viral entry into host cells [2, 3]. SARS-CoV binds to the angiotensin-converting enzyme (ACE)2 which is present on nonimmune cells, such as respiratory and intestinal epithelial cells, endothelial cells, kidney cells (renal tubules) and cerebral neurons and immune cells, such as alveolar monocytes/macrophages [4-6]. Of note, CD209L or liver/lymph node special intercellular adhesion molecule-3-grabbing non-integrin (SIGN) and dendritic cell (DC)-SIGN are alternative receptors for SARS-CoV but with lower affinity [7]. In the case of MERS-CoV, S proteins bind to the host cell receptor dipeptidyl peptidase 4 (DPP4 or CD26) which is broadly expressed on intestinal, alveolar, renal, hepatic and prostate cells as well as on activated leukocytes [8]. Then, viruses replicate in target cells with release of mature virions, which, in turn, invade new target cells [9]. Evidence has been provided that SARSCoV proteins are cleaved into two subunits, S1 and S2, respectively, and the amino acids 318-510 of the S1 represent the receptor-binding domain (RBD) which binds to ACE2 [10, 11]. Quite importantly, in the context of RBD there is the receptor-binding motif (RBM) (amino acids 424- 494), which accounts for complete binding to ACE2 [11]. Moreover, by means of two residues at positions 479 and 487 RBD allows virus progression and tropism [10, 11]. In the case of MERSCoV, its RBM binds to DPP4 with residues 484-567, thus, suggesting that its RBD differs from that of SARS-CoV [12, 13]. In a very recent paper, Wan and associates [14] have investigated the receptor recognition by COVID-19 (a new term to indicate the 2019-nCoV in Wuhan) on the bases of structural studies. In this respect, the sequence of COVID-19 RBM is similar to that of SARSCoV, thus, implicating that ACE2 may represent the binding receptors for COVID-19. Furthermore, gln493 residue of COVID-19 RBM seems to allow interaction with human ACE2, thus, suggesting the ability of this virus to infect human cells. According, to Wan and associates structural analysis [14], COVID-19 binds to human ACE2 with a lesser efficiency than human SARS-CoV (2002) but with higher affinity than human SARS-CoV (2003). Furthermore, same authors predicted that a single mutation at the 501 position may enhance the COVID-19 RBD binding capacity to human ACE2 and this evolution should be monitored in infected patients [14]. These predictive findings by Wan and associates [14] are confirmed by two contemporary studies by Letko and Muster [15] and Peng and associates [16]. In particular, the report by Peng and associates [16], points out the possible origin of COVID-19 from bats [16]. From a pathogenic point of view, evidence has been provided that binding of S2 to ACE2 receptor leads to its down-regulation with subsequent lung damage in the course of SARS-CoV infection [17]. Down-regulation of ACE2 causes excessive production of angiotensin (ANG) II by the related enzyme ACE with stimulation of ANG type 1a receptor (AT1R) and enhanced lung vascular permeability [18]. In particular, same authors have reported that recombinant ACE2 could attenuate severe acute lung injury in mice [18]. Moreover, Battle and associates [19] also proposed to use already available recombinant ACE2 for intercepting COVID-19 and attenuating infection. In the previous paragraphs, the presence of ACE2 on immune cells has been pointed out and, by analogy to epithelial cells, this receptor may also be down-regulated following viral entry. Therefore, in CoV-infected animal models and in infected humans further investigations are required to clarify a possible reduced expression of ACE2 on immune cells. In fact, in the course of SARS-CoV infection, a number of immune disorders have been detected. Three reports have demonstrated the ability of CoV to inhibit interferon (IFN)- production in the course of SARS acting as IFN antagonist [20-22]. In senescent Balb/c mice, depletion of T lymphocytes is associated to more severe interstitial pneumonitis and delayed clearance of SARS-CoV, thus, suggesting a protective role played by these cells [23]. In this connection, both SARS-CoV and MERS-CoV have been shown to induce T cell apoptosis, thus, aggravating the clinical course of disease [24, 25]. Quite interestingly, memory CD8+ T cells specific for SARS-CoV M and N proteins have been detected up to 11 years post-infection [26]. As far as humoral immune responsiveness is concerned, evidence has been provided that S1 subunit from MERS-CoV is highly immunogenic in mice [27]. Moreover, monoclonal antibodies have been shown to be highly neutralizing against MERS-CoV replication and endowed with post exposure effectiveness in susceptible mice [28, 29]. Human neutralizing antibodies have also been isolated from a recovered patient, thus, suggesting the role of humoral immunity in the control of the persistence of CoV in the host [30]. In particular, IgG response occurs early in infection and its prolonged production may serve for virus clearance during recovery also in view of the absence of viremia in convalescent sera from SARS patients [31]. According to current literature, severity of COVID-19 infection correlates with lymphopenia and patients who died from COVID-19 had lower lymphocyte counts when compared to survivors [32, 33]. These data suggest that lymphocyte-mediated anti-viral activity is poorly effective against COVID-19. Despite lymphopenia, evidence for an exaggerate release of proinflammatory cytokines [interleukin (IL)-1 and IL-6] has been reported in the course acute respiratory syndrome in COVID19 infected patients, thus, aggravating the clinical course of disease [34]. As recently reported, during COVID-19 pandemic in both Italy and China higher frequency of fatalities have been observed in the frail elderly population with previous comorbidities [35]. It is well known that decline of immunity occurs in ageing and, therefore, COVID-19 may gain easier access to the respiratory tract in frail elderly patients [36]. There is evidence that ACE2 protects from severe acute lung failure and operates as a negative regulator of the renin-angiotensin system (RAS) [18, 37]. It is well known that ANG II via activation of the AT1R promotes detrimental effects on the host, such as, vasoconstriction, reactive oxygen species generation, inflammation and matrix remodelling [38]. ACE2 counterbalances the noxious effects exhibited by ANG II and AT1R via activation of AT2R which arrests cell growth, inflammation and fibrosis [39]. In this framework, Gurwitz [40] proposed to use AT1R blockers, such as losartan, as a potential treatment of COVID-19 infection. In fact, losartan as well as olmesartan, used for treating hypertension in patients, were able to increase ACE2 expression after 28 days treatment of rats with myocardial infarction [41]. Then, Gurwitz suggests to evaluate severity of symptoms in COVID-19 infected patients under previous chronic treatment with AT1R blockers in comparison to COVID-19 infected patients who did not take AT1R blockers [40]. Quite interestingly, 75% of aged COVID-19 infected patients admitted to Italian hospitals had hypertension [unpublished data]. However, the putative effects of ACE-2 down-regulation on the cardiovascular system in the course of COVID-19 pandemic need more intensive studies. Taken together, these evidences suggest that CoV-induced down-regulation of ACE2 activates RAS with collateral damage to organs, such as lungs, in the course of SARS-related pneumonia. Then, putative therapeutic measures aimed at increasing ACE2 levels on respiratory epithelial cells should be taken into serious consideration. Quite interestingly, over the past few years, three key papers have demonstrated the ability of a polyphenol, resveratrol (RES), to experimentally deactivate the RAS system in maternal and post-weaning high fat diet, arterial ageing and high fat diet, respectively [42-44]. In all these experimental models, RES led to an increase of ACE2 with reduction of organ damage, such as liver steatosis and aorta media thickness and decrease of adipose tissue mass, respectively. As far as the mechanism of action of RES is concerned, this polyphenol is able to activate sirtuin (Sirt)1 [45-47]. In turn, Sirt1 down-regulates AT1R expression via ACE2 up-regulation [43, 48]. Of importance, Lin and associates [48] have demonstrated the ability of RES to in vitro inhibit MERS-CoV infection of Vero E6 cells, thus, prolonging cell survival in virtue of an anti-apoptotic mechanism. These findings suggest a direct antiviral effect exerted by RES. It would be very interestingly to evaluate the direct effects of RES on COVID-19, in vitro. The data above discussed strongly suggest, that RES, as an activators of ACE2, should be investigated in animal models of CoV-induced severe pneumonia, also taking into account the antioxidant, anti-inflammatory and immunomodulating effects exerted by polyphenols [49]. Then, successful animal studies may pave the way for RES-based human trials in COVID-infected patients. Note added in proof During the reviewing process of this perspective other related papers have been published. Hanff and associates [50] have discussed the possible association between COVID-19-associated cardiovascular mortality and dysregulation of the Renin Angiotensin System (RAS). From a pharmacologic point of view, RAS inhibition leads to upregulation of ACE2, thus, attenuating acute respiratory syndrome and myocarditis in COVID-19-infected patients. Conversely, increase in ACE2 expression may facilitate the access into the host of COVID-19, thus, aggravating the clinical picture. Such a dilemma would be solved by clinical trials based on RAS blo
vslevssr
vslevssr
2020-04-27
10.2174/1871530320666200427112902
3.5
Monoclonal antibodies for the S2 subunit of spike of SARS-CoV cross-react with the newly-emerged SARS-CoV-2
The emergence of a novel coronavirus, SARS-CoV-2, at the end of 2019 has resulted in widespread human infections across the globe. While genetically distinct from SARS-CoV, the etiological agent that caused an outbreak of severe acute respiratory syndrome (SARS) in 2003, both coronaviruses exhibit receptor binding domain (RBD) conservation and utilize the same host cell receptor, angiotensin-converting enzyme 2 (ACE2), for virus entry. Therefore, it will be important to test the cross-reactivity of antibodies that have been previously generated against the surface spike (S) glycoprotein of SARS-CoV in order to aid research on the newly emerged SARS-CoV-2. Here, we show that an immunogenic domain in the S2 subunit of SARS-CoV S is highly conserved in multiple strains of SARS-CoV-2. Consistently, four murine monoclonal antibodies (mAbs) raised against this immunogenic SARS-CoV fragment were able to recognise the S protein of SARS-CoV-2 expressed in a mammalian cell line. Importantly, one of them (mAb 1A9) was demonstrated to detect S in SARS-CoV-2-infected cells. To our knowledge, this is the first study showing that mAbs targeting the S2 domain of SARS-CoV can cross-react with SARS-CoV-2 and this observation is consistent with the high sequence conservation in the S2 subunit. These cross-reactive mAbs may serve as tools useful for SARS-CoV-2 research as well as for the development of diagnostic assays for its associated coronavirus disease COVID-19.
vu7u11yk
vu7u11yk
2020-03-07
10.1101/2020.03.06.980037
3.5
Molecular docking studies on Jensenone from eucalyptus essential oil as a potential inhibitor of COVID 19 corona virus infection
COVID-19, a member of corona virus family is spreading its tentacles across the world due to lack of drugs at present. However, the main viral proteinase (Mpro/3CLpro) has recently been regarded as a suitable target for drug design against SARS infection due to its vital role in polyproteins processing necessary for coronavirus reproduction. The present in silico study was designed to evaluate the effect of Jensenone, a essential oil component from eucalyptus oil, on Mpro by docking study. In the present study, molecular docking studies were conducted by using 1-click dock and swiss dock tools. Protein interaction mode was calculated by Protein Interactions Calculator.The calculated parameters such as binding energy, and binding site similarity indicated effective binding of Jensenone to COVID-19 proteinase. Active site prediction further validated the role of active site residues in ligand binding. PIC results indicated that, Mpro/ Jensenone complexes forms hydrophobic interactions, hydrogen bond interactions and strong ionic interactions. Therefore, Jensenone may represent potential treatment potential to act as COVID-19 Mpro inhibitor. However, further research is necessary to investigate their potential medicinal use.
vufygjcc
vufygjcc
2020-04-01
2.5
MERS, SARS and other coronaviruses as causes of pneumonia
Human coronaviruses (HCoVs) have been considered to be relatively harmless respiratory pathogens in the past. However, after the outbreak of the severe acute respiratory syndrome (SARS) and emergence of the Middle East respiratory syndrome (MERS), HCoVs have received worldwide attention as important pathogens in respiratory tract infection. This review focuses on the epidemiology, pathogenesis and clinical characteristics among SARS‐coronaviruses (CoV), MERS‐CoV and other HCoV infections.
vuonolxg
vuonolxg
2017-10-20
10.1111/resp.13196
3.5
Can mathematical modelling solve the current Covid-19 crisis?
Since COVID-19 transmission started in late January, mathematical modelling has been at the forefront of shaping the decisions around different non-pharmaceutical interventions to confine its’ spread in the UK and worldwide. This Editorial discusses the importance of modelling in understanding Covid-19 spread, highlights different modelling approaches and suggests that while modelling is important, no one model can give all the answers.
vuyiqo64
vuyiqo64
2020-04-24
10.1186/s12889-020-08671-z
2.5
Virus Infection and Titration of SARS-CoV in Mouse Lung.
Two critical steps when investigating an animal model of a virus infection are consistently successfully infecting animals and accurately determining viral titers in tissue throughout the course of infection. Here we discuss in detail how to infect mice with SARS-CoV and then quantify the titer of virus in the lung.
vv0q3id5
vv0q3id5
2014
2.5
Bat SARS-Like WIV1 coronavirus uses the ACE2 of multiple animal species as receptor and evades IFITM3 restriction via TMPRSS2 activation of membrane fusion.
Diverse SARS-like coronaviruses (SL-CoVs) have been identified from bats and other animal species. Like SARS-CoV, some bat SL-CoVs, such as WIV1, also use angiotensin converting enzyme 2 (ACE2) from human and bat as entry receptor. However, whether these viruses can also use the ACE2 of other animal species as their receptor remains to be determined. We report herein that WIV1 has a broader tropism to ACE2 orthologs than SARS-CoV isolate Tor2. Among the 9 ACE2 orthologs examined, human ACE2 exhibited the highest efficiency to mediate the infection of WIV1 pseudotyped virus. The efficiency of human ACE2 to support WIV1 infectious entry is similar to that of mild SARS-CoV isolate GD03 and two civet cat SL-CoVs, but approximately 50% of that to SARS-CoV Tor2. Our findings thus imply that WIV1 has the potential to infect a wide range of wild animals and may directly jump to humans. We also showed that cell entry of WIV1 could be restricted by interferon induced transmembrane proteins (IFITMs). However, WIV1 could exploit the airway protease TMPRSS2 to activate spike-mediated membrane fusion and partially evade the IFITM3 restriction. Interestingly, we also found that amphotericin B, an antimycotic drug commonly used in clinic for patients with severe fungal infections, could enhance the infectious entry of SARS-CoVs and SL-CoVs by evading IFITM3-mediated restriction. Collectively, our findings further underscore the risk of exposure to animal SL-CoVs and highlight the vulnerability of patients who take amphotericin B to infection by SL-CoVs, including the most recently emerging severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).
vx0dl0iv
vx0dl0iv
2020-06-30
10.1080/22221751.2020.1787797
5
Why is it difficult to accurately predict the COVID-19 epidemic?
Since the COVID-19 outbreak in Wuhan City in December of 2019, numerous model predictions on the COVID-19 epidemics in Wuhan and other parts of China have been reported. These model predictions have shown a wide range of variations. In our study, we demonstrate that nonidentifiability in model calibrations using the confirmed-case data is the main reason for such wide variations. Using the Akaike Information Criterion (AIC) for model selection, we show that an SIR model performs much better than an SEIR model in representing the information contained in the confirmed-case data. This indicates that predictions using more complex models may not be more reliable compared to using a simpler model. We present our model predictions for the COVID-19 epidemic in Wuhan after the lockdown and quarantine of the city on January 23, 2020. We also report our results of modeling the impacts of the strict quarantine measures undertaken in the city after February 7 on the time course of the epidemic, and modeling the potential of a second outbreak after the return-to-work in the city.
vx2t7jgu
vx2t7jgu
2020-03-25
10.1016/j.idm.2020.03.001
1.5
Scutellaria baicalensis extract and baicalein inhibit replication of SARS-CoV-2 and its 3C-like protease in vitro
COVID-19 has become a global pandemic that threatens millions of people worldwide. There is an urgent call for developing effective drugs against the virus (SARS-CoV-2) causing this disease. The main protease of SARS-CoV-2, 3C-like protease (3CLpro), is highly conserved across coronaviruses and is essential for the maturation process of viral polyprotein. Scutellariae radix (Huangqin in Chinese), the root of Scutellaria baicalensis has been widely used in traditional Chinese medicine to treat viral infection related symptoms. The extracts of S. baicalensis have exhibited broad spectrum antiviral activities. We studied the anti-SARS-CoV-2 activity of S. baicalensis and its ingredient compounds. We found that the ethanol extract of S. baicalensis inhibits SARS-CoV-2 3CLpro activity in vitro and the replication of SARS-CoV-2 in Vero cells with an EC50 of 0.74 μg/ml. Among the major components of S. baicalensis, baicalein strongly inhibits SARS-CoV-2 3CLpro activity with an IC50 of 0.39 μM. We further identified four baicalein analogue compounds from other herbs that inhibit SARS-CoV-2 3CLpro activity at microM concentration. Our study demonstrates that the extract of S. baicalensis has effective anti-SARS-CoV-2 activity and baicalein and analogue compounds are strong SARS-CoV-2 3CLpro inhibitors.
vy0mvzeb
vy0mvzeb
2020-04-11
10.1101/2020.04.10.035824
2
Interaction of the spike protein RBD from SARS-CoV-2 with ACE2: Similarity with SARS-CoV, hot-spot analysis and effect of the receptor polymorphism
The spread of COVID-19 caused by the SARS-CoV-2 outbreak has been growing since its first identification in December 2019. The publishing of the first SARS-CoV-2 genome made a valuable source of data to study the details about its phylogeny, evolution, and interaction with the host. Protein-protein binding assays have confirmed that Angiotensin-converting enzyme 2 (ACE2) is more likely to be the cell receptor through which the virus invades the host cell. In the present work, we provide an insight into the interaction of the viral spike Receptor Binding Domain (RBD) from different coronavirus isolates with host ACE2 protein. By calculating the binding energy score between RBD and ACE2, we highlighted the putative jump in the affinity from a progenitor form of SARS-CoV-2 to the current virus responsible for COVID-19 outbreak. Our result was consistent with previously reported phylogenetic analysis and corroborates the opinion that the interface segment of the spike protein RBD might be acquired by SARS-CoV-2 via a complex evolutionary process rather than a progressive accumulation of mutations. We also highlighted the relevance of Q493 and P499 amino acid residues of SARS-CoV-2 RBD for binding to human ACE2 and maintaining the stability of the interface. Moreover, we show from the structural analysis that it is unlikely for the interface residues to be the result of genetic engineering. Finally, we studied the impact of eight different variants located at the interaction surface of ACE2, on the complex formation with SARS-CoV-2 RBD. We found that none of them is likely to disrupt the interaction with the viral RBD of SARS-CoV-2.
vy1obqyp
vy1obqyp
2020
4.5
Computers and viral diseases. Preliminary bioinformatics studies on the design of a synthetic vaccine and a preventative peptidomimetic antagonist against the SARS-CoV-2 (2019-nCoV, COVID-19) coronavirus
This paper concerns study of the genome of the Wuhan Seafood Market isolate believed to represent the causative agent of the disease COVID-19. This is to find a short section or sections of viral protein sequence suitable for preliminary design proposal for a peptide synthetic vaccine and a peptidomimetic therapeutic, and to explore some design possibilities. The project was originally directed towards a use case for the Q-UEL language and its implementation in a knowledge management and automated inference system for medicine called the BioIngine, but focus here remains mostly on the virus itself. However, using Q-UEL systems to access relevant and emerging literature, and to interact with standard publically available bioinformatics tools on the Internet, did help quickly identify sequences of amino acids that are well conserved across many coronaviruses including 2019-nCoV. KRSFIEDLLFNKV was found to be particularly well conserved in this study and corresponds to the region around one of the known cleavage sites of the SARS virus that are believed to be required for virus activation for cell entry. This sequence motif and surrounding variations formed the basis for proposing a specific synthetic vaccine epitope and peptidomimetic agent. The work can, nonetheless, be described in traditional bioinformatics terms, and readily reproduced by others, albeit with the caveat that new data and research into 2019-nCoV is emerging and evolving at an explosive pace. Preliminary studies using molecular modeling and docking, and in that context the potential value of certain known herbal extracts, are also described.
vydgwa8o
vydgwa8o
2020
5
Medication for COVID-19—an Overview of Approaches Currently Under Study
BACKGROUND: With the worldwide spread of SARS-CoV-2 infection, it is becoming increasingly urgent to develop a vaccine to prevent COVID-19, as well as effective drugs to treat it. METHODS: This article is based on a selective literature search in PubMed and ClinicalTrials.gov, followed by an assessment of the ongoing clinical trials that were revealed by the search. RESULTS: A number of substances have been found to prevent the reproduction of SARS-CoV-2 in vitro. These include virustatic agents that have already been approved for the treatment of other types of viral infection, as well as drugs that are currently used for entirely different purposes. High in vitro activity has been found for the nucleotide analogue remdesivir, for the antimalarial drug chloroquine, and for nitazoxanide, a drug used to treat protozoan infections. Because the virus enters human cells by way of the membrane-associated angiotensin converting enzyme 2 (ACE2), keeping the virus from docking to this receptor is a conceivable treatment approach. Transmembrane protease serine 2 (TMPRSS2) plays a role in the fusion of the virus with cells; inhibitors of this enzyme are known as well. The potential therapeutic efficacy and tolerability of these and other active substances remain to be investigated in clinical trials. At present, more than 80 trials on COVID-10 have already been registered with ClinicalTrials.gov. Some initial findings should already be available in late April 2020. CONCLUSION: Clinical trials are now indispensable in order to determine the true clinical benefits and risks of the substances that have been found to be active against SARS-CoV-2 in vitro. There is not yet any recommendation for the therapeutic use of any particular agent beyond standard supportive treatment.
vyeescn8
vyeescn8
2020-03-27
10.3238/arztebl.2020.0213
5
ISNI 2010 Abstracts: Tuesday October 26(th), 2010 10th Course of the European School of Neuroimmunology
vymlfsdn
vymlfsdn
2010-11-15
10.1016/j.jneuroim.2010.08.001
1
Control Strategies to Curtail Transmission of COVID-19
Recently, the World Health Organization has declared the outbreak of a severe acute respiratory syndrome coronavirius as a pandemic, and declared it as Public Health Emergency of International Concern. More than 6,83,536 positive cases and 32,139 deaths caused by coronavirus 2019 affecting 199 countries and territories. This pandemic can transform into an extremely destructive form if we still do not take it seriously. In this present study, we propose a generalized SEIR model of COVID-2019 to study the behavior of its transmission under different control strategies.
vytmwmoj
vytmwmoj
2020-04-07
10.1101/2020.04.04.20053173
1
In vitro evaluation of antiviral activity of single and combined repurposable drugs against SARS-CoV-2
In response to the current pandemic caused by the novel SARS-CoV-2, identifying and validating effective therapeutic strategies is more than ever necessary. We evaluated the in vitro antiviral activities of a shortlist of compounds, known for their cellular broad-spectrum activities, together with drugs that are currently under evaluation in clinical trials for COVID-19 patients. We report the antiviral effect of remdesivir, lopinavir, chloroquine, umifenovir, berberine and cyclosporine A in Vero E6 cells model of SARS-CoV-2 infection, with estimated 50% inhibitory concentrations of 0.99, 5.2, 1.38, 3.5, 10.6 and 3 μM, respectively. Virus-directed plus host-directed drug combinations were also investigated. We report a strong antagonism between remdesivir and berberine, in contrast with remdesivir/diltiazem, for which we describe high levels of synergy, with mean Loewe synergy scores of 12 and peak values above 50. Combination of host-directed drugs with direct acting antivirals underscore further validation in more physiological models, yet they open up interesting avenues for the treatment of COVID-19.
vzyrcmu4
vzyrcmu4
2020-07-15
10.1016/j.antiviral.2020.104878
5
Responding to the COVID-19 pandemic in complex humanitarian crises
w0ghfo3g
w0ghfo3g
2020-03-21
10.1186/s12939-020-01162-y
3.5
Nerve growth factor reduces amiloride‐sensitive Na(+) transport in human airway epithelial cells
Nerve growth factor (NGF) is overexpressed in patients with inflammatory lung diseases, including virus infections. Airway surface liquid (ASL), which is regulated by epithelial cell ion transport, is essential for normal lung function. No information is available regarding the effect of NGF on ion transport of airway epithelium. To investigate whether NGF can affect ion transport, human primary air‐interface cultured epithelial cells were placed in Ussing chambers to obtain transepithelial voltage (−7.1 ± 3.4 mV), short‐circuit current (I(sc), 5.9 ± 1.0 μA), and transepithelial resistance (750 Ω·cm(2)), and to measure responses to ion transport inhibitors. Amiloride (apical, 3.5 × 10(−5) mol/L) decreased I(sc) by 55.3%. Apically applied NGF (1 ng/mL) reduced I(sc) by 5.3% in 5 min; basolaterally applied NGF had no effect. The response to amiloride was reduced (41.6%) in the presence of NGF. K‐252a (10 nmol/L, apical) did not itself affect Na(+) transport, but it attenuated the NGF‐induced reduction in Na(+) transport, indicating the participation of the trkA receptor in the NGF‐induced reduction in Na(+) transport. PD‐98059 (30 μmol/L, apical and basolateral) did not itself affect Na(+) transport, but attenuated the NGF‐induced reduction in Na(+) transport, indicating that trkA activated the Erk 1/2 signaling cascade. NGF stimulated phosphorylation of Erk 1/2 and the β‐subunit of ENaC. K‐252a and PD‐98059 inhibited these responses. NGF had no effect on I(sc) in the presence of apical nystatin (50 μmol/L). These results indicate that NGF inhibits Na(+) transport through a trkA‐Erk 1/2‐activated signaling pathway linked to ENaC phosphorylation.
w0ju0dcr
w0ju0dcr
2014-07-17
10.14814/phy2.12073
4.5
Antibody therapies for the treatment of COVID-19
An outbreak of COVID-19, the disease caused by infection of the coronavirus SARS-CoV-2, that began in December 2019 in Wuhan, China has caused more than 2,990,559 confirmed human infections and 207,446 deaths as of April 27, 2020 (Coronavirus COVID-19 Global Cases by the Center for Systems Science and Engineering (CSSE) at Johns Hopkins University). Scientists are working quickly on multiple aspects of the pandemic. Genetic analyses are conducted to reveal the source and evolution of SARS-CoV-2, providing knowledge that can be used to contain it and to avoid future outbreaks. Epidemiological studies which incorporates lessons learned from outbreaks of previous related viral diseases can guide development of public health measures effective to contain the current and future outbreaks. Basic virology studies reveal viral structure and function. Pathology studies inform development of strategies to interfere with infection. COVID-19 prevention and treatment strategies are being developed in preclinical and clinical studies. Antibody-based therapy is one viable treatment option. Here, we discuss some of the most active areas of developing strategies to treat COVID-19, focusing on approaches to generate neutralizing antibodies against SARS-CoV-2 for prophylactic and therapeutic treatment of COVID-19. SIGNIFICANCE: Development of SARS-CoV-2 neutralizing antibodies with the desired efficacy and safety profile is a critical part of the toolbox of therapies for the treatment of COVID-19. We discuss in this review the current state of discovery and development of such antibodies.
w1ep0wq8
w1ep0wq8
2020-04-30
10.1093/abt/tbaa007
3.5
Repurposing of clinically developed drugs for treatment of Middle East respiratory syndrome coronavirus infection.
Outbreaks of emerging infections present health professionals with the unique challenge of trying to select appropriate pharmacologic treatments in the clinic with little time available for drug testing and development. Typically, clinicians are left with general supportive care and often untested convalescent-phase plasma as available treatment options. Repurposing of approved pharmaceutical drugs for new indications presents an attractive alternative to clinicians, researchers, public health agencies, drug developers, and funding agencies. Given the development times and manufacturing requirements for new products, repurposing of existing drugs is likely the only solution for outbreaks due to emerging viruses. In the studies described here, a library of 290 compounds was screened for antiviral activity against Middle East respiratory syndrome coronavirus (MERS-CoV) and severe acute respiratory syndrome coronavirus (SARS-CoV). Selection of compounds for inclusion in the library was dependent on current or previous FDA approval or advanced clinical development. Some drugs that had a well-defined cellular pathway as target were included. In total, 27 compounds with activity against both MERS-CoV and SARS-CoV were identified. The compounds belong to 13 different classes of pharmaceuticals, including inhibitors of estrogen receptors used for cancer treatment and inhibitors of dopamine receptor used as antipsychotics. The drugs identified in these screens provide new targets for in vivo studies as well as incorporation into ongoing clinical studies.
w3045qsc
w3045qsc
2014
10.1128/aac.03036-14
2.5
Immunoglobulin fragment F(ab’)(2) against RBD potently neutralizes SARS-CoV-2 in vitro
COVID-19, which is caused by the emerging human coronavirus SARS-CoV-2, has become a global pandemic that poses a serious threat to human health. To date, no vaccines or specific antiviral drugs have been approved for the treatment of this disease in clinic. Herein, therapeutic antibodies for SARS-CoV-2 were obtained from hyperimmune equine plasma. First, a recombinant SARS-CoV-2 spike protein receptor-binding domain (RBD) was obtained in gram-level quantities through high-cell density fermentation of Chinese hamster ovary cells. Then, the binding of the RBD to the SARS-CoV-2 receptor, human angiotensin-converting enzyme 2, was verified by several biochemical methods. The efficacy of the RBD in triggering antibody response in vivo was subsequently tested in both mice and equines, and the results showed that the RBD triggered high-titer neutralizing antibody production in vivo. Immunoglobulin F(ab’)(2) fragments were prepared from equine antisera via removal of the Fc region from the immunoglobulins. Finally, a neutralization test with live virus demonstrated that RBD-specific F(ab’)(2) inhibited SARS-CoV-2 with an EC(50) of 0.07 μg/ml and an EC(80) of 0.18 μg/ml, showing a potent inhibitory effect on SARS-CoV-2. These results highlight RBD-specific equine immunoglobulin F(ab’)(2) fragment as a candidate for the treatment of SARS-CoV-2.
w33nspfl
w33nspfl
2020-07-10
10.1016/j.antiviral.2020.104868
5
Analysis of the susceptibility to COVID-19 in pregnancy and recommendations on potential drug screening
To analyze the susceptibility of SARS-CoV-2 in pregnancy and the drugs that can be used to treat pregnancy with COVID-19, so as to provide evidence for drug selection in clinic. By reviewing the existing literature, this paper analyzes the susceptibility of pregnant women to virus, especially to SARS-CoV-2, from the aspects of anatomical, reproductive endocrine and immune changes during pregnancy and screens effective and fetal-safe treatments from the existing drugs. The anatomical structure of the respiratory system is changed during pregnancy, and the virus transmitted by droplets and aerosols is more easily inhaled by pregnant women and is difficult to remove. Furthermore, the prognosis is worse after infection when compared with non-pregnancy women. And changes in reproductive hormones and immune systems during pregnancy collectively make them more susceptible to certain infections. More importantly, angiotensin-converting enzyme (ACE)-2, the SARS-CoV-2 receptor, has been proven highly increased during pregnancy, which may contribute to the susceptibility to SARS-CoV-2. When it comes to treatment, specific drugs for COVID-19 have not been found at present, and taking old drugs for new use in treating COVID-19 has become an emergency method for the pandemic. Particularly, drugs that show superior maternal and fetal safety are worthy of consideration for pregnant women with COVID-19, such as chloroquine, metformin, statins, lobinavir/ritonavir, glycyrrhizic acid, and nanoparticle-mediated drug delivery (NMDD), etc. Pregnant women are susceptible to COVID-19, and special attention should be paid to the selection of drugs that are both effective for maternal diseases and friendly to the fetus. However, there are still many deficiencies in the study of drug safety during pregnancy, and broad-spectrum, effective and fetal-safe drugs for pregnant women need to be developed so as to cope with more infectious diseases in the future.
w44lquq9
w44lquq9
2020-04-23
10.1007/s10096-020-03897-6
3.5
Abelson Kinase Inhibitors Are Potent Inhibitors of Severe Acute Respiratory Syndrome Coronavirus and Middle East Respiratory Syndrome Coronavirus Fusion.
UNLABELLED The highly pathogenic severe acute respiratory syndrome coronavirus (SARS-CoV) and Middle East respiratory syndrome coronavirus (MERS-CoV) cause significant morbidity and morality. There is currently no approved therapeutic for highly pathogenic coronaviruses, even as MERS-CoV is spreading throughout the Middle East. We previously screened a library of FDA-approved drugs for inhibitors of coronavirus replication in which we identified Abelson (Abl) kinase inhibitors, including the anticancer drug imatinib, as inhibitors of both SARS-CoV and MERS-CoV in vitro Here we show that the anti-CoV activity of imatinib occurs at the early stages of infection, after internalization and endosomal trafficking, by inhibiting fusion of the virions at the endosomal membrane. We specifically identified the imatinib target, Abelson tyrosine-protein kinase 2 (Abl2), as required for efficient SARS-CoV and MERS-CoV replication in vitro These data demonstrate that specific approved drugs can be characterized in vitro for their anticoronavirus activity and used to identify host proteins required for coronavirus replication. This type of study is an important step in the repurposing of approved drugs for treatment of emerging coronaviruses. IMPORTANCE Both SARS-CoV and MERS-CoV are zoonotic infections, with bats as the primary source. The 2003 SARS-CoV outbreak began in Guangdong Province in China and spread to humans via civet cats and raccoon dogs in the wet markets before spreading to 37 countries. The virus caused 8,096 confirmed cases of SARS and 774 deaths (a case fatality rate of ∼10%). The MERS-CoV outbreak began in Saudi Arabia and has spread to 27 countries. MERS-CoV is believed to have emerged from bats and passed into humans via camels. The ongoing outbreak of MERS-CoV has resulted in 1,791 cases of MERS and 640 deaths (a case fatality rate of 36%). The emergence of SARS-CoV and MERS-CoV provides evidence that coronaviruses are currently spreading from zoonotic sources and can be highly pathogenic, causing serious morbidity and mortality in humans. Treatment of SARS-CoV and MERS-CoV infection is limited to providing supportive therapy consistent with any serious lung disease, as no specific drugs have been approved as therapeutics. Highly pathogenic coronaviruses are rare and appear to emerge and disappear within just a few years. Currently, MERS-CoV is still spreading, as new infections continue to be reported. The outbreaks of SARS-CoV and MERS-CoV and the continuing diagnosis of new MERS cases highlight the need for finding therapeutics for these diseases and potential future coronavirus outbreaks. Screening FDA-approved drugs streamlines the pipeline for this process, as these drugs have already been tested for safety in humans.
w6bk2x1n
w6bk2x1n
2016
10.1128/jvi.01429-16
0.5
Interaction of severe acute respiratory syndrome-coronavirus and NL63 coronavirus spike proteins with angiotensin converting enzyme-2
Although in different groups, the coronaviruses severe acute respiratory syndrome-coronavirus (SARS-CoV) and NL63 use the same receptor, angiotensin converting enzyme (ACE)-2, for entry into the host cell. Despite this common receptor, the consequence of entry is very different; severe respiratory distress in the case of SARS-CoV but frequently only a mild respiratory infection for NL63. Using a wholly recombinant system, we have investigated the ability of each virus receptor-binding protein, spike or S protein, to bind to ACE-2 in solution and on the cell surface. In both assays, we find that the NL63 S protein has a weaker interaction with ACE-2 than the SARS-CoV S protein, particularly in solution binding, but the residues required for contact are similar. We also confirm that the ACE-2-binding site of NL63 S lies between residues 190 and 739. A lower-affinity interaction with ACE-2 might partly explain the different pathological consequences of infection by SARS-CoV and NL63.
w6gmscv4
w6gmscv4
2008-11-16
10.1099/vir.0.2008/003962-0
3.5
A guideline for homology modeling of the proteins from newly discovered betacoronavirus, 2019 novel coronavirus (2019‐nCoV)
During an outbreak of respiratory diseases including atypical pneumonia in Wuhan, a previously unknown β‐coronavirus was detected in patients. The newly discovered coronavirus is similar to some β‐coronaviruses found in bats but different from previously known SARS‐CoV and MERS‐CoV. High sequence identities and similarities between 2019‐nCoV and SARS‐CoV were found. In this study, we searched the homologous templates of all nonstructural and structural proteins of 2019‐nCoV. Among the nonstructural proteins, the leader protein (nsp1), the papain‐like protease (nsp3), the nsp4, the 3C‐like protease (nsp5), the nsp7, the nsp8, the nsp9, the nsp10, the RNA‐directed RNA polymerase (nsp12), the helicase (nsp13), the guanine‐N7 methyltransferase (nsp14), the uridylate‐specific endoribonuclease (nsp15), the 2'‐O‐methyltransferase (nsp16), and the ORF7a protein could be built on the basis of homology templates. Among the structural proteins, the spike protein (S‐protein), the envelope protein (E‐protein), and the nucleocapsid protein (N‐protein) can be constructed based on the crystal structures of the proteins from SARS‐CoV. It is known that PL‐Pro, 3CL‐Pro, and RdRp are important targets for design antiviral drugs against 2019‐nCoV. And S protein is a critical target candidate for inhibitor screening or vaccine design against 2019‐nCoV because coronavirus replication is initiated by the binding of S protein to cell surface receptors. It is believed that these proteins should be useful for further structure‐based virtual screening and related computer‐aided drug development and vaccine design.
w72ma7fp
w72ma7fp
2020-03-29
10.1002/jmv.25768
4.5
The tetraspanin CD9 facilitates MERS-coronavirus entry by scaffolding host cell receptors and proteases
Infection by enveloped coronaviruses (CoVs) initiates with viral spike (S) proteins binding to cellular receptors, and is followed by proteolytic cleavage of receptor-bound S proteins, which prompts S protein-mediated virus-cell membrane fusion. Infection therefore requires close proximity of receptors and proteases. We considered whether tetraspanins, scaffolding proteins known to facilitate CoV infections, hold receptors and proteases together on cell membranes. Using knockout cell lines, we found that the tetraspanin CD9, but not the tetraspanin CD81, formed cell-surface complexes of dipeptidyl peptidase 4 (DPP4), the MERS-CoV receptor, and the type II transmembrane serine protease (TTSP) member TMPRSS2, a CoV-activating protease. This CD9-facilitated condensation of receptors and proteases allowed MERS-CoV pseudoviruses to enter cells rapidly and efficiently. Without CD9, MERS-CoV viruses were not activated by TTSPs, and they trafficked into endosomes to be cleaved much later and less efficiently by cathepsins. Thus, we identified DPP4:CD9:TTSP as the protein complexes necessary for early, efficient MERS-CoV entry. To evaluate the importance of these complexes in an in vivo CoV infection model, we used recombinant Adenovirus 5 (rAd5) vectors to express human DPP4 in mouse lungs, thereby sensitizing the animals to MERS-CoV infection. When the rAd5-hDPP4 vectors co-expressed small RNAs silencing Cd9 or Tmprss2, the animals were significantly less susceptible, indicating that CD9 and TMPRSS2 facilitated robust in vivo MERS-CoV infection of mouse lungs. Furthermore, the S proteins of virulent mouse-adapted MERS-CoVs acquired a CD9-dependent cell entry character, suggesting that CD9 is a selective agent in the evolution of CoV virulence.
w7cn9iqp
w7cn9iqp
2017-07-31
10.1371/journal.ppat.1006546
4.5
Molecular Docking Analysis Of Some Phytochemicals On Two SARS-CoV-2 Targets: Potential Lead Compounds Against Two Target Sites of SARS-CoV-2 Obtained from Plants
COV spike (S) glycoprotein and Mpro are two key targets that have been identified for vaccines and drug development against the COVID-19 disease. Virtual screening of some compounds of plants origin that have shown antiviral activities were carried out on the two targets, 6lu7 and 6vsb by docking with the PyRx software. The binding affinities were compared with other compounds and drugs already identified as potential ligands for 6lu7 and 6vsb as well as Chloroquine and hydroxychloroquine. The docked compounds with best binding affinities were also filtered for drug likeness using the SwissADME and PROTOX platforms on the basis of Physicochemical properties and toxicity respectively. The docking results revealed that scopodulcic acid and dammarenolic acid had the best binding affinity on the s-glycoprotein and Mpro protein targets respectively. Silybinin also demonstrated a good binding affinity to both protein targets making it a potential candidate for further evaluation as repurposed candidate for SARS COV2 with likelihood of having a multitarget activity.
w84qtud6
w84qtud6
2020-06-09
10.1101/2020.03.31.017657
0.5
How to handle patients with autoimmune rheumatic and inflammatory bowel diseases in the COVID-19 era: An expert opinion
• A correct patient risk stratification is of paramount importance for the proper management of economic and human resources. • It's fundamental to prioritize clinical trials evaluating dosing, prophylaxis, and treatment with immunosuppressant in COVID-19 in order to avoid either an overuse and a treatment shortage. • Future controlled studies may highlight in our patients a potential preventive role of immunosuppressant therapies in the development of severe forms of Covid-19. • Despite the overall risk of infection in rheumatic and gastroenterological diseases a conclusive association between these diseases and COVID −19 remains questionable.
w8ewm8ve
w8ewm8ve
2020-05-05
10.1016/j.autrev.2020.102574
3.5
Medical imaging informatics research and development trends—an editorial
w8f6ip1k
w8f6ip1k
2005-02-01
10.1016/j.compmedimag.2004.09.003
3.5
Recombinant protein vaccines produced in insect cells
The baculovirus-insect cell expression system is a well known tool for the production of complex proteins. The technology is also used for commercial manufacture of various veterinary and human vaccines. This review paper provides an overview of how this technology can be applied to produce a multitude of vaccine candidates. The key advantage of this recombinant protein manufacturing platform is that a universal “plug and play” process may be used for producing a broad range of protein-based prophylactic and therapeutic vaccines for both human and veterinary use while offering the potential for low manufacturing costs. Large scale mammalian cell culture facilities previously established for the manufacturing of monoclonal antibodies that have now become obsolete due to yield improvement could be deployed for the manufacturing of these vaccines. Alternatively, manufacturing capacity could be established in geographic regions that do not have any vaccine production capability. Dependent on health care priorities, different vaccines could be manufactured while maintaining the ability to rapidly convert to producing pandemic influenza vaccine when the need arises.
w932k1v6
w932k1v6
2012-02-27
10.1016/j.vaccine.2012.01.016
3.5
High seroreactivity against SARS-CoV-2 Spike epitopes in a pre SARS-CoV-2 cohort: implications for antibody testing and vaccine design
Little is known about the quality of polyclonal antibody responses in COVID-19 patients, and how it correlates with disease severity or patients' prior exposure to other pathogens. The whole polyclonal antibody repertoire in a retrospective cohort of 538 individuals was mapped against SARS-CoV-2 spike (S) glycoprotein, the main target of antibody immune responses in SARS-CoV-2 infection. Bioinformatic predictions identified 15 major B cell epitopes for S of SARS-CoV-2. Several epitopes localised in RBD of S including those spanning the ACE2-binding site, the highly conserved cryptic epitope of the neutralizing antibody of SARS-CoV, and fusion/entry domains of HR1 and HR2 of S protein of SARS-CoV-2. Intriguingly, some of these epitopes have cross-reactivity to antigens of common pathogens, potentially affecting SARS-CoV-2 infection outcome. High level of anti-Spike SARS-CoV-2 seroreactivity in populations with no history of exposure to SARS-CoV-2 is of clinical relevance and could underpin better understanding of COVID-19 pathophysiology in different populations and provide a blueprint for design of effective vaccines and developing better strategies for antibody testing.
w98i9l5i
w98i9l5i
2020-05-22
10.1101/2020.05.18.20105189
4
In silico identification of clinically approved medicines against the main protease of SARS-CoV-2, causative agent of covid-19
The COVID-19 pandemic triggered by SARS-CoV-2 is a worldwide health disaster. Main protease is an attractive drug target among coronaviruses, due to its vital role in processing the polyproteins that are translated from the viral RNA. There is presently no exact drug or treatment for this diseases caused by SARS-CoV-2. In the present study, we report the potential inhibitory activity of some FDA approved drugs against SARS-CoV-2 main protease by molecular docking study to investigate their binding affinity in protease active site. Docking studies revealed that drug Oseltamivir (anti-H1N1 drug), Rifampin (anti-TB drug), Maraviroc, Etravirine, Indinavir, Rilpivirine (anti-HIV drugs) and Atovaquone, Quinidine, Halofantrine, Amodiaquine, Tetracylcine, Azithromycin, hydroxycholoroquine (anti-malarial drugs) among others binds in the active site of the protease with similar or higher affinity. However, the in-silico abilities of the drug molecules tested in this study, further needs to be validated by carrying out in vitro and in vivo studies. Moreover, this study spreads the potential use of current drugs to be considered and used to comprise the fast expanding SARS-CoV-2 infection.
w9mij6c6
w9mij6c6
2020-04-25
2
Long-term protection from SARS coronavirus infection conferred by a single immunization with an attenuated VSV-based vaccine
Abstract Although the recent SARS coronavirus (SARS-CoV) that appeared in 2002 has now been contained, the possibility of re-emergence of SARS-CoV remains. Due to the threat of re-emergence, the overall fatality rate of ∼10%, and the rapid dispersion of the virus via international travel, viable vaccine candidates providing protection from SARS are clearly needed. We developed an attenuated VSV recombinant (VSV-S) expressing the SARS coronavirus (SARS-CoV) spike (S) protein. In cells infected with this recombinant, S protein was synthesized, glycosylated at approximately 17 Asn residues, and transported via the Golgi to the cell surface. Mice vaccinated with VSV-S developed SARS-neutralizing antibody and were able to control a challenge with SARS-CoV performed at 1 month or 4 months after a single vaccination. We also demonstrated, by passive antibody transfer, that the antibody response induced by the vaccine was sufficient for controlling SARS-CoV infection. A VSV-vectored SARS vaccine could have significant advantages over other SARS vaccine candidates described to date.
w9rqnz9h
w9rqnz9h
2005-09-30
10.1016/j.virol.2005.06.016
3.5
DNA vaccine protection against SARS-CoV-2 in rhesus macaques
The global COVID-19 pandemic caused by the SARS-CoV-2 virus has made the development of a vaccine a top biomedical priority. In this study, we developed a series of DNA vaccine candidates expressing different forms of the SARS-CoV-2 Spike (S) protein and evaluated them in 35 rhesus macaques. Vaccinated animals developed humoral and cellular immune responses, including neutralizing antibody titers comparable to those found in convalescent humans and macaques infected with SARS-CoV-2. Following vaccination, all animals were challenged with SARS-CoV-2, and the vaccine encoding the full-length S protein resulted in >3.1 and >3.7 log(10) reductions in median viral loads in bronchoalveolar lavage and nasal mucosa, respectively, as compared with sham controls. Vaccine-elicited neutralizing antibody titers correlated with protective efficacy, suggesting an immune correlate of protection. These data demonstrate vaccine protection against SARS-CoV-2 in nonhuman primates.
w9zyshzb
w9zyshzb
2020-05-20
10.1126/science.abc6284
5
Antibody-dependent SARS coronavirus infection is mediated by antibodies against spike proteins
Abstract The severe acute respiratory syndrome coronavirus (SARS-CoV) still carries the potential for reemergence, therefore efforts are being made to create a vaccine as a prophylactic strategy for control and prevention. Antibody-dependent enhancement (ADE) is a mechanism through which dengue viruses, feline coronaviruses, and HIV viruses take advantage of anti-viral humoral immune responses to infect host target cells. Here we describe our observations of SARS-CoV using ADE to enhance the infectivity of a HL-CZ human promonocyte cell line. Quantitative-PCR and immunofluorescence staining results indicate that SARS-CoV is capable of replication in HL-CZ cells, and of displaying virus-induced cytopathic effects and increased levels of TNF-α, IL-4 and IL-6 two days post-infection. According to flow cytometry data, the HL-CZ cells also expressed angiotensin converting enzyme 2 (ACE2, a SARS-CoV receptor) and higher levels of the FcγRII receptor. We found that higher concentrations of anti-sera against SARS-CoV neutralized SARS-CoV infection, while highly diluted anti-sera significantly increased SARS-CoV infection and induced higher levels of apoptosis. Results from infectivity assays indicate that SARS-CoV ADE is primarily mediated by diluted antibodies against envelope spike proteins rather than nucleocapsid proteins. We also generated monoclonal antibodies against SARS-CoV spike proteins and observed that most of them promoted SARS-CoV infection. Combined, our results suggest that antibodies against SARS-CoV spike proteins may trigger ADE effects. The data raise new questions regarding a potential SARS-CoV vaccine, while shedding light on mechanisms involved in SARS pathogenesis.
wajt5xe0
wajt5xe0
2014-08-22
10.1016/j.bbrc.2014.07.090
1.5
Recalibrating Veterinary Medicine through Animal Welfare Science and Ethics for the 2020s
SIMPLE SUMMARY: This article emphasizes the importance of educating veterinarians and veterinary students in animal welfare science and veterinary ethics, so that they can ably advance pertinent scientific knowledge and promote ethical thinking as trusted animal advocates in the 2020s. In light of this public expectation, a number of challenges are raised for veterinarians and the veterinary profession. These challenges involve: (1) re-envisioning the nature of disease treatment that goes beyond traditional conceptions of health or clinical matters, and which include animal welfare; (2) re-imagining disease prevention at the intersection of animal-human-ecosystem health; (3) developing core competencies in animal welfare science and ethics in order to provide professional leadership in animal welfare; and (4) taking a more active role in the development of novel networked devices, monitoring technologies and automated animal welfare solutions, and understanding their effects on the welfare of animals, human-animal relationships, and the veterinary profession in general. ABSTRACT: What should leading discourses and innovation regarding animal welfare look like for the veterinary profession in the 2020s? This essay considers four main challenges into which veterinarians are increasingly being drawn, as they respond to increasing public expectation for them to be scientific and moral authorities in animal welfare in addition to their traditional role as trusted health experts. They include: (1) to go beyond traditional conceptions of health by adopting a holistic view that also considers animal welfare, not only disease treatment; (2) to reimagine their professional duties when it comes to disease prevention at the intersection of animal-human-ecosystem health; (3) to develop core competencies/proficiency in animal welfare science and ethics in order to navigate discourses concerning competing priorities and socio-political ideologies and to provide professional leadership in animal welfare; (4) to provide feedback on novel networked devices, monitoring technologies and automated animal welfare solutions and their impact on animals’ welfare. To competently navigate the intricacies of the socio-political and connected world as trusted authorities and conduits for innovation in and through animal welfare, veterinarians and veterinary students are encouraged to: (a) develop core competencies in veterinary ethics, animal welfare science and deliberative capacities that are well-informed by current multidisciplinary frameworks, such as One Health; (b) engage interested parties in more effective collaboration and ethical decision-making in order to address animal welfare related concerns within their immediate sphere of influence (e.g., in a given community); and (c) participate in the process of engineering and technological design that incorporates animals’ welfare data (such as their preferences) for real-time animal monitoring through adding animal scientific and values-aware evidence in information technology systems. In order to tackle these challenges, four pillars are suggested to help guide veterinarians and the veterinary profession. They are: Collaboration, Critical Engagement, Centeredness on Research, and Continuous Self-Critique.
wbbotohj
wbbotohj
2020-04-09
10.3390/ani10040654
4.5
Middle East respiratory syndrome coronavirus: a comprehensive review
The Middle East respiratory syndrome coronavirus was first identified in 2012 and has since then remained uncontrolled. Cases have been mostly reported in the Middle East, however travel-associated cases and outbreaks have also occurred. Nosocomial and zoonotic transmission of the virus appear to be the most important routes. The infection is severe and highly fatal thus necessitating rapid and efficacious interventions. Here, we performed a comprehensive review of published literature and summarized the epidemiology of the virus. In addition, we summarized the virological aspects of the infection and reviewed the animal models used as well as vaccination and antiviral tested against it.
wbd0s4fo
wbd0s4fo
2016-01-20
10.1007/s11684-016-0430-6
1.5
High seroprevalence for SARS-CoV-2 among household members of essential workers detected using a dried blood spot assay
Objective: Serological testing is needed to investigate the extent of transmission of SARS-CoV-2 from front-line essential workers to their household members. However, the requirement for serum/plasma limits serological testing to clinical settings where it is feasible to collect and process venous blood. To address this problem we developed a serological test for SARS-CoV-2 IgG antibodies that requires only a single drop of finger stick capillary whole blood, collected in the home and dried on filter paper (dried blood spot, DBS). Methods: An ELISA to the receptor binding domain of the SARS-CoV-2 spike protein was optimized to quantify IgG antibodies in DBS. Samples were self-collected from a community sample of 232 participants enriched with health care workers, including 30 known COVID-19 cases and their household members. Results: Among 30 individuals sharing a household with a virus-confirmed case of COVID-19, 80% were seropositive. Of 202 community individuals without prior confirmed acute COVID-19 diagnoses, 36% were seropositive. Of documented convalescent COVID-19 cases from the community, 29 of 30 (97%) were seropositive for IgG antibodies to the receptor binding domain. Conclusion: DBS ELISA provides a minimally-invasive alternative to venous blood collection. Early analysis suggests a high rate of transmission among household members. High rates of seroconversion were also noted following recovery from infection. Serological testing for SARS-CoV-2 IgG antibodies in DBS samples can facilitate seroprevalence assessment in community settings to address epidemiological questions, monitor duration of antibody responses, and assess if antibodies against the spike protein correlate with protection from reinfection.
wddj6hrv
wddj6hrv
2020-06-02
10.1101/2020.06.01.20119602
4.5
Systematic review and critical appraisal of prediction models for diagnosis and prognosis of COVID-19 infection
Objective To review and critically appraise published and preprint reports of models that aim to predict either (i) presence of existing COVID-19 infection, (ii) future complications in individuals already diagnosed with COVID-19, or (iii) models to identify individuals at high risk for COVID-19 in the general population. Design Rapid systematic review and critical appraisal of prediction models for diagnosis or prognosis of COVID-19 infection. Data sources PubMed, EMBASE via Ovid, Arxiv, medRxiv and bioRxiv until 24th March 2020. Study selection Studies that developed or validated a multivariable COVID-19 related prediction model. Two authors independently screened titles, abstracts and full text. Data extraction Data from included studies were extracted independently by at least two authors based on the CHARMS checklist, and risk of bias was assessed using PROBAST. Data were extracted on various domains including the participants, predictors, outcomes, data analysis, and prediction model performance. Results 2696 titles were screened. Of these, 27 studies describing 31 prediction models were included for data extraction and critical appraisal. We identified three models to predict hospital admission from pneumonia and other events (as a proxy for covid-19 pneumonia) in the general population; 18 diagnostic models to detect COVID-19 infection in symptomatic individuals (13 of which were machine learning utilising computed tomography (CT) results); and ten prognostic models for predicting mortality risk, progression to a severe state, or length of hospital stay. Only one of these studies used data on COVID-19 cases outside of China. Most reported predictors of presence of COVID-19 in suspected patients included age, body temperature, and signs and symptoms. Most reported predictors of severe prognosis in infected patients included age, sex, features derived from CT, C-reactive protein, lactic dehydrogenase, and lymphocyte count. Estimated C-index estimates for the prediction models ranged from 0.73 to 0.81 in those for the general population (reported for all 3 general population models), from 0.81 to > 0.99 in those for diagnosis (reported for 13 of the 18 diagnostic models), and from 0.85 to 0.98 in those for prognosis (reported for 6 of the 10 prognostic models). All studies were rated at high risk of bias, mostly because of non-representative selection of control patients, exclusion of patients who had not experienced the event of interest by the end of the study, and poor statistical analysis, including high risk of model overfitting. Reporting quality varied substantially between studies. A description of the study population and intended use of the models was absent in almost all reports, and calibration of predictions was rarely assessed. Conclusion COVID-19 related prediction models are quickly entering the academic literature, to support medical decision making at a time where this is urgently needed. Our review indicates proposed models are poorly reported and at high risk of bias. Thus, their reported performance is likely optimistic and using them to support medical decision making is not advised. We call for immediate sharing of the individual participant data from COVID-19 studies to support collaborative efforts in building more rigorously developed prediction models and validating (evaluating) existing models. The aforementioned predictors identified in multiple included studies could be considered as candidate predictors for new models. We also stress the need to follow methodological guidance when developing and validating prediction models, as unreliable predictions may cause more harm than benefit when used to guide clinical decisions. Finally, studies should adhere to the TRIPOD statement to facilitate validating, appraising, advocating and clinically using the reported models. Systematic review registration protocol: osf.io/ehc47/, registration: osf.io/wy245
wefj7is3
wefj7is3
2020-03-27
10.1101/2020.03.24.20041020
1
Suramin inhibits SARS-CoV-2 infection in cell culture by interfering with early steps of the replication cycle
The SARS-CoV-2 pandemic that originated from Wuhan, China, in December 2019 has impacted public health, society and economy and the daily lives of billions of people in an unprecedented manner. There are currently no specific registered antiviral drugs to treat or prevent SARS-CoV-2 infections. Therefore, drug repurposing would be the fastest route to provide at least a temporary solution while better, more specific drugs are being developed. Here we demonstrate that the antiparasitic drug suramin inhibits SARS-CoV-2 replication, protecting Vero E6 cells with an EC50 of â¼20 µM, which is well below the maximum attainable level in human serum. Suramin also decreased the viral load by 2-3 logs when Vero E6 cells or cells of a human lung epithelial cell line (Calu-3) were treated. Time of addition and plaque reduction assays performed on Vero E6 cells showed that suramin acts on early steps of the replication cycle, possibly preventing binding or entry of the virus. In a primary human airway epithelial cell culture model, suramin also inhibited the progression of infection. The results of our preclinical study warrant further investigation and suggest it is worth evaluating whether suramin provides any benefit for COVID-19 patients, which obviously requires safety studies and well-designed, properly controlled randomized clinical trials.
wf2tbbo2
wf2tbbo2
2020
4
Deep Learning on Chest X-ray Images to Detect and Evaluate Pneumonia Cases at the Era of COVID-19
Coronavirus disease 2019 (COVID-19) is an infectious disease with first symptoms similar to the flu. COVID-19 appeared first in China and very quickly spreads to the rest of the world, causing then the 2019-20 coronavirus pandemic. In many cases, this disease causes pneumonia. Since pulmonary infections can be observed through radiography images, this paper investigates deep learning methods for automatically analyzing query chest X-ray images with the hope to bring precision tools to health professionals towards screening the COVID-19 and diagnosing confirmed patients. In this context, training datasets, deep learning architectures and analysis strategies have been experimented from publicly open sets of chest X-ray images. Tailored deep learning models are proposed to detect pneumonia infection cases, notably viral cases. It is assumed that viral pneumonia cases detected during an epidemic COVID-19 context have a high probability to presume COVID-19 infections. Moreover, easy-to-apply health indicators are proposed for estimating infection status and predicting patient status from the detected pneumonia cases. Experimental results show possibilities of training deep learning models over publicly open sets of chest X-ray images towards screening viral pneumonia. Chest X-ray test images of COVID-19 infected patients are successfully diagnosed through detection models retained for their performances. The efficiency of proposed health indicators is highlighted through simulated scenarios of patients presenting infections and health problems by combining real and synthetic health data.
wfq7y3nk
wfq7y3nk
2020-04-05
3.5
Les infections à coronavirus humains
Résumé Les coronavirus humains (HCoV) sont des virus à ARN simple brin. Il existe actuellement quatre coronavirus dits « classiques » ou « nouveaux », dont la circulation est hivernale. Ils sont à l’origine d’infections respiratoires modérées dans la population générale. Cependant, les infections peuvent être plus sévères dans les populations susceptibles. Notamment, les HCoV sont impliqués dans 2 à 7% des hospitalisations consécutives à une infection respiratoire, en particulier chez les enfants et les personnes âgées ou immunodéprimées. De ce fait, ils appartiennent au panel de virus respiratoires recherchés lors des diagnostics de routine des infections respiratoires par des outils de biologie moléculaire. Ces coronavirus dits circulants sont à distinguer des deux coronavirus émergents, le SARS-CoV et le MERS-CoV qui sont associés à des pathologies respiratoires plus sévères. Ils se distinguent des autres HCoV par leur potentiel épidémique plus élevé, leur impact sanitaire plus important et leur mode de circulation atypique. À l’instar des paramyxovirus et des virus Influenza, les coronavirus doivent être surveillés pour leur risque d’émergence dans la population humaine à partir d’un réservoir animal. Summary Human coronaviruses (HCoV) are single strand RNA viruses. To date, there are four so-called « classical » or « novel » HCoVs, characterized by a winter circulation. These coronaviruses are responsible for mild respiratory infection in general population. However, HCoVs are associated to more severe respiratory tract infection among susceptible population. Indeed, HCoVs account for 2 to 7% of hospitalizations due to a respiratory infection, particularly among children, immunocompromised or elderly people. Thereby, HCoVs are included in the panel of respiratory viruses detected in routine using molecular biology tools. These four circulating HCoVs have to be distinguished from the two emerging HCoVs: SARS-CoV and MERS-CoV. These later are associated to a more severe respiratory infection and differ from other HCoVs by their increased epidemic potential, their more important health impact, and their atypical circulation. Such as paramyxoviruses and Influenza viruses, coronaviruses have to be monitored due to their associated risk of emergence in human population from animal reservoirs.
wg7cpimw
wg7cpimw
2016-12-31
10.1016/s1773-035x(16)30369-0
2.5
Recent insights for the emerging COVID-19: drug discovery, therapeutic options and vaccine development
SARS-CoV-2 has been marked as a highly pathogenic coronavirus of COVID-19 disease into the human population, causing over 5.5 million confirmed cases worldwide. As COVID-19 has posed a global threat with significant human casualties and severe economic losses, there is a pressing demand to further understand the current situation and develop rational strategies to contain the drastic spread of the virus. Although there are no specific antiviral therapies that have proven effective in randomized clinical trials, currently, the rapid detection technology along with several promising therapeutics for COVID-19 have mitigated its drastic transmission. Besides, global institutions and corporations have commenced to parse out effective vaccines for the prevention of COVID-19. Herein, the present review will give exhaustive details of extensive researches concerning the drug discovery and therapeutic options for COVID-19 as well as some insightful discussions of the status of COVID-19.
wgau58zl
wgau58zl
2020-07-04
10.1016/j.ajps.2020.06.001
5
Meeting report: 28th International Conference on Antiviral Research in Rome, Italy
Abstract The 28th International Conference on Antiviral Research (ICAR) was held in Rome, Italy from May 11 to 15, 2015. This article summarizes the principal invited lectures. Phillip Furman, the Elion award recipient, described the research leading to sofosbuvir. Dennis Liotta, who received the Holý award, described how an investigation into HIV entry inhibitors led to a new therapy for cancer patients. Erica Ollmann Saphire, winner of the Prusoff Young Investigator award, explored the world of viral proteins and how they remodel to perform different essential roles in viral replication. The keynote addresses, by Raffaele De Francesco and Michael Manns, reported on the remarkable progress made in the therapy of chronic HCV infections. A third keynote address, by Armand Sprecher, related the difficulties and successes of Médicins Sans Frontières in West Africa ravaged by the Ebola outbreak. There were three mini-symposia on RNA Viruses, Antiviral Chemistry and Emerging Viruses. There was a good collection of talks on RNA viruses (norovirus, rabies, dengue, HEV, HCV, and RSV). A highlight of the chemistry was the preparation of prodrugs for nucleotide triphosphates as this opens a door to new options. The third mini-symposium emphasized how research work in the antiviral area is continuing to expand and needs to do so with a sense of urgency. Although this meeting report covers only a few of the presentations, it aims to illustrate the great diversity of topics discussed at ICAR, bringing together knowledge and expertise from the whole spectrum of antiviral research.
wh0uw4xr
wh0uw4xr
2015-11-30
10.1016/j.antiviral.2015.09.015
0.5
A Systematic Review of therapeutic agents for the treatment of the Middle East Respiratory Syndrome Coronavirus (MERS-CoV)
Abstract Background The Middle East Respiratory Syndrome Coronavirus (MERS-CoV) was first described in 2012 and attracted a great international attention due to multiple healthcare associated outbreaks. The disease carries a high case fatality rate of 34.5%, and there is no internationally or nationally recommended therapy. Method We searched MEDLINE, Science Direct, Embase and Scopus databases for relevant papers published till March 2019 describing in vitro, in vivo or human therapy of MERS. Results Initial search identified 62 articles: 52 articles were from Medline, 6 from Embase, and 4 from Science Direct. Based on the inclusions and exclusions criteria, 30 articles were included in the final review and comprised: 22 in vitro studies, 8 studies utilizing animal models, 13 studies in humans, and one study included both in vitro and animal model. There are a few promising therapeutic agents on the horizon. The combination of lopinavir/ritonavir and interferon-beta- 1b showed excellent results in common marmosets and currently is in a randomized control trial. Ribavirin and interferon were the most widely used combination and experience comes from a number of observational studies. Although, the data are heterogenous, this combination might be of potential benefit and deserve further investigation. There were no randomized clinical trials to recommend specific therapy for the treatment of MERS-CoV infection. Only one such study is planned for randomization and is pending completion. The study is based on a combination of lopinavir/ritonavir and interferon-beta- 1b. A fully human polyclonal IgG antibody (SAB-301) was safe and well tolerated in healthy individuals and this agent may deserve further testing for efficacy. Conclusion Despite multiple studies in humans there is no consensus on the optimal therapy for MERS-CoV. Randomized clinical trials are needed and potential therapies should be evaluated only in such clinical trials. In order to further enhance the therapeutic aroma for MERS-CoV infection, repurposing old drugs against MERS-CoV is an interesting strategy and deserves further consideration and use in clinical settings.
wicc796j
wicc796j
2019-08-31
10.1016/j.tmaid.2019.06.012
2
The anticoagulant nafamostat potently inhibits SARS-CoV-2 infection in vitro: an existing drug with multiple possible therapeutic effects
Although infection by SARS-CoV-2, the causative agent of COVID-19, is spreading rapidly worldwide, no drug has been shown to be sufficiently effective for treating COVID-19. We previously found that nafamostat mesylate, an existing drug used for disseminated intravascular coagulation (DIC), effectively blocked MERS-CoV S protein-initiated cell fusion by targeting TMPRSS2, and inhibited MERS-CoV infection of human lung epithelium-derived Calu-3 cells. Here we established a quantitative fusion assay dependent on SARS-CoV-2 S protein, ACE2 and TMPRSS2, and found that nafamostat mesylate potently inhibited the fusion while camostat mesylate was about 10-fold less active. Furthermore, nafamostat mesylate blocked SARS-CoV-2 infection of Calu-3 cells with an EC50 around 10 nM, which is below its average blood concentration after intravenous administration through continuous infusion. These findings, together with accumulated clinical data regarding its safety, make nafamostat a likely candidate drug to treat COVID-19.
witgquy6
witgquy6
2020-04-23
10.1101/2020.04.22.054981
2
Endocytosis of the receptor-binding domain of SARS-CoV spike protein together with virus receptor ACE2
Abstract Cell entry of severe acute respiratory syndrome coronavirus (SARS-CoV) is mediated by the viral spike (S) protein. Amino acids 319–510 on the S protein have been mapped as the receptor-binding domain (RBD), which mediates binding to the SARS-CoV receptor angiotensin converting enzyme 2 (ACE2) on SARS-CoV susceptible cells. In this study, we expressed a fusion protein containing the human codon-optimized RBD of the SARS-CoV spike protein linked to the Fc portion of human IgG1 (named RBD-Fc) in HEK293 cells. The RBD-Fc protein was purified by affinity chromatography. The flow cytometry assay showed that the purified RBD-Fc protein could bind to ACE2. We demonstrated that the RBD spike protein alone could be internalized into SARS-CoV susceptible cells together with ACE2. We also showed that the removal of N-glycans from the RBD spike protein did not abolish this phenomenon. Our discoveries may have some implications for the development of the SARS vaccine.
wku1sd9k
wku1sd9k
2008-09-30
10.1016/j.virusres.2008.03.004
4.5
Molecular immune pathogenesis and diagnosis of COVID-19
Coronavirus disease 2019 (COVID-19) is a kind of viral pneumonia which is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The emergence of SARS-CoV-2 has been marked as the third introduction of a highly pathogenic coronavirus into the human population after the severe acute respiratory syndrome coronavirus (SARS-CoV) and the Middle East respiratory syndrome coronavirus (MERS-CoV) in the twenty-first century. In this minireview, we provide a brief introduction of the general features of SARS-CoV-2 and discuss current knowledge of molecular immune pathogenesis, diagnosis and treatment of COVID-19 on the base of the present understanding of SARS-CoV and MERS-CoV infections, which may be helpful in offering novel insights and potential therapeutic targets for combating the SARS-CoV-2 infection.
wl121lg4
wl121lg4
2020-03-05
10.1016/j.jpha.2020.03.001
1.5
Ribavirin and interferon-β synergistically inhibit SARS-associated coronavirus replication in animal and human cell lines
Abstract Initial in vitro investigations demonstrated type I interferons (IFNs: IFN-α, IFN-β) to inhibit replication of SARS coronavirus (SARS-CoV), but found the nucleoside analogue ribavirin ineffective in Vero cells. In this report, ribavirin was shown to inhibit SARS-CoV replication in five different cell types of animal or human origin at therapeutically achievable concentrations. Since clinical anti-SARS-CoV activity of type I interferons or ribavirin is limited, we investigated the combination of IFN-β and ribavirin. Determination of the virus yield indicated highly synergistic anti-SARS-CoV action of the combination suggesting the consideration of ribavirin plus IFN-β for the treatment of SARS.
wl83d6gs
wl83d6gs
2005-01-28
10.1016/j.bbrc.2004.11.128
2
Receptor recognition and cross-species infections of SARS coronavirus
Abstract Receptor recognition is a major determinant of the host range, cross-species infections, and pathogenesis of the severe acute respiratory syndrome coronavirus (SARS-CoV). A defined receptor-binding domain (RBD) in the SARS-CoV spike protein specifically recognizes its host receptor, angiotensin-converting enzyme 2 (ACE2). This article reviews the latest knowledge about how RBDs from different SARS-CoV strains interact with ACE2 from several animal species. Detailed research on these RBD/ACE2 interactions has established important principles on host receptor adaptations, cross-species infections, and future evolution of SARS-CoV. These principles may apply to other emerging animal viruses, including the recently emerged Middle East respiratory syndrome coronavirus (MERS-CoV). This paper forms part of a series of invited articles in Antiviral Research on “From SARS to MERS: 10years of research on highly pathogenic human coronaviruses”.
wm6yey1v
wm6yey1v
2013-10-31
10.1016/j.antiviral.2013.08.014
3.5
Improved Molecular Diagnosis of COVID-19 by the Novel, Highly Sensitive and Specific COVID-19-RdRp/Hel Real-Time Reverse Transcription-PCR Assay Validated In Vitro and with Clinical Specimens
On 31 December 2019, the World Health Organization was informed of a cluster of cases of pneumonia of unknown etiology in Wuhan, China. Subsequent investigations identified a novel coronavirus, now named severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), from the affected patients. Highly sensitive and specific laboratory diagnostics are important for controlling the rapidly evolving SARS-CoV-2-associated coronavirus disease 2019 (COVID-19) epidemic. In this study, we developed and compared the performance of three novel real-time reverse transcription-PCR (RT-PCR) assays targeting the RNA-dependent RNA polymerase (RdRp)/helicase (Hel), spike (S), and nucleocapsid (N) genes of SARS-CoV-2 with that of the reported RdRp-P2 assay, which is used in >30 European laboratories. Among the three novel assays, the COVID-19-RdRp/Hel assay had the lowest limit of detection in vitro (1.8 50% tissue culture infective doses [TCID50]/ml with genomic RNA and 11.2 RNA copies/reaction with in vitro RNA transcripts). Among 273 specimens from 15 patients with laboratory-confirmed COVID-19 in Hong Kong, 77 (28.2%) were positive by both the COVID-19-RdRp/Hel and RdRp-P2 assays. The COVID-19-RdRp/Hel assay was positive for an additional 42 RdRp-P2-negative specimens (119/273 [43.6%] versus 77/273 [28.2%]; P < 0.001), including 29/120 (24.2%) respiratory tract specimens and 13/153 (8.5%) non-respiratory tract specimens. The mean viral load of these specimens was 3.21 × 104 RNA copies/ml (range, 2.21 × 102 to 4.71 × 105 RNA copies/ml). The COVID-19-RdRp/Hel assay did not cross-react with other human-pathogenic coronaviruses and respiratory pathogens in cell culture and clinical specimens, whereas the RdRp-P2 assay cross-reacted with SARS-CoV in cell culture. The highly sensitive and specific COVID-19-RdRp/Hel assay may help to improve the laboratory diagnosis of COVID-19.
wmd4ehfx
wmd4ehfx
2020
3.5
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) envelope (E) protein harbors a conserved BH3-like sequence
The authors have withdrawn their manuscript whilst they perform additional experiments to test some of their conclusions further. Therefore, the authors do not wish this work to be cited as reference for the project. If you have any questions, please contact the corresponding author.
wolpnbxa
wolpnbxa
2020-06-09
10.1101/2020.04.09.033522
2.5
In vitro antimicrobial activities of animal-used quinoxaline 1,4-di-N-oxides against mycobacteria, mycoplasma and fungi
BACKGROUND: The quinoxaline 1,4-di-N-oxides (QdNOs) were known as potent antibacterial agents. For the purpose of evaluating the bioactivity of existing animal-used QdNOs drugs against representative pathogenic microorganism, the representative drugs of quinoxalines including cyadox, mequindox, quinocetone and their metabolites were submitted to the in vitro evaluation for antituberculosis, antimycoplasma, antifungal and antiviral activities. RESULTS: In antituberculosis assays, the prototype compounds were active (MIC = 4 ~ 8 μg/mL) against Mycobacterium tuberculosis H37Rv and M. bovis. Combined antimicrobial susceptibility test indicated that cyadox, mequindox and quinocetone combined with rifampicin had additive effect against M. tuberculosis complex with Fractional Inhibitory Concentration Index (FIC) of 0.75. Results of antifungal assays showed that quinocetone was active against Microsporum canis with MIC of 8 μg/mL. Antimycoplasma screening showed a generally good activity of quinocetone against Mycoplasma gallisepticum and Mycoplasma hyopneumoniae, with MIC between 8 and 16 μg/mL. As shown from the combined antimicrobial susceptibility test, cyadox, mequindox and quinocetone combined with tetracycline had additive effect against Mycoplasma gallisepticum with FIC of 0.75. These compounds were also submitted to antiviral assay against infectious bursal disease virus, porcine reproductive and respiratory syndrome virus, porcine parvovirus and classical swine fever virus. The results obtained showed that these QdNOs and their metabolites have no inhibitory activity against these viruses in vitro. CONCLUSIONS: QdNOs exhibit antimicrobial activities against mycobacteria, mycoplasma and fungi. This study gives new insight in further application of QdNOs and offers a way to promote the healthcare of animal husbandry. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12917-016-0812-7) contains supplementary material, which is available to authorized users.
wonwes6p
wonwes6p
2016-09-06
10.1186/s12917-016-0812-7
2.5
Screening and testing for a suitable untransfected cell line for SARS-CoV-2 studies
At present, the novel pandemic coronavirus SARS-CoV-2 is a major global threat to human health and hence demands united research activities at different levels. Finding appropriate cell systems for drug screening and testing molecular interactions of the virus with the host cell is mandatory for drug development and understanding the mechanisms of viral entry and replication. For this, we selected human cell lines represented in the Cancer Cell Line Encyclopedia (CCLE) based on RNA-seq data determined transcript levels of ACE2 and TMPRSS2, two membrane proteins that have been identified to aid SARS-CoV-2 entry into the host cell. mRNA and protein expression of these host factors were verified via RQ-PCR and western blot. We then tested permissiveness of these cell lines towards SARS-CoV-2 infection, cytopathic effect, and viral replication finding limited correlation between receptor expression and infectability. One of the candidate cancer cell lines, the human colon cancer cell line CL-14, tested positive for SARS-CoV-2 infection. Our data argue that SARS-CoV-2 in vitro infection models need careful selection and validation since ACE2/TMPRSS2 receptor expression on its own does not guarantee permissiveness to the virus. Author summary In the midst of the pandemic outbreak of corona-virus SARS-CoV-2 therapeutics for disease treatment are still to be tested and the virus-host-interactions are to be elucidated. Drug testing and viral studies are commonly conducted with genetically manipulated cells. In order to find a cell model system without genetic modification we screened human cell lines for two proteins known to facilitate entry of SARS-CoV-2. We confirmed and quantified permissiveness of current cell line infection models, but dismissed a number of receptor-positive cell lines that did not support viral replication. Importantly, ACE2/TMPRSS2 co-expression seems to be necessary for viral entry but is not sufficient to predict permissiveness of various cancer cell lines. Moreover, the expression of specific splice variants and the absence of missense mutations of the host factors might hint on successful infection and virus replication of the cell lines.
wp3v00uk
wp3v00uk
2020-07-09
10.1101/2020.07.09.195040
5
Identification and evaluation of potent Middle East respiratory syndrome coronavirus (MERS-CoV) 3CLPro inhibitors
Abstract Middle East respiratory syndrome coronavirus (MERS-CoV) causes severe acute respiratory illness with fever, cough and shortness of breath. Up to date, it has resulted in 1826 human infections, including 649 deaths. Analogous to picornavirus 3C protease (3Cpro), 3C-like protease (3CLpro) is critical for initiation of the MERS-CoV replication cycle and is thus regarded as a validated drug target. As presented here, our peptidomimetic inhibitors of enterovirus 3Cpro (6b, 6c and 6d) inhibited 3CLpro of MERS-CoV and severe acute respiratory syndrome coronavirus (SARS-CoV) with IC50 values ranging from 1.7 to 4.7 μM and from 0.2 to 0.7 μM, respectively. In MERS-CoV-infected cells, the inhibitors showed antiviral activity with EC50 values ranging from 0.6 to 1.4 μM, by downregulating the viral protein production in cells as well as reducing secretion of infectious viral particles into culture supernatants. They also suppressed other α- and β-CoVs from human and feline origin. These compounds exhibited good selectivity index (over 70 against MERS-CoV) and could lead to the development of broad-spectrum antiviral drugs against emerging CoVs and picornaviruses.
wr10ar5p
wr10ar5p
2017-05-31
10.1016/j.antiviral.2017.02.007
2
Artificial intelligence approach fighting COVID-19 with repurposing drugs
Background: The ongoing COVID-19 pandemic has caused more than 193,825 deaths during the past few months. A quick-to-be-identified cure for the disease will be a therapeutic medicine that has prior use experiences in patients in order to resolve the current pandemic situation before it could become worsening. Artificial intelligence (AI) technology is hereby applied to identify the marketed drugs with potential for treating COVID-19. Material and methods: An AI platform was established to identify potential old drugs with anti-coronavirus activities by using two different learning databases; one consisted of the compounds reported or proven active against SARS-CoV, SARS-CoV-2, human immunodeficiency virus, influenza virus, and the other one containing the known 3C-like protease inhibitors. All AI predicted drugs were then tested for activities against a feline coronavirus in in vitro cell-based assay. These assay results were feedbacks to the AI system for relearning and thus to generate a modified AI model to search for old drugs again. Results: After a few runs of AI learning and prediction processes, the AI system identified 80 marketed drugs with potential. Among them, 8 drugs (bedaquiline, brequinar, celecoxib, clofazimine, conivaptan, gemcitabine, tolcapone, and vismodegib) showed in vitro activities against the proliferation of a feline infectious peritonitis (FIP) virus in Fcwf-4 cells. In addition, 5 other drugs (boceprevir, chloroquine, homoharringtonine, tilorone, and salinomycin) were also found active during the exercises of AI approaches. Conclusion: Having taken advantages of AI, we identified old drugs with activities against FIP coronavirus. Further studies are underway to demonstrate their activities against SARS-CoV-2 in vitro and in vivo at clinically achievable concentrations and doses. With prior use experiences in patients, these old drugs if proven active against SARS-CoV-2 can readily be applied for fighting COVID-19 pandemic.
wrzh32lh
wrzh32lh
2020
4.5
Structural Basis for Potent Neutralization of Betacoronaviruses by Single-domain Camelid Antibodies
The pathogenic Middle East respiratory syndrome coronavirus (MERS-CoV), severe acute respiratory syndrome coronavirus (SARS-CoV-1) and COVID-19 coronavirus (SARS-CoV-2) have all emerged into the human population with devastating consequences. These viruses make use of a large envelope protein called spike (S) to engage host cell receptors and catalyze membrane fusion. Because of the vital role that these S proteins play, they represent a vulnerable target for the development of therapeutics to combat these highly pathogenic coronaviruses. Here, we describe the isolation and characterization of single-domain antibodies (VHHs) from a llama immunized with prefusion-stabilized coronavirus spikes. These VHHs are capable of potently neutralizing MERS-CoV or SARS-CoV-1 S pseudotyped viruses. The crystal structures of these VHHs bound to their respective viral targets reveal two distinct epitopes, but both VHHs block receptor binding. We also show cross-reactivity between the SARS-CoV-1 S-directed VHH and SARS-CoV-2 S, and demonstrate that this cross-reactive VHH is capable of neutralizing SARS-CoV-2 S pseudotyped viruses as a bivalent human IgG Fc-fusion. These data provide a molecular basis for the neutralization of pathogenic betacoronaviruses by VHHs and suggest that these molecules may serve as useful therapeutics during coronavirus outbreaks.
wtvjjc7p
wtvjjc7p
2020-03-28
10.1101/2020.03.26.010165
1
The looming pandemic of COVID-19: What therapeutic options do we have now?
wuaxatrb
wuaxatrb
2020-04-21
10.1097/jcma.0000000000000310
2.5
Weak Induction of Interferon Expression by SARS-CoV-2 Supports Clinical Trials of Interferon Lambda to Treat Early COVID-19
wvubak45
wvubak45
2020-04-17
10.1093/cid/ciaa453
3.5
Coronavirus membrane fusion mechanism offers a potential target for antiviral development
The coronavirus disease 2019 (COVID-19) pandemic has focused attention on the need to develop effective therapies against the causative agent, SARS-CoV-2, and also against other pathogenic coronaviruses (CoV) that have emerged in the past or might appear in future. Researchers are therefore focusing on steps in the CoV replication cycle that may be vulnerable to inhibition by broad-spectrum or specific antiviral agents. The conserved nature of the fusion domain and mechanism across the CoV family make it a valuable target to elucidate and develop pan-CoV therapeutics. In this article, we review the role of the CoV spike protein in mediating fusion of the viral and host cell membranes, summarizing the results of research on SARS-CoV, MERS-CoV, and recent peer-reviewed studies of SARS-CoV-2, and suggest that the fusion mechanism be investigated as a potential antiviral target. We also provide a supplemental file containing background information on the biology, epidemiology, and clinical features of all human-infecting coronaviruses, along with a phylogenetic tree of these coronaviruses.
wwdn6uo2
wwdn6uo2
2020-04-06
10.1016/j.antiviral.2020.104792
3.5
Chapter 25 Preclinical Toxicology of Vaccines 1
Immunity to targeted infectious diseases may be conferred or enhanced by vaccines, which are manufactured from recombinant forms as well as inactivated or attenuated organisms. These vaccines have to meet requirements for safety, quality and efficacy. In addition to antigenic components, various adjuvants may be included in vaccines to evoke an effective immune response. To ensure the safety of new vaccines, preclinical toxicology studies are conducted prior to the initiation of, and concurrently with, clinical studies. There are five different types of preclinical toxicology study in the evaluation of vaccine safety: single and/or repeat dose, reproductive and developmental, mutagenicity, carcinogenicity, and safety pharmacology. If any adverse effects are observed in the course of these studies, they should be fully evaluated and a final safety decision made accordingly. Successful preclinical toxicology studies depend on multiple factors including: using the appropriate study designs, using the right animal model, and evoking an effective immune response. Additional in vivo and in vitro assays that establish the identity, purity, safety, and potency of the vaccine play a significant role in assessing critical characteristics of vaccine safety.
wwiopinv
wwiopinv
2013-12-31
10.1016/b978-0-12-387815-1.00025-3
1.5
Structure of Mpro from COVID-19 virus and discovery of its inhibitors
A new coronavirus (CoV) identified as COVID-19 virus is the etiological agent responsible for the 2019-2020 viral pneumonia outbreak that commenced in Wuhan1–4. Currently there is no targeted therapeutics and effective treatment options remain very limited. In order to rapidly discover lead compounds for clinical use, we initiated a program of combined structure-assisted drug design, virtual drug screening and high-throughput screening to identify new drug leads that target the COVID-19 virus main protease (Mpro). Mpro is a key CoV enzyme, which plays a pivotal role in mediating viral replication and transcription, making it an attractive drug target for this virus5,6. Here, we identified a mechanism-based inhibitor, N3, by computer-aided drug design and subsequently determined the crystal structure of COVID-19 virus Mpro in complex with this compound. Next, through a combination of structure-based virtual and high-throughput screening, we assayed over 10,000 compounds including approved drugs, drug candidates in clinical trials, and other pharmacologically active compounds as inhibitors of Mpro. Six of these inhibit Mpro with IC50 values ranging from 0.67 to 21.4 μM. Ebselen also exhibited promising antiviral activity in cell-based assays. Our results demonstrate the efficacy of this screening strategy, which can lead to the rapid discovery of drug leads with clinical potential in response to new infectious diseases where no specific drugs or vaccines are available.
wx7nheay
wx7nheay
2020-02-27
10.1101/2020.02.26.964882
1
Interaction of the spike protein RBD from SARS-CoV-2 with ACE2: similarity with SARS-CoV, hot-spot analysis and effect of the receptor polymorphism
The spread of COVID-19 caused by the SARS-CoV-2 outbreak has been growing since its first identification in December 2019. The publishing of the first SARS-CoV-2 genome made a valuable source of data to study the details about its phylogeny, evolution, and interaction with the host. Protein-protein binding assays have confirmed that Angiotensin-converting enzyme 2 (ACE2) is more likely to be the cell receptor through which the virus invades the host cell. In the present work, we provide an insight into the interaction of the viral spike Receptor Binding Domain (RBD) from different coronavirus isolates with host ACE2 protein. By calculating the binding energy score between RBD and ACE2, we highlighted the putative jump in the affinity from a progenitor form of SARS-CoV-2 to the current virus responsible for COVID-19 outbreak. Our result was consistent with previously reported phylogenetic analysis and corroborates the opinion that the interface segment of the spike protein RBD might be acquired by SARS-CoV-2 via a complex evolutionary process rather than a progressive accumulation of mutations. We also highlighted the relevance of Q493 and P499 amino acid residues of SARS-CoV-2 RBD for binding to human ACE2 and maintaining the stability of the interface. Moreover, we show from the structural analysis that it is unlikely for the interface residues to be the result of genetic engineering. Finally, we studied the impact of eight different variants located at the interaction surface of ACE2, on the complex formation with SARS-CoV-2 RBD. We found that none of them is likely to disrupt the interaction with the viral RBD of SARS-CoV-2.
wynyrumi
wynyrumi
2020-05-07
10.1101/2020.03.04.976027
1
Targeting ACE2-RBD interaction as a platform for COVID19 therapeutics: Development and drug repurposing screen of an AlphaLISA proximity assay
The COVID-19 pandemic, caused by SARS-CoV-2, is a pressing public health emergency garnering rapid response from scientists across the globe. Host cell invasion is initiated through direct binding of the viral spike protein to the host receptor angiotensin-converting enzyme 2 (ACE2). Disrupting the spike-ACE2 interaction is a potential therapeutic target for treating COVID-19. We have developed a proximity-based AlphaLISA assay to measure binding of SARS-CoV-2 spike protein Receptor Binding Domain (RBD) to ACE2. Utilizing this assay platform, a drug-repurposing screen against 3,384 small molecule drugs and pre-clinical compounds was performed, yielding 25 high-quality, small-molecule hits that can be evaluated in cell-based models. This established AlphaLISA RBD-ACE2 platform can facilitate evaluation of biologics or small molecules that can perturb this essential viral-host interaction to further the development of interventions to address the global health pandemic.
wz2wrgpk
wz2wrgpk
2020-06-16
10.1101/2020.06.16.154708
5
Improved Molecular Diagnosis of COVID-19 by the Novel, Highly Sensitive and Specific COVID-19-RdRp/Hel Real-Time Reverse Transcription-PCR Assay Validated In Vitro and with Clinical Specimens
On 31 December 2019, the World Health Organization was informed of a cluster of cases of pneumonia of unknown etiology in Wuhan, China. Subsequent investigations identified a novel coronavirus, now named severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), from the affected patients. Highly sensitive and specific laboratory diagnostics are important for controlling the rapidly evolving SARS-CoV-2-associated coronavirus disease 2019 (COVID-19) epidemic. In this study, we developed and compared the performance of three novel real-time reverse transcription-PCR (RT-PCR) assays targeting the RNA-dependent RNA polymerase (RdRp)/helicase (Hel), spike (S), and nucleocapsid (N) genes of SARS-CoV-2 with that of the reported RdRp-P2 assay, which is used in >30 European laboratories. Among the three novel assays, the COVID-19-RdRp/Hel assay had the lowest limit of detection in vitro (1.8 50% tissue culture infective doses [TCID50]/ml with genomic RNA and 11.2 RNA copies/reaction with in vitro RNA transcripts). Among 273 specimens from 15 patients with laboratory-confirmed COVID-19 in Hong Kong, 77 (28.2%) were positive by both the COVID-19-RdRp/Hel and RdRp-P2 assays. The COVID-19-RdRp/Hel assay was positive for an additional 42 RdRp-P2-negative specimens (119/273 [43.6%] versus 77/273 [28.2%]; P < 0.001), including 29/120 (24.2%) respiratory tract specimens and 13/153 (8.5%) non-respiratory tract specimens. The mean viral load of these specimens was 3.21 × 104 RNA copies/ml (range, 2.21 × 102 to 4.71 × 105 RNA copies/ml). The COVID-19-RdRp/Hel assay did not cross-react with other human-pathogenic coronaviruses and respiratory pathogens in cell culture and clinical specimens, whereas the RdRp-P2 assay cross-reacted with SARS-CoV in cell culture. The highly sensitive and specific COVID-19-RdRp/Hel assay may help to improve the laboratory diagnosis of COVID-19.
wzd51alu
wzd51alu
2020
3.5
Anti-SARS coronavirus 3C-like protease effects of Isatis indigotica root and plant-derived phenolic compounds
Abstract The 3C-like protease (3CLpro) of SARS-coronavirus mediates the proteolytic processing of replicase polypeptides 1a and 1ab into functional proteins, becoming an important target for the drug development. In this study, Isatis indigotica root extract, five major compounds of I. indigotica root, and seven plant-derived phenolic compounds were tested for anti-SARS-CoV 3CLpro effects using cell-free and cell-based cleavage assays. Cleavage assays with the 3CLpro demonstrated that IC50 values were in micromolar ranges for I. indigotica root extract, indigo, sinigrin, aloe emodin and hesperetin. Sinigrin (IC50: 217μM) was more efficient in blocking the cleavage processing of the 3CLpro than indigo (IC50: 752μM) and beta-sitosterol (IC50: 1210μM) in the cell-based assay. Only two phenolic compounds aloe emodin and hesperetin dose-dependently inhibited cleavage activity of the 3CLpro, in which the IC50 was 366μM for aloe emodin and 8.3μM for hesperetin in the cell-based assay.
x0z68jos
x0z68jos
2005-10-31
10.1016/j.antiviral.2005.07.002
2.5
Prophylactic and therapeutic remdesivir (GS-5734) treatment in the rhesus macaque model of MERS-CoV infection
The continued emergence of Middle East Respiratory Syndrome (MERS) cases with a high case fatality rate stresses the need for the availability of effective antiviral treatments. Remdesivir (GS-5734) effectively inhibited MERS coronavirus (MERS-CoV) replication in vitro, and showed efficacy against Severe Acute Respiratory Syndrome (SARS)-CoV in a mouse model. Here, we tested the efficacy of prophylactic and therapeutic remdesivir treatment in a nonhuman primate model of MERS-CoV infection, the rhesus macaque. Prophylactic remdesivir treatment initiated 24 h prior to inoculation completely prevented MERS-CoV-induced clinical disease, strongly inhibited MERS-CoV replication in respiratory tissues, and prevented the formation of lung lesions. Therapeutic remdesivir treatment initiated 12 h postinoculation also provided a clear clinical benefit, with a reduction in clinical signs, reduced virus replication in the lungs, and decreased presence and severity of lung lesions. The data presented here support testing of the efficacy of remdesivir treatment in the context of a MERS clinical trial. It may also be considered for a wider range of coronaviruses, including the currently emerging novel coronavirus 2019-nCoV.
x1fzgiy6
x1fzgiy6
2020
5
Prevention and Control Strategies for SARS-CoV-2 Infection
The population of 168 countries all over the world is struggling with the outbreak of COVID-19. The outbreak is declared as pandemic and public health emergency of international concern declared by WHO. SARS-CoV-2 responsible for the present health emergency exhibited close resemblance with SARS-CoV. Both the viruses are zoonotic and belong to a large family of viruses Coronaviridae. The complete virus particle is made up of four major structural proteins, namely spikes (S), nucleocapsid (N), membrane (M), and envelope (E) encoded by virus genome. The S protein of virus shows similarity to S protein of SARS-CoV. COVID-19 spreads from person to person, and this makes it more vulnerable for causing infection. Several efforts are taken to find prevention strategies for COVID-19. Researchers across the globe are working to find effective vaccination for SARS-CoV-2. There is no vaccine or medication available till date for COVID-19. Preventive measures such as social distancing, awareness, maintenance of hygiene, isolation, and movement restrictions can help in control of COVID-19 spread. Proper sanitization and cleaned and sanitized public transport can be effective in inhibiting the spread of the virus. In the present situation of medical emergency, cooperation and support by following advices from the WHO and government only facilitate everyone to come over.
x1u70y1x
x1u70y1x
2020-04-30
10.1007/978-981-15-4814-7_11
3.5
Optimization Method for Forecasting Confirmed Cases of COVID-19 in China
In December 2019, a novel coronavirus, called COVID-19, was discovered in Wuhan, China, and has spread to different cities in China as well as to 24 other countries. The number of confirmed cases is increasing daily and reached 34,598 on 8 February 2020. In the current study, we present a new forecasting model to estimate and forecast the number of confirmed cases of COVID-19 in the upcoming ten days based on the previously confirmed cases recorded in China. The proposed model is an improved adaptive neuro-fuzzy inference system (ANFIS) using an enhanced flower pollination algorithm (FPA) by using the salp swarm algorithm (SSA). In general, SSA is employed to improve FPA to avoid its drawbacks (i.e., getting trapped at the local optima). The main idea of the proposed model, called FPASSA-ANFIS, is to improve the performance of ANFIS by determining the parameters of ANFIS using FPASSA. The FPASSA-ANFIS model is evaluated using the World Health Organization (WHO) official data of the outbreak of the COVID-19 to forecast the confirmed cases of the upcoming ten days. More so, the FPASSA-ANFIS model is compared to several existing models, and it showed better performance in terms of Mean Absolute Percentage Error (MAPE), Root Mean Squared Relative Error (RMSRE), Root Mean Squared Relative Error (RMSRE), coefficient of determination ([Formula: see text]), and computing time. Furthermore, we tested the proposed model using two different datasets of weekly influenza confirmed cases in two countries, namely the USA and China. The outcomes also showed good performances.
x1zq2i9h
x1zq2i9h
2020-03-02
10.3390/jcm9030674
1
Hot Topic Commentary on COVID-19
The recent pandemic outbreak of COVID-19 (severe acute respiratory syndrome coronavirus 2; SARS-CoV-2) worldwide caught the health care systems in every country around the world by storm and without a proper defense mechanism to cope and control such a pandemic. In this special Theme issue, we would like to discuss the latest treatment modalities available around the world in tackling this dreadful disease.
x3dz0zct
x3dz0zct
2020-05-11
10.1007/s40495-020-00215-8
3.5
Applications of Paper as a support material in biomedical sciences: A Decadal review
Abstract: In human history, the paper has long been used as a platform to record and preserve information. However, over the decades, paper has found its application in Biomedical Sciences, too. Both paper-based microfluidic devices (μPADs) and paper-based cultures and scaffolds have shown immense potential to be used as a sensor as well as a supporting material for in vitro tissue engineering. μPADs can be used to perform low-cost and fast biomolecular assays at Point-Of-Care (POC). They are being used to detect various biomarkers like viral proteins, metabolites, oncogenes, and antigens; and conditions like Venous Thromboembolism (VTE). On the other hand, the paper has also been used to develop paper-based 3D cultures and scaffolds to test drugs, and monitor cytotoxic effects in vitro cell microenvironments and also as implantable tissues. In this review, we intend to enumerate the development in the field of μPADs, paper-based cell cultures, and paper-based scaffolds and their plethora of applications over the last decade.
x3lrlzsd
x3lrlzsd
2020-04-09
10.1016/j.sintl.2020.100004
3.5
Prophylactic and therapeutic remdesivir (GS-5734) treatment in the rhesus macaque model of MERS-CoV infection
The continued emergence of Middle East Respiratory Syndrome (MERS) cases with a high case fatality rate stresses the need for the availability of effective antiviral treatments. Remdesivir (GS-5734) effectively inhibited MERS coronavirus (MERS-CoV) replication in vitro, and showed efficacy against Severe Acute Respiratory Syndrome (SARS)-CoV in a mouse model. Here, we tested the efficacy of prophylactic and therapeutic remdesivir treatment in a nonhuman primate model of MERS-CoV infection, the rhesus macaque. Prophylactic remdesivir treatment initiated 24 h prior to inoculation completely prevented MERS-CoV−induced clinical disease, strongly inhibited MERS-CoV replication in respiratory tissues, and prevented the formation of lung lesions. Therapeutic remdesivir treatment initiated 12 h postinoculation also provided a clear clinical benefit, with a reduction in clinical signs, reduced virus replication in the lungs, and decreased presence and severity of lung lesions. The data presented here support testing of the efficacy of remdesivir treatment in the context of a MERS clinical trial. It may also be considered for a wider range of coronaviruses, including the currently emerging novel coronavirus 2019-nCoV.
x50tvq3a
x50tvq3a
2020-03-24
10.1073/pnas.1922083117
2.5
Differential neurodegenerative phenotypes are associated with heterogeneous voiding dysfunction in a coronavirus-induced model of multiple sclerosis
Patients with multiple sclerosis (MS) develop a variety of lower urinary tract symptoms (LUTS). We previously characterized a murine model of neurogenic bladder dysfunction induced by a neurotropic strain of a coronavirus. In the present study, we further study the role of long-lasting neurodegeneration on the development of neurogenic bladder dysfunction in mice with corona-virus induced encephalitis (CIE). Long-term follow up study revealed three phenotypes of neurodegenerative symptom development: recovery (REC group), chronic progression (C-PRO group) and chronic disease with relapsing-remitting episodes (C-RELAP group). The levels of IL-1β in REC group, IL-10 in C-RELAP group, and IL-1β, IL-6, IL-10 and TNF-α in C-PRO group were diminished in the brain. The levels of TNF-α in REC group and INF-γ, IL-2, TGF-β and TNF-α in the C-PRO group were also diminished in the urinary bladder. Mice in C-RELAP group showed a delayed recovery of voiding function. In vitro contractility studies determined a decreased basal detrusor tone and reduced amplitude of nerve-mediated contractions in C-RELAP group, whereas C-PRO group had elevated muscle-mediated contractions. In conclusion, mice with CIE developed three phenotypes of neurologic impairment mimicking different types of MS progression in humans and showed differential mechanisms driving neurogenic bladder dysfunction.
x58r5cpv
x58r5cpv
2019-07-26
10.1038/s41598-019-47407-x
2
Human iPSC-Derived Cardiomyocytes are Susceptible to SARS-CoV-2 Infection
Coronavirus disease 2019 (COVID-19) is a viral pandemic caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). COVID-19 is predominantly defined by respiratory symptoms, but cardiac complications including arrhythmias, heart failure, and viral myocarditis are also prevalent. Although the systemic ischemic and inflammatory responses caused by COVID-19 can detrimentally affect cardiac function, the direct impact of SARS-CoV-2 infection on human cardiomyocytes is not well-understood. We used human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) as a model system to examine the mechanisms of cardiomyocyte-specific infection by SARS-CoV-2. Microscopy and immunofluorescence demonstrated that SARS-CoV-2 can enter and replicate within hiPSC-CMs, localizing at perinuclear locations within the cytoplasm. Viral cytopathic effect induced hiPSC-CM apoptosis and cessation of beating after 72 hours of infection. These studies show that SARS-CoV-2 can infect hiPSC-CMs in vitro, establishing a model for elucidating the mechanisms of infection and potentially a cardiac-specific antiviral drug screening platform.
x5t90x56
x5t90x56
2020-04-21
10.1101/2020.04.21.051912
2
Cyberbiosecurity Challenges of Pathogen Genome Databases
Pathogen detection, identification, and tracking is shifting from non-molecular methods, DNA fingerprinting methods, and single gene methods to methods relying on whole genomes. Viral Ebola and influenza genome data are being used for real-time tracking, while food-borne bacterial pathogen outbreaks and hospital outbreaks are investigated using whole genomes in the UK, Canada, the USA and the other countries. Also, plant pathogen genomes are starting to be used to investigate plant disease epidemics such as the wheat blast outbreak in Bangladesh. While these genome-based approaches provide never-seen advantages over all previous approaches with regard to public health and biosecurity, they also come with new vulnerabilities and risks with regard to cybersecurity. The more we rely on genome databases, the more likely these databases will become targets for cyber-attacks to interfere with public health and biosecurity systems by compromising their integrity, taking them hostage, or manipulating the data they contain. Also, while there is the potential to collect pathogen genomic data from infected individuals or agricultural and food products during disease outbreaks to improve disease modeling and forecast, how to protect the privacy of individuals, growers, and retailers is another major cyberbiosecurity challenge. As data become linkable to other data sources, individuals and groups become identifiable and potential malicious activities targeting those identified become feasible. Here, we define a number of potential cybersecurity weaknesses in today's pathogen genome databases to raise awareness, and we provide potential solutions to strengthen cyberbiosecurity during the development of the next generation of pathogen genome databases.
x6s34z1s
x6s34z1s
2019-05-15
10.3389/fbioe.2019.00106
1.5
Predicting Mortality Risk in Patients with COVID-19 Using Artificial Intelligence to Help Medical Decision-Making
In the wake of COVID-19 disease, caused by the SARS-CoV-2 virus, we designed and developed a predictive model based on Artificial Intelligence (AI) and Machine Learning algorithms to determine the health risk and predict the mortality risk of patients with COVID-19. In this study, we used documented data of 117,000 patients world-wide with laboratory-confirmed COVID-19. This study proposes an AI model to help hospitals and medical facilities decide who needs to get attention first, who has higher priority to be hospitalized, triage patients when the system is overwhelmed by overcrowding, and eliminate delays in providing the necessary care. The results demonstrate 93% overall accuracy in predicting the mortality rate. We used several machine learning algorithms including Support Vector Machine (SVM), Artificial Neural Networks, Random Forest, Decision Tree, Logistic Regression, and K-Nearest Neighbor (KNN) to predict the mortality rate in patients with COVID-19. In this study, the most alarming symptoms and features were also identified. Finally, we used a separate dataset of COVID-19 patients to evaluate our developed model accuracy, and used confusion matrix to make an in-depth analysis of our classifiers and calculate the sensitivity and specificity of our model.
x70501t3
x70501t3
2020-04-01
10.1101/2020.03.30.20047308
1.5
Measures for diagnosing and treating infections by a novel coronavirus responsible for a pneumonia outbreak originating in Wuhan, China
Abstract On 10 January 2020, a new coronavirus causing a pneumonia outbreak in Wuhan City in central China was denoted as 2019-nCoV by the World Health Organization (WHO). As of 24 January 2020, there were 887 confirmed cases of 2019-nCoV infection, including 26 deaths, reported in China and other countries. Therefore, combating this new virus and stopping the epidemic is a matter of urgency. Here, we focus on advances in research and development of fast diagnosis methods, as well as potential prophylactics and therapeutics to prevent or treat 2019-nCoV infection.
x95h80nq
x95h80nq
2020-03-31
10.1016/j.micinf.2020.01.003
1.5
Replication of human coronaviruses SARS-CoV, HCoV-NL63 and HCoV-229E is inhibited by the drug FK506
Abstract Recent research has shown that Coronavirus (CoV) replication depends on active immunophilin pathways. Here we demonstrate that the drug FK506 (Tacrolimus) inhibited strongly the growth of human coronaviruses SARS-CoV, HCoV-NL63 and HCoV-229E at low, non-cytotoxic concentrations in cell culture. As shown by plaque titration, qPCR, Luciferase- and green fluorescent protein (GFP) reporter gene expression, replication was diminished by several orders of magnitude. Knockdown of the cellular FK506-binding proteins FKBP1A and FKBP1B in CaCo2 cells prevented replication of HCoV-NL63, suggesting the requirement of these members of the immunophilin family for virus growth.
xanqvdhn
xanqvdhn
2012-04-30
10.1016/j.virusres.2012.02.002
1.5
Multiple sclerosis: experimental models and reality
One of the most frequent statements, provided in different variations in the introduction of experimental studies on multiple sclerosis (MS), is that “Multiple sclerosis is a demyelinating autoimmune disease and experimental autoimmune encephalomyelitis (EAE) is a suitable model to study its pathogenesis”. However, so far, no single experimental model covers the entire spectrum of the clinical, pathological, or immunological features of the disease. Many different models are available, which proved to be highly useful for studying different aspects of inflammation, demyelination, remyelination, and neurodegeneration in the central nervous system. However, the relevance of results from such models for MS pathogenesis has to be critically validated. Current EAE models are mainly based on inflammation, induced by auto-reactive CD4(+) T-cells, and these models reflect important aspects of MS. However, pathological data and results from clinical trials in MS indicate that CD8(+) T-cells and B-lymphocytes may play an important role in propagating inflammation and tissue damage in established MS. Viral models may reflect key features of MS-like inflammatory demyelination, but are difficult to use due to their very complex pathogenesis, involving direct virus-induced and immune-mediated mechanisms. Furthermore, evidence for a role of viruses in MS pathogenesis is indirect and limited, and an MS-specific virus infection has not been identified so far. Toxic models are highly useful to unravel mechanisms of de- and remyelination, but do not reflect other important aspects of MS pathology and pathogenesis. For all these reasons, it is important to select the right experimental model to answer specific questions in MS research.
xbfguoj4
xbfguoj4
2016-10-20
10.1007/s00401-016-1631-4
1
The epidemiology and clinical information about COVID-19
In December 2019, pneumonia of unknown cause occurred in Wuhan, Hubei Province, China. On 7 January 2020, a novel coronavirus, named as severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), was identified in the throat swab sample of one patient. The World Health Organization (WHO) announced the epidemic disease caused by SARS-CoV-2 as coronavirus disease 2019 (COVID-19). Currently, COVID-19 has spread widely around the world, affecting more than seventy countries. China, with a huge burden of this disease, has taken strong measures to control the spread and improve the curative rate of COVID-19. In this review, we summarized the epidemiological characteristics, clinical features, diagnosis, treatment, and prognosis of COVID-19. A comprehensive understanding will help to control the disease.
xbpb9nfi
xbpb9nfi
2020-04-14
10.1007/s10096-020-03874-z
4.5
Candidate drugs against SARS-CoV-2 and COVID-19
Outbreak and pandemic of coronavirus SARS-CoV-2 in 2019/2020 will challenge global health for the future. Because a vaccine against the virus will not be available in the near future, we herein try to offer a pharmacological strategy to combat the virus. There exists a number of candidate drugs that may inhibit infection with and replication of SARS-CoV-2. Such drugs comprise inhibitors of TMPRSS2 serine protease and inhibitors of angiotensin-converting enzyme 2 (ACE2). Blockade of ACE2, the host cell receptor for the S protein of SARS-CoV-2 and inhibition of TMPRSS2, which is required for S protein priming may prevent cell entry of SARS-CoV-2. Further, chloroquine and hydroxychloroquine, and off-label antiviral drugs, such as the nucleotide analogue remdesivir, HIV protease inhibitors lopinavir and ritonavir, broad-spectrum antiviral drugs arbidol and favipiravir as well as antiviral phytochemicals available to date may limit spread of SARS-CoV-2 and morbidity and mortality of COVID-19 pandemic.
xef6fr39
xef6fr39
2020
5
Severe acute respiratory syndrome and tuberculosis
Respiratory infectious diseases such as severe acute respiratory syndrome and tuberculosis create unique risks for anyone who may be exposed. A brief history of each disease is discussed in this article. The pathogenesis, manifestations, and therapy (where applicable) are also addressed. Recommendations for limiting secondary transmission are given based on the Centers for Disease Control and Prevention guidelines on infection control in health care facilities.
xf1k5uj1
xf1k5uj1
2004-09-30
10.1016/j.atc.2004.06.002
0.5
Conditional Cell Reprogramming for Modeling Host-Virus Interactions and Human Viral Diseases.
Conventional cancer and transformed cell lines are widely used in cancer biology and other fields within biology. These cells usually have abnormalities from the original tumor itself, but may also develop abnormalities due to genetic manipulation, or genetic and epigenetic changes during long term passages. Primary cultures may maintain lineage functions as the original tissue types, yet they have a very limited life span or population doubling time because of the nature of cellular senescence. Primary cultures usually have very low yields, and the high variability from any original tissue specimens, largely limiting their applications in research. Animal models are often used for studies of virus infections, disease modeling, development of antiviral drugs and vaccines. Human viruses often need a series of passages in vivo in order to adapt to the host environment because of variable receptors on the cell surface and may have intracellular restrictions from the cell types or host species. Here we describe a long term cell culture system, conditionally reprogrammed cells (CRCs), and its applications in modeling human viral diseases and drug discovery. Using feeder layer co-culture in presence of Y-27632 (conditional reprogramming, CR), CRCs can be obtained and rapidly propagated from surgical specimens, core or needle biopsies, and other minimally invasive or non-invasive specimens, for example, nasal cavity brushing. CRCs preserve their lineage functions, and provide biologically relevant and physiological conditions, which are suitable for studies of viral entry and replication, innate immune responses of host cells, and discovery of antiviral drugs. In this review, we summarize applications of CR technology in modeling host-virus interactions and human viral diseases, including SARS-CoV-2 and COVID-19, and anti-viral discovery. This article is protected by copyright. All rights reserved.
xg53p4sv
xg53p4sv
2020-06-01
10.1002/jmv.26093
5
The Anticoagulant Nafamostat Potently Inhibits SARS-CoV-2 S Protein-Mediated Fusion in a Cell Fusion Assay System and Viral Infection In Vitro in a Cell-Type-Dependent Manner.
Although infection by SARS-CoV-2, the causative agent of coronavirus pneumonia disease (COVID-19), is spreading rapidly worldwide, no drug has been shown to be sufficiently effective for treating COVID-19. We previously found that nafamostat mesylate, an existing drug used for disseminated intravascular coagulation (DIC), effectively blocked Middle East respiratory syndrome coronavirus (MERS-CoV) S protein-mediated cell fusion by targeting transmembrane serine protease 2 (TMPRSS2), and inhibited MERS-CoV infection of human lung epithelium-derived Calu-3 cells. Here we established a quantitative fusion assay dependent on severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) S protein, angiotensin I converting enzyme 2 (ACE2) and TMPRSS2, and found that nafamostat mesylate potently inhibited the fusion while camostat mesylate was about 10-fold less active. Furthermore, nafamostat mesylate blocked SARS-CoV-2 infection of Calu-3 cells with an effective concentration (EC)50 around 10 nM, which is below its average blood concentration after intravenous administration through continuous infusion. On the other hand, a significantly higher dose (EC50 around 30 mM) was required for VeroE6/TMPRSS2 cells, where the TMPRSS2-independent but cathepsin-dependent endosomal infection pathway likely predominates. Together, our study shows that nafamostat mesylate potently inhibits SARS-CoV-2 S protein-mediated fusion in a cell fusion assay system and also inhibits SARS-CoV-2 infection in vitro in a cell-type-dependent manner. These findings, together with accumulated clinical data regarding nafamostat's safety, make it a likely candidate drug to treat COVID-19.
xge5hxel
xge5hxel
2020-06-10
10.3390/v12060629
4
First Reported Cases of SARS-CoV-2 Infection in Companion Animals - New York, March-April 2020
On April 22, CDC and the U.S. Department of Agriculture (USDA) reported cases of two domestic cats with confirmed infection with SARS-CoV-2, the virus that causes coronavirus disease 2019 (COVID-19). These are the first reported companion animals (including pets and service animals) with SARS-CoV-2 infection in the United States, and among the first findings of SARS-CoV-2 symptomatic companion animals reported worldwide. These feline cases originated from separate households and were epidemiologically linked to suspected or confirmed human COVID-19 cases in their respective households. Notification of presumptive positive animal test results triggered a One Health* investigation by state and federal partners, who determined that no further transmission events to other animals or persons had occurred. Both cats fully recovered. Although there is currently no evidence that animals play a substantial role in spreading COVID-19, CDC advises persons with suspected or confirmed COVID-19 to restrict contact with animals during their illness and to monitor any animals with confirmed SARS-CoV-2 infection and separate them from other persons and animals at home (1).
xgnv3eiw
xgnv3eiw
2020
5
Chapter 28 Experimental Infections of the Common Marmoset (Callithrix jacchus)
Abstract Interest in the use of marmosets for experimental infectious disease has dramatically increased in the last decade. These animals are native to the Atlantic coastal forests in northeastern Brazil. The majority of experimental animals come from the National Primate Research Centers and other breeding facilities. They are advantageous because of their relative small size, weighting 350–400g as adults, their life span is compact compared with other nonhuman primate (NHP), and they produce offspring by 3years of age. They are free of Herpes B virus and, it is believed, to date, other dangerous human pathogens (Abbot et al., 2003) [1]. We describe here the experimental infections of marmosets to human pathogens. While it is always interesting to compare various NHPs with each other, the importance of an animal model is always in comparing its similarities to human infections.
xixdcdm1
xixdcdm1
2019-12-31
10.1016/b978-0-12-811829-0.00028-5
1
Caring for children and adolescents with eating disorders in the current COVID-19 pandemic: A Singapore perspective
Abstract Our public pediatric tertiary hospital in Singapore has been a part of a robust public heath response to COVID-19 that has been calibrated in a timely manner to the evolving international situation. As of mid-March, Singapore remains in a containment mode with enhanced surveillance and limited community spread. Within this context, our service for pediatric eating disorder care has had to make significant adaptations to our models of service delivery as well as respond to the changing psychosocial needs of our patients. Given infection control requirements, we have instituted modular staffing for our inpatient and outpatient settings, necessitating task shifting and an increased use of technology for communication. Due to reduced outpatient capacity and the need to minimize non-urgent trips to the hospital, we have implemented telemedicine and have leveraged on partnerships with school counselors and other community partners. “Coronaphobia” has influenced our patients’ willingness to attend visits and worsened existing health anxiety for some. Responsiveness to families’ and patients’ health and financial concerns has been essential. As COVID-19 impacts more countries, our institution’s experience can provide insight into challenges and possible adaptations to providing ongoing care for eating disorder patients in this environment.
xjco8xb0
xjco8xb0
2020-04-06
10.1016/j.jadohealth.2020.03.037
1.5
Revisiting potential druggable targets against SARS‐CoV‐2 and repurposing therapeutics under preclinical study and clinical trials: A comprehensive review
Coronavirus disease‐19 (COVID‐19), caused by severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2), is one of the most contagious diseases in human history that has already affected millions of lives worldwide. To date, no vaccines or effective therapeutics have been discovered yet that may successfully treat COVID‐19 patients or contain the transmission of the virus. Scientific communities across the globe responded rapidly and have been working relentlessly to develop drugs and vaccines, which may require considerable time. In this uncertainty, repurposing the existing antiviral drugs could be the best strategy to speed up the discovery of effective therapeutics against SARS‐CoV‐2. Moreover, drug repurposing may leave some vital information on druggable targets that could be capitalized in target‐based drug discovery. Information on possible drug targets and the progress on therapeutic and vaccine development also needs to be updated. In this review, we revisited the druggable targets that may hold promise in the development of the anti‐SARS‐CoV‐2 agent. Progresses on the development of potential therapeutics and vaccines that are under the preclinical studies and clinical trials have been highlighted. We anticipate that this review will provide valuable information that would help to accelerate the development of therapeutics and vaccines against SARS‐CoV‐2 infection.
xkoilncd
xkoilncd
2020-07-06
10.1002/ddr.21709
5
Comparing the binding interactions in the receptor binding domains of SARS-CoV-2 and SARS-CoV
COVID-19, since emerged in Wuhan, China, has been a major concern due to its high infection rate, leaving more than one million infected people around the world. Huge number of studies tried to reveal the structure of the SARS-CoV-2 compared to the SARS-CoV-1, in order to suppress this high infection rate. Some of these studies showed that the mutations in the SARS-CoV-1 Spike protein might be responsible for its higher affinity to the ACE2 human cell receptor. In this work, we used molecular dynamics simulations and Monte Carlo sampling to compare the binding affinities of the spike proteins of SARS-CoV and SARS-CoV-2 to the ACE2. We found that the SARS-CoV-2 binds to ACE2 stronger than SARS-CoV by 7 kcal/mol, due to enhanced electrostatic interactions. The major contributions to the electrostatic binding energies are resulting from the salt-bridges formed between R426 and ACE2-E329 in case of SARS-CoV and K417 and ACE2-D30 for SARS-CoV2. In addition, there is no significant contribution from a single mutant to the binding energies. However, these mutations induce sophisticated structural changes that enhance the binding energies. Our results also indicate that the SARS-CoV-2 is unlikely a lab engineered virus.
xpbcoipf
xpbcoipf
2020-04-05
3.5
TACE antagonists blocking ACE2 shedding caused by the spike protein of SARS-CoV are candidate antiviral compounds
Abstract Because outbreaks of severe acute respiratory syndrome coronavirus (SARS-CoV) might reemerge, identifying antiviral compounds is of key importance. Previously, we showed that the cellular factor TNF-α converting enzyme (TACE), activated by the spike protein of SARS-CoV (SARS-S protein), was positively involved in viral entry, implying that TACE is a possible target for developing antiviral compounds. To demonstrate this possibility, we here tested the effects of TACE inhibitors on viral entry. In vitro and in vivo data revealed that the TACE inhibitor TAPI-2 attenuated entry of both pseudotyped virus expressing the SARS-S protein in a lentiviral vector backbone and infectious SARS-CoV. TAPI-2 blocked both the SARS-S protein-induced shedding of angiotensin-converting enzyme 2 (ACE2), a receptor of SARS-CoV, and TNF-α production in lung tissues. Since the downregulation of ACE2 by SARS-S protein was proposed as an etiological event in the severe clinical manifestations, our data suggest that TACE antagonists block SARS-CoV infection and also attenuate its severe clinical outcome.
xpqd9j5s
xpqd9j5s
2010-03-31
10.1016/j.antiviral.2009.12.001
2.5
Crystal structure of Nsp15 endoribonuclease NendoU from SARS-CoV-2
Severe Acute Respiratory Syndrome Coronavirus 2 is rapidly spreading around the world. There is no existing vaccine or proven drug to prevent infections and stop virus proliferation. Although this virus is similar to human and animal SARS- and MERS-CoVs the detailed information about SARS-CoV-2 proteins structures and functions is urgently needed to rapidly develop effective vaccines, antibodies and antivirals. We applied high-throughput protein production and structure determination pipeline at the Center for Structural Genomics of Infectious Diseases to produce SARS-CoV-2 proteins and structures. Here we report the high-resolution crystal structure of endoribonuclease Nsp15/NendoU from SARS-CoV-2 – a virus causing current world-wide epidemics. We compare this structure with previously reported models of Nsp15 from SARS and MERS coronaviruses.
xq1cxrvf
xq1cxrvf
2020-03-03
10.1101/2020.03.02.968388
1
From SARS-CoV to SARS-CoV-2: safety and broad-spectrum are important for coronavirus vaccine development
The global pandemic of COVID-19 caused by SARS-CoV-2 (also known as 2019-nCoV and HCoV-19) has posed serious threats to public health and economic stability worldwide, thus calling for development of vaccines against SARS-CoV-2 and other emerging and reemerging coronaviruses. Since SARS-CoV-2 and SARS-CoV have high similarity of their genomic sequences and share the same cellular receptor (ACE2), it is essential to learn the lessons and experiences from the development of SARS-CoV vaccines for the development of SARS-CoV-2 vaccines. In this review, we summarized the current knowledge on the advantages and disadvantages of the SARS-CoV vaccine candidates and prospected the strategies for the development of safe, effective and broad-spectrum coronavirus vaccines for prevention of infection by currently circulating SARS-CoV-2 and other emerging and reemerging coronaviruses that may cause future epidemics or pandemics.
xtqvtleb
xtqvtleb
2020-05-11
10.1016/j.micinf.2020.05.004
3.5
The epidemiology and pathogenesis of coronavirus disease (COVID-19) outbreak
Abstract Coronavirus disease (COVID-19) is caused by SARS-COV2 and represents the causative agent of a potentially fatal disease that is of great global public health concern. Based on the large number of infected people that were exposed to the wet animal market in Wuhan City, China, it is suggested that this is likely the zoonotic origin of COVID-19. Person-to-person transmission of COVID-19 infection led to the isolation of patients that were subsequently administered a variety of treatments. Extensive measures to reduce person-to-person transmission of COVID-19 have been implemented to control the current outbreak. Special attention and efforts to protect or reduce transmission should be applied in susceptible populations including children, health care providers, and elderly people. In this review, we highlights the symptoms, epidemiology, transmission, pathogenesis, phylogenetic analysis and future directions to control the spread of this fatal disease.
xuczplaf
xuczplaf
2020-05-31
10.1016/j.jaut.2020.102433
1
Molecular Advances in Severe Acute Respiratory Syndrome-associated Coronavirus (SARS-CoV)
The sudden outbreak of severe acute respiratory syndrome (SARS) in 2002 prompted the establishment of a global scientific network subsuming most of the traditional rivalries in the competitive field of virology. Within months of the SARS outbreak, collaborative work revealed the identity of the disastrous pathogen as SARS-associated coronavirus (SARS-CoV). However, although the rapid identification of the agent represented an important breakthrough, our understanding of the deadly virus remains limited. Detailed biological knowledge is crucial for the development of effective countermeasures, diagnostic tests, vaccines and antiviral drugs against the SARS-CoV. This article reviews the present state of molecular knowledge about SARS-CoV, from the aspects of comparative genomics, molecular biology of viral genes, evolution, and epidemiology, and describes the diagnostic tests and the anti-viral drugs derived so far based on the available molecular information.
xuj4yymz
xuj4yymz
2016-11-28
10.1016/s1672-0229(03)01031-3
3.5
SARS-CoV-2 and COVID-19: What are our options? Where should we focus our attention on to find new drugs and strategies?
xuqsskin
xuqsskin
2020-04-22
10.1016/j.tmaid.2020.101685
3.5
Conditionally Reprogrammed Human Normal Airway Epithelial Cells at ALI: A Physiological Model for Emerging Viruses
Cancer cell lines have been used widely in cancer biology, and as biological or functional cell systems in many biomedical research fields. These cells are usually defective for many normal activities or functions due to significant genetic and epigenetic changes. Normal primary cell yields and viability from any original tissue specimens are usually relatively low or highly variable. These normal cells cease after a few passages or population doublings due to very limited proliferative capacity. Animal models (ferret, mouse, etc.) are often used to study virus-host interaction. However, viruses usually need to be adapted to the animals by several passages due to tropism restrictions including viral receptors and intracellular restrictions. Here we summarize applications of conditionally reprogrammed cells (CRCs), long-term cultures of normal airway epithelial cells from human nose to lung generated by conditional cell reprogramming (CR) technology, as an ex vivo model in studies of emerging viruses. CR allows to robustly propagate cells from non-invasive or minimally invasive specimens, for example, nasal or endobronchial brushing. This process is rapid (2 days) and conditional. The CRCs maintain their differentiation potential and lineage functions, and have been used for studies of adenovirus, rhinovirus, respiratory syncytial virus, influenza viruses, parvovirus, and SARS-CoV. The CRCs can be easily used for air-liquid interface (ALI) polarized 3D cultures, and these coupled CRC/ALI cultures mimic physiological conditions and are suitable for studies of viral entry including receptor binding and internalization, innate immune responses, viral replications, and drug discovery as an ex vivo model for emerging viruses.
xuwpaumj
xuwpaumj
2020-06-17
10.1007/s12250-020-00244-z
4
Molecular detection of SARS-CoV-2 in formalin-fixed, paraffin-embedded specimens
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the cause of human coronavirus disease 2019 (COVID-19), emerged in Wuhan, China, in December 2019. The virus rapidly spread globally, resulting in a public health crisis including almost 5 million cases and 323,256 deaths as of May 21, 2020. Here, we describe the identification and evaluation of commercially available reagents and assays for the molecular detection of SARS-CoV-2 in infected FFPE cell pellets. We identified a suitable rabbit polyclonal anti-SARS-CoV spike protein antibody and a mouse monoclonal anti-SARS-CoV nucleocapsid protein (NP) antibody for cross-detection of the respective SARS-CoV-2 proteins by IHC and immunofluorescence assay (IFA). Next, we established RNAscope in situ hybridization (ISH) to detect SARS-CoV-2 RNA. Furthermore, we established a multiplex FISH (mFISH) to detect positive-sense SARS-CoV-2 RNA and negative-sense SARS-CoV-2 RNA (a replicative intermediate indicating viral replication). Finally, we developed a dual staining assay using IHC and ISH to detect SARS-CoV-2 antigen and RNA in the same FFPE section. It is hoped that these reagents and assays will accelerate COVID-19 pathogenesis studies in humans and in COVID-19 animal models.
xv2tev5n
xv2tev5n
2020
5
COVID-19 Coronavirus spike protein analysis for synthetic vaccines, a peptidomimetic antagonist, and therapeutic drugs, and analysis of a proposed achilles’ heel conserved region to minimize probability of escape mutations and drug resistance
Abstract This paper continues a recent study of the spike protein sequence of the COVID-19 virus (SARS-CoV-2). It is also in part an introductory review to relevant computational techniques for tackling viral threats, using COVID-19 as an example. Q-UEL tools for facilitating access to knowledge and bioinformatics tools were again used for efficiency, but the focus in this paper is even more on the virus. Subsequence KRSFIEDLLFNKV of the S2′ spike glycoprotein proteolytic cleavage site continues to appear important. Here it is shown to be recognizable in the common cold coronaviruses, avian coronaviruses and possibly as traces in the nidoviruses of reptiles and fish. Its function or functions thus seem important to the coronaviruses. It might represent SARS-CoV-2 Achilles’ Heel, less likely to acquire resistance by mutation, as has happened in some early SARS vaccine studies discussed in the previous paper. Preliminary conformational analysis of the receptor (ACE2) binding site of the spike protein is carried suggesting that while it is somewhat conserved, it appears to be more variable than KRSFIEDLLFNKV. However compounds like emodin that inhibit SARS entry, apparently by binding ACE2, might also have functions at several different human protein binding studies. The enzyme 11β-hydroxysteroid dehydrogenase type 1 is again argued to be a convenient model pharmacophore perhaps representing an ensemble of targets, and it is noted that it occurs both in lung and alimentary tract. Perhaps it benefits the virus to block an inflammatory response by inhibiting the dehydrogenase, but a fairly complex web involves several possible targets.
xvfl7ycj
xvfl7ycj
2020-04-11
10.1016/j.compbiomed.2020.103749
2
Recurrence of positive SARS-CoV-2 RNA in COVID-19: A case report
Abstract The ongoing outbreak of COVID-19 that began in Wuhan, China, has constituted a Public Health Emergency of International Concern, with cases confirmed in multiple countries. Currently, patients are the primary source of infection. We report a confirmed case of COVID-19 whose oropharyngeal swab test of SARS-CoV-2 RNA turned positive in convalescence. This case highlights the importance of active surveillance of SARS-CoV-2 RNA for infectivity assessment.
xvnv17zy
xvnv17zy
2020-04-30
10.1016/j.ijid.2020.03.003
3.5
Building trust while influencing online COVID-19 content in the social media world
xwcaycmq
xwcaycmq
2020-04-21
10.1016/s2589-7500(20)30084-4
3.5
A Novel Coronavirus (COVID-19) Outbreak A Call for Action
xwjtjopl
xwjtjopl
2020-02-19
10.1016/j.chest.2020.02.014
1.5
“Amantadine disrupts lysosomal gene expression; potential therapy for COVID19”
SARS-coronavirus 2 is the causal agent of the COVID-19 outbreak. SARS-Cov-2 entry into a cell is dependent upon binding of the viral spike (S) protein to cellular receptor and on cleavage of the spike protein by the host cell proteases such as Cathepsin L and Cathepsin B. CTSL/B are crucial elements of lysosomal pathway and both enzymes are almost exclusively located in the lysosomes.CTSL disruption offers potential for CoVID-19 therapies. The mechanisms of disruption include: decreasing expression of CTSL, direct inhibition of CTSL activity and affecting the conditions of CTSL environment (increase pH in lysosomes). We have conducted a high throughput drug screen gene expression analysis to identify compounds that would downregulate the expression of CTSL/CTSB. One of the top significant results shown to downregulate the expression of the CTSL gene is Amantadine. Amantadine was approved by the US Food and Drug Administration in 1968 as a prophylactic agent for influenza and later for Parkinson’s disease. It is available as a generic drug.. Amantadine in addition to downregulating CTSL appears to further disrupt lysosomal pathway, hence interfering with the capacity of the virus to replicate. It acts as a lysosomotropic agent altering the CTSL functional environment. We hypothesize that Amantadine could decrease the viral load in SARS-CoV-2 positive patients and as such it may serve as a potent therapeutic decreasing the replication and infectivity of the virus likely leading to better clinical outcomes. Clinical studies will be needed to examine the therapeutic utility of amantadine in COVID-19 infection.
xwmr7up9
xwmr7up9
2020-04-05
10.1101/2020.04.05.026187
1
The role and response of palliative care and hospice services in epidemics and pandemics: a rapid review to inform practice during the COVID-19 pandemic
Abstract Cases of COVID-19 are escalating rapidly across the globe, with the mortality risk being especially high among those with existing illness and multimorbidity. This study aimed to synthesise evidence for the role and response of palliative care and hospice teams to viral epi/pandemics, to inform the COVID-19 pandemic response. We conducted a rapid systematic review according to PRISMA guidelines in five databases. Of 3094 papers identified, ten were included in this narrative synthesis. Included studies were from West Africa, Taiwan, Hong Kong, Singapore, the United States and Italy. All had an observational design. Findings were synthesised using a previously proposed framework according to ‘systems’ (policies, training and protocols, communication and coordination, data), ‘staff’ (deployment, skill mix, resilience), ‘space’ (community provision, use of technology) and ‘stuff’ (medicines and equipment, personal protective equipment). We conclude that hospice and palliative services have an essential role in the response to COVID-19 by: 1) responding rapidly and flexibly; 2) ensuring protocols for symptom management are available, and training non-specialists in their use; 3) being involved in triage; 4) considering shifting resources into the community; 5) considering redeploying volunteers to provide psychosocial and bereavement care; 6) facilitating camaraderie among staff and adopt measures to deal with stress; 7) using technology to communicate with patients and carers; 8) adopting standardised data collection systems to inform operational changes and improve care.
xwqhaaij
xwqhaaij
2020-04-08
10.1016/j.jpainsymman.2020.03.029
1
Recent discovery and development of inhibitors targeting coronaviruses
Human coronaviruses (CoVs) are enveloped viruses with a positive-sense single-stranded RNA genome. Currently, six human CoVs have been reported including human coronavirus 229E (HCoV-229E), OC43 (HCoV-OC43), NL63 (HCoV-NL63), HKU1 (HCoV-HKU1), severe acute respiratory syndrome (SARS) coronavirus (SARS-CoV), and MiddleEast respiratory syndrome (MERS) coronavirus (MERS-CoV). They cause moderate to severe respiratory and intestinal infections in humans. In this review, we focus on recent advances in the research and development of small-molecule anti-human coronavirus therapies targeting different stages of the CoV life cycle.
xxblr8qd
xxblr8qd
2020-01-30
10.1016/j.drudis.2020.01.015
1.5
Impact of immune enhancement on Covid-19 polyclonal hyperimmune globulin therapy and vaccine development
Abstract The pandemic spread of a novel coronavirus – SARS coronavirus-2 (SARS-CoV-2) as a cause of acute respiratory illness, named Covid-19, is placing the healthcare systems of many countries under unprecedented stress. Global economies are also spiraling towards a recession in fear of this new life-threatening disease. Vaccines that prevent SARS-CoV-2 infection and therapeutics that reduces the risk of severe Covid-19 are thus urgently needed. A rapid method to derive antiviral treatment for Covid-19 is the use of convalescent plasma derived hyperimmune globulin. However, both hyperimmune globulin and vaccine development face a common hurdle – the risk of antibody-mediated disease enhancement. The goal of this review is to examine the body of evidence supporting the hypothesis of immune enhancement that could be pertinent to Covid-19. We also discuss how this risk could be mitigated so that both hyperimmune globulin and vaccines could be rapidly translated to overcome the current global health crisis.
xxdrjngv
xxdrjngv
2020-04-16
10.1016/j.ebiom.2020.102768
2.5
Characterization of the receptor-binding domain (RBD) of 2019 novel coronavirus: implication for development of RBD protein as a viral attachment inhibitor and vaccine
The outbreak of Coronavirus Disease 2019 (COVID-19) has posed a serious threat to global public health, calling for the development of safe and effective prophylactics and therapeutics against infection of its causative agent, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), also known as 2019 novel coronavirus (2019-nCoV). The CoV spike (S) protein plays the most important roles in viral attachment, fusion and entry, and serves as a target for development of antibodies, entry inhibitors and vaccines. Here, we identified the receptor-binding domain (RBD) in SARS-CoV-2 S protein and found that the RBD protein bound strongly to human and bat angiotensin-converting enzyme 2 (ACE2) receptors. SARS-CoV-2 RBD exhibited significantly higher binding affinity to ACE2 receptor than SARS-CoV RBD and could block the binding and, hence, attachment of SARS-CoV-2 RBD and SARS-CoV RBD to ACE2-expressing cells, thus inhibiting their infection to host cells. SARS-CoV RBD-specific antibodies could cross-react with SARS-CoV-2 RBD protein, and SARS-CoV RBD-induced antisera could cross-neutralize SARS-CoV-2, suggesting the potential to develop SARS-CoV RBD-based vaccines for prevention of SARS-CoV-2 and SARS-CoV infection.
xy7w8hbz
xy7w8hbz
2020
4
Flattening the COVID-19 Curve With Natural Killer Cell Based Immunotherapies
Natural Killer (NK) cells are innate immune responders critical for viral clearance and immunomodulation. Despite their vital role in viral infection, the contribution of NK cells in fighting SARS-CoV-2 has not yet been directly investigated. Insights into pathophysiology and therapeutic opportunities can therefore be inferred from studies assessing NK cell phenotype and function during SARS, MERS, and COVID-19. These studies suggest a reduction in circulating NK cell numbers and/or an exhausted phenotype following infection and hint toward the dampening of NK cell responses by coronaviruses. Reduced circulating NK cell levels and exhaustion may be directly responsible for the progression and severity of COVID-19. Conversely, in light of data linking inflammation with coronavirus disease severity, it is necessary to examine NK cell potential in mediating immunopathology. A common feature of coronavirus infections is that significant morbidity and mortality is associated with lung injury and acute respiratory distress syndrome resulting from an exaggerated immune response, of which NK cells are an important component. In this review, we summarize the current understanding of how NK cells respond in both early and late coronavirus infections, and the implication for ongoing COVID-19 clinical trials. Using this immunological lens, we outline recommendations for therapeutic strategies against COVID-19 in clearing the virus while preventing the harm of immunopathological responses.
xypg6evo
xypg6evo
2020-06-23
10.3389/fimmu.2020.01512
5
Is traditional Chinese medicine useful in the treatment of COVID-19?
y0ypkmme
y0ypkmme
2020-03-25
10.1016/j.ajem.2020.03.046
2.5
Identification of IgG antibody response to SARS-CoV-2 spike protein and its receptor binding domain does not predict rapid recovery from COVID-19
Diagnostic testing and evaluation of patient immunity against the novel severe acute respiratory syndrome (SARS) corona virus that emerged last year (SARS-CoV-2) are essential for health and economic crisis recovery of the world. It is suggested that potential acquired immunity against SARS-CoV-2 from prior exposure may be determined by detecting the presence of circulating IgG antibodies against viral antigens, such as the spike glycoprotein and its receptor binding domain (RBD). Testing our asymptomatic population for evidence of COVID-19 immunity would also offer valuable epidemiologic data to aid health care policies and health care management. Currently, there are over 100 antibody tests that are being used around the world without approval from the FDA or similar regulatory bodies, and they are mostly for rapid and qualitative assessment, with different degrees of error rates. ELISA-based testing for sensitive and rigorous quantitative assessment of SARS-CoV-2 antibodies can potentially offer mechanistic insights into the COVID-19 disease and aid communities uniquely challenged by limited financial resources and access to commercial testing products. Employing recombinant SARS-CoV-2 RBD and spike protein generated in the laboratory, we devised a quantitative ELISA for the detection of circulating serum antibodies. Serum from twenty SARS-CoV-2 RT-PCR confirmed COVID-19 hospitalized patients were used to detect circulating IgG titers against SARS-CoV-2 spike protein and RBD. Quantitative detection of IgG antibodies to the spike glycoprotein or the RBD in patient samples was not always associated with faster recovery, compared to patients with borderline antibody response to the RBD. One patient who did not develop antibodies to the RBD completely recovered from COVID-19. In surveying 99 healthy donor samples (procured between 2017-February 2020), we detected RBD antibodies in one donor from February 2020 collection with three others exhibiting antibodies to the spike protein but not the RBD. Collectively, our study suggests that more rigorous and quantitative analysis, employing large scale sample sets, is required to determine whether antibodies to SARS-CoV-2 spike protein or RBD is associated with protection from COVID-19 disease. It is also conceivable that humoral response to SARS-CoV-2 spike protein or RBD works in association with adaptive T cell response to determine clinical sequela and severity of COVID-19 disease.
y1afswkm
y1afswkm
2020-05-06
10.1101/2020.05.01.20087684
3.5
Animal models of mechanisms of SARS-CoV-2 infection and COVID-19 pathology
The coronavirus disease 2019 (COVID-19) pandemic caused by SARS-CoV-2 infections has led to substantial unmet need for treatments, many of which will require testing in appropriate animal models of this disease. Vaccine trials are already underway, but there remains an urgent need to find other therapeutic approaches to either target SARS-CoV-2 or the complications arising from viral infection, particularly the dysregulated immune response and systemic complications which have been associated with progression to severe COVID-19. At the time of writing, in vivo studies of SARS-CoV-2 infection have been described using macaques, cats, ferrets, hamsters, and transgenic mice expressing human angiotensin I converting enzyme 2 (ACE2). These infection models have already been useful for studies of transmission and immunity, but to date only partially model the mechanisms implicated in human severe COVID-19. There is therefore an urgent need for development of animal models for improved evaluation of efficacy of drugs identified as having potential in the treatment of severe COVID-19. These models need to recapitulate key mechanisms of COVID-19 severe acute respiratory distress syndrome and reproduce the immunopathology and systemic sequelae associated with this disease. Here, we review the current models of SARS-CoV-2 infection and COVID-19-related disease mechanisms and suggest ways in which animal models can be adapted to increase their usefulness in research into COVID-19 pathogenesis and for assessing potential treatments.
y1b1vf1b
y1b1vf1b
2020
4
Potential Treatments for COVID-19; a Narrative Literature Review
SARS-CoV-2 is a newly emerging human infectious coronavirus that causes COVID-19, which has been recognized as a pandemic by the World Health Organization (WHO) on March 11(th). There is still no vaccine or definitive treatment for this virus because its pathogenesis and proliferation pathways are still unknown. Therefore, in this article, new potential COVID-19 therapies are briefly reviewed.
y29kct7v
y29kct7v
2020-03-21
1.5
Pharmacologic Treatment of Transplant Recipients Infected With SARS-CoV-2: Considerations Regarding Therapeutic Drug Monitoring and Drug–Drug Interactions
COVID-19 is a novel infectious disease caused by the severe acute respiratory distress (SARS)-coronavirus-2 (SARS-CoV-2). Several therapeutic options are currently emerging but none with universal consensus or proven efficacy. Solid organ transplant recipients are perceived to be at increased risk of severe COVID-19 because of their immunosuppressed conditions due to chronic use of immunosuppressive drugs (ISDs). It is therefore likely that solid organ transplant recipients will be treated with these experimental antivirals. METHODS: This article is not intended to provide a systematic literature review on investigational treatments tested against COVID-19; rather, the authors aim to provide recommendations for therapeutic drug monitoring of ISDs in transplant recipients infected with SARS-CoV-2 based on a review of existing data in the literature. RESULTS: Management of drug–drug interactions between investigational anti-SARS-CoV-2 drugs and immunosuppressants is a complex task for the clinician. Adequate immunosuppression is necessary to prevent graft rejection while, if critically ill, the patient may benefit from pharmacotherapeutic interventions directed at limiting SARS-CoV-2 viral replication. Maintaining ISD concentrations within the desired therapeutic range requires a highly individualized approach that is complicated by the pandemic context and lack of hindsight. CONCLUSIONS: With this article, the authors inform the clinician about the potential interactions of experimental COVID-19 treatments with ISDs used in transplantation. Recommendations regarding therapeutic drug monitoring and dose adjustments in the context of COVID-19 are provided.
y2vnvc1w
y2vnvc1w
2020-04-23
10.1097/ftd.0000000000000761
3.5
Artificial Intelligence Forecasting of Covid-19 in China
BACKGROUND An alternative to epidemiological models for transmission dynamics of Covid-19 in China, we propose the artificial intelligence (AI)-inspired methods for real-time forecasting of Covid-19 to estimate the size, lengths and ending time of Covid-19 across China. METHODS We developed a modified stacked auto-encoder for modeling the transmission dynamics of the epidemics. We applied this model to real-time forecasting the confirmed cases of Covid-19 across China. The data were collected from January 11 to February 27, 2020 by WHO. We used the latent variables in the auto-encoder and clustering algorithms to group the provinces/cities for investigating the transmission structure. RESULTS We forecasted curves of cumulative confirmed cases of Covid-19 across China from Jan 20, 2020 to April 20, 2020. Using the multiple-step forecasting, the estimated average errors of 6-step, 7-step, 8-step, 9-step and 10-step forecasting were 1.64%, 2.27%, 2.14%, 2.08%, 0.73%, respectively. We predicted that the time points of the provinces/cities entering the plateau of the forecasted transmission dynamic curves varied, ranging from Jan 21 to April 19, 2020. The 34 provinces/cities were grouped into 9 clusters. CONCLUSIONS The accuracy of the AI-based methods for forecasting the trajectory of Covid-19 was high. We predicted that the epidemics of Covid-19 will be over by the middle of April. If the data are reliable and there are no second transmissions, we can accurately forecast the transmission dynamics of the Covid-19 across the provinces/cities in China. The AI-inspired methods are a powerful tool for helping public health planning and policymaking.
y3joi01a
y3joi01a
2020-02-17
2
Cell-based antiviral screening against coronaviruses: Developing virus-specific and broad-spectrum inhibitors
To combat the public health threat from emerging coronaviruses (CoV), the development of antiviral therapies with either virus-specific or pan-CoV activities is necessary. An important step in antiviral drug development is the screening of potential inhibitors in cell-based systems. The recent emergence of the Middle East respiratory syndrome (MERS)-CoV necessitates adapting methods that have been used to identify antivirals against the severe, acute respiratory syndrome (SARS)-CoV and developing new approaches to more efficiently screen antiviral drugs. In this article we review cell-based assays using infectious virus (BSL-3) and surrogate assays (BSL-2) that can be implemented to accelerate antiviral development against MERS-CoV and future emergent coronaviruses. This paper forms part of a series of invited articles in Antiviral Research on “From SARS to MERS: 10 years of research on highly pathogenic human coronaviruses.”
y3zrt52j
y3zrt52j
2014-01-01
10.1016/j.antiviral.2013.11.004
0.5
Coronavirus Infections in Children Including COVID-19: An Overview of the Epidemiology, Clinical Features, Diagnosis, Treatment and Prevention Options in Children
Coronaviruses (CoVs) are a large family of enveloped, single-stranded, zoonotic RNA viruses. Four CoVs commonly circulate among humans: HCoV2-229E, -HKU1, -NL63 and -OC43. However, CoVs can rapidly mutate and recombine leading to novel CoVs that can spread from animals to humans. The novel CoVs severe acute respiratory syndrome coronavirus (SARS-CoV) emerged in 2002 and Middle East respiratory syndrome coronavirus (MERS-CoV) in 2012. The 2019 novel coronavirus (SARS-CoV-2) is currently causing a severe outbreak of disease (termed COVID-19) in China and multiple other countries, threatening to cause a global pandemic. In humans, CoVs mostly cause respiratory and gastrointestinal symptoms. Clinical manifestations range from a common cold to more severe disease such as bronchitis, pneumonia, severe acute respiratory distress syndrome, multi-organ failure and even death. SARS-CoV, MERS-CoV and SARS-CoV-2 seem to less commonly affect children and to cause fewer symptoms and less severe disease in this age group compared with adults, and are associated with much lower case-fatality rates. Preliminary evidence suggests children are just as likely as adults to become infected with SARS-CoV-2 but are less likely to be symptomatic or develop severe symptoms. However, the importance of children in transmitting the virus remains uncertain. Children more often have gastrointestinal symptoms compared with adults. Most children with SARS-CoV present with fever, but this is not the case for the other novel CoVs. Many children affected by MERS-CoV are asymptomatic. The majority of children infected by novel CoVs have a documented household contact, often showing symptoms before them. In contrast, adults more often have a nosocomial exposure. In this review, we summarize epidemiologic, clinical and diagnostic findings, as well as treatment and prevention options for common circulating and novel CoVs infections in humans with a focus on infections in children.
y4cqgbm2
y4cqgbm2
2020-03-12
10.1097/inf.0000000000002660
3.5
SARS vaccines: where are we?
In this review, the current state of vaccine development against human severe acute respiratory syndrome (SARS) coronavirus, focusing on recently published data is assessed. We discuss which strategies have been assessed immunologically and which have been evaluated in SARS coronavirus challenge models. We discuss inactivated vaccines, virally and bacterially vectored vaccines, recombinant protein and DNA vaccines, as well as the use of attenuated vaccines. Data regarding the correlates of protection, animal models and the available evidence regarding potential vaccine enhancement of SARS disease are discussed. While there is much evidence that various vaccine strategies against SARS are safe and immunogenic, vaccinated animals still display significant disease upon challenge. Current data suggest that intranasal vaccination may be crucial and that new or combination strategies may be required for good protective efficacy against SARS in humans.
y4eyse0y
y4eyse0y
2014-01-09
10.1586/erv.09.43
0.5
A Mouse Model for Betacoronavirus Subgroup 2c Using a Bat Coronavirus Strain HKU5 Variant
Cross-species transmission of zoonotic coronaviruses (CoVs) can result in pandemic disease outbreaks. Middle East respiratory syndrome CoV (MERS-CoV), identified in 2012, has caused 182 cases to date, with ~43% mortality, and no small animal model has been reported. MERS-CoV and Pipistrellus bat coronavirus (BtCoV) strain HKU5 of Betacoronavirus (β-CoV) subgroup 2c share >65% identity at the amino acid level in several regions, including nonstructural protein 5 (nsp5) and the nucleocapsid (N) protein, which are significant drug and vaccine targets. BtCoV HKU5 has been described in silico but has not been shown to replicate in culture, thus hampering drug and vaccine studies against subgroup 2c β-CoVs. We report the synthetic reconstruction and testing of BtCoV HKU5 containing the severe acute respiratory syndrome (SARS)-CoV spike (S) glycoprotein ectodomain (BtCoV HKU5-SE). This virus replicates efficiently in cell culture and in young and aged mice, where the virus targets airway and alveolar epithelial cells. Unlike some subgroup 2b SARS-CoV vaccines that elicit a strong eosinophilia following challenge, we demonstrate that BtCoV HKU5 and MERS-CoV N-expressing Venezuelan equine encephalitis virus replicon particle (VRP) vaccines do not cause extensive eosinophilia following BtCoV HKU5-SE challenge. Passage of BtCoV HKU5-SE in young mice resulted in enhanced virulence, causing 20% weight loss, diffuse alveolar damage, and hyaline membrane formation in aged mice. Passaged virus was characterized by mutations in the nsp13, nsp14, open reading frame 5 (ORF5) and M genes. Finally, we identified an inhibitor active against the nsp5 proteases of subgroup 2c β-CoVs. Synthetic-genome platforms capable of reconstituting emerging zoonotic viral pathogens or their phylogenetic relatives provide new strategies for identifying broad-based therapeutics, evaluating vaccine outcomes, and studying viral pathogenesis.
y4zoyqua
y4zoyqua
2014-03-25
10.1128/mbio.00047-14
0.5
Hydroxychloroquine Proves Ineffective in Hamsters and Macaques Infected with SARS-CoV-2
We remain largely without effective prophylactic/therapeutic interventions for COVID-19. Although many human clinical trials are ongoing, there remains a deficiency of supportive preclinical drug efficacy studies. Here we assessed the prophylactic/therapeutic efficacy of hydroxychloroquine (HCQ), a drug of interest for COVID-19 management, in two animal models. When used for prophylaxis or treatment neither the standard human malaria dose (6.5 mg/kg) nor a high dose (50 mg/kg) of HCQ had any beneficial effect on clinical disease or SARS-CoV-2 kinetics (replication/shedding) in the Syrian hamster disease model. Similarly, HCQ prophylaxis/treatment (6.5 mg/kg) did not significantly benefit clinical outcome nor reduce SARS-CoV-2 replication/shedding in the upper and lower respiratory tract in the rhesus macaque disease model. In conclusion, our preclinical animal studies do not support the use of HCQ in prophylaxis/treatment of COVID-19.
y5cbp2yz
y5cbp2yz
2020-06-11
10.1101/2020.06.10.145144
4
Are Nonhuman Primates Good Models for SARS?
y607uvg6
y607uvg6
2006-09-26
10.1371/journal.pmed.0030411
0.5
COVID-19 Clinical Trials: A Primer for the Cardiovascular and Cardio-Oncology Communities
Abstract The COVID-19 pandemic has resulted in a proliferation of clinical trials that are designed to slow the spread of SARS-CoV-2, the virus that causes COVID-19. The overwhelming majority of cardiovascular and cancer patients are at increased risk for SARS-CoV-2 infection; accordingly, the cardiovascular and cardio-oncology communities are playing a major role in caring for COVID-19 patients. Many of the therapeutic agents that are being used to treat patients with COVID-19 are repurposed treatments for influenza, drugs that were not effective in Ebola patients, or treatments for malaria that were developed decades ago, and are unlikely to be familiar to the cardiovascular and cardio-oncology communities. Here we have provided a foundation for cardiovascular and cardio-oncology physicians who are on the frontline providing care to COVID-19 patients, so that they can better understand the emerging cardiovascular epidemiology of COVID-19, as well as the biological rationale for the clinical trials that are ongoing for the treatment of COVID-19 patients.
y74jbnb2
y74jbnb2
2020-04-16
10.1016/j.jacbts.2020.04.003
2
Extended SIR prediction of the epidemics trend of COVID-19 in Italy and compared with Hunan, China
Background: Coronavirus Disease 2019 (COVID19) is currently a global public health threat. Outside of China, Italy is one of the most suffering countries with the COVID19 epidemic. It is important to predict the epidemics trend of COVID19 epidemic in Italy to help develop public health strategies. Methods: We used time series data of COVID 19 from Jan 22,2020 to Mar 16,2020. An infectious disease dynamic extended susceptible infected removed (eSIR) model, which covers the effects of different intervention measures in dissimilar periods, was applied to estimate the epidemic trend in Italy. The basic reproductive number was estimated using Markov Chain Monte Carlo methods and presented using the resulting posterior mean and 95% credible interval (CI). Hunan, with similar total number of populations in Italy, was used as a comparative item. Results: In the eSIR model, we estimated that the basic reproductive number for COVID 19 was respectively 4.10 (95% CI: 2.15 to 6.77) in Italy and 3.15(95% CI: 1.71 to 5.21) in Hunan. There would be totally 30 086 infected cases (95%CI:7920-81 869) under the current country blockade and the endpoint would be Apr 25 (95%CI: Mar 30 to Aug 07) in Italy. If the country blockade is imposed 5 day later, the total number of infected cases would expand the infection scale 1.50 times. Conclusion: Italy's current strict measures can efficaciously prevent the further spread of COVID19 and should be maintained. Necessary strict public health measures be implemented as soon as possible in other European countries with a high number of COVID19 cases. The most effective strategy needs to be confirmed in further studies.
y7giefdw
y7giefdw
2020-03-20
10.1101/2020.03.18.20038570
1
Of chloroquine and COVID-19
Abstract Recent publications have brought attention to the possible benefit of chloroquine, a broadly used antimalarial drug, in the treatment of patients infected by the novel emerged coronavirus (SARS-CoV-2). The scientific community should consider this information in light of previous experiments with chloroquine in the field of antiviral research.
y7lrp0gc
y7lrp0gc
2020-05-31
10.1016/j.antiviral.2020.104762
1.5
Determining the spatial effects of COVID-19 using the spatial panel data model
Abstract This study investigates the propagation power and effects of the coronavirus disease 2019 (COVID-19) in light of published data. We examine the factors affecting COVID-19 together with the spatial effects, and use spatial panel data models to determine the relationship among the variables including their spatial effects. Using spatial panel models, we analyse the relationship between confirmed cases of COVID-19, deaths thereof, and recovered cases due to treatment. We accordingly determine and include the spatial effects in this examination after establishing the appropriate model for COVID-19. The most efficient and consistent model is interpreted with direct and indirect spatial effects.
y7o8ovf9
y7o8ovf9
2020-04-07
10.1016/j.spasta.2020.100443
1
Neuropilin-1 is a host factor for SARS-CoV-2 infection
SARS-CoV-2 is the causative agent of COVID-19, a coronavirus disease that has infected more than 6.6 million people and caused over 390,000 deaths worldwide1,2. The Spike (S) protein of the virus forms projections on the virion surface responsible for host cell attachment and penetration. This viral glycoprotein is synthesized as a precursor in infected cells and, to be active, must be cleaved to two associated polypeptides: S1 and S2(3,4). For SARS-CoV-2 the cleavage is catalysed by furin, a host cell protease, which cleaves the S protein precursor at a specific sequence motif that generates a polybasic Arg-Arg-Ala-Arg (RRAR) C-terminal sequence on S1. This sequence motif conforms to the C-end rule (CendR), which means that the C-terminal sequence may allow the protein to associate with cell surface neuropilin-1 (NRP1) and neuropilin-2 (NRP2) receptors5. Here we demonstrate using immunoprecipitation, site-specific mutagenesis, structural modelling, and antibody blockade that, in addition to engaging the known receptor ACE2, S1 can bind to NRP1 through the canonical CendR mechanism. This interaction enhances infection by SARS-CoV-2 in cell culture. NRP1 thus serves as a host factor for SARS-CoV-2 infection, and provides a therapeutic target for COVID-19.
ya8qpqy9
ya8qpqy9
2020-06-05
10.1101/2020.06.05.134114
4
JAK1 inhibition blocks lethal sterile immune responses: implications for COVID-19 therapy
Cytokine storms are drivers of pathology and mortality in myriad viral infections affecting the human population. In SARS-CoV-2-infected patients, the strength of the cytokine storm has been associated with increased risk of acute respiratory distress syndrome, myocardial damage, and death. However, the therapeutic value of attenuating the cytokine storm in COVID-19 remains to be defined. Here, we report results obtained using a novel mouse model of lethal sterile anti-viral immune responses. Using a mouse model of Down syndrome (DS) with a segmental duplication of a genomic region encoding four of the six interferon receptor genes (Ifnrs), we demonstrate that these animals overexpress Ifnrs and are hypersensitive to IFN stimulation. When challenged with viral mimetics that activate Toll-like receptor signaling and IFN anti-viral responses, these animals overproduce key cytokines, show exacerbated liver pathology, rapidly lose weight, and die. Importantly, the lethal immune hypersensitivity, accompanying cytokine storm, and liver hyperinflammation are blocked by treatment with a JAK1-specific inhibitor. Therefore, these results point to JAK1 inhibition as a potential strategy for attenuating the cytokine storm and consequent organ failure during overdrive immune responses. Additionally, these results indicate that people with DS, who carry an extra copy of the IFNR gene cluster encoded on chromosome 21, should be considered at high risk during the COVID-19 pandemic. One Sentence Summary Inhibition of the JAK1 kinase prevents pathology and mortality caused by a rampant innate immune response in mice.
yabt72jf
yabt72jf
2020-04-09
10.1101/2020.04.07.024455
5
Structure, function and antigenicity of the SARS-CoV-2 spike glycoprotein
The recent emergence of a novel coronavirus associated with an ongoing outbreak of pneumonia (Covid-2019) resulted in infections of more than 72,000 people and claimed over 1,800 lives. Coronavirus spike (S) glycoprotein trimers promote entry into cells and are the main target of the humoral immune response. We show here that SARS-CoV-2 S mediates entry in VeroE6 cells and in BHK cells transiently transfected with human ACE2, establishing ACE2 as a functional receptor for this novel coronavirus. We further demonstrate that the receptor-binding domains of SARS-CoV-2 S and SARS-CoV S bind with similar affinities to human ACE2, which correlates with the efficient spread of SARS-CoV-2 among humans. We found that the SARS-CoV-2 S glycoprotein harbors a furin cleavage site at the boundary between the S1/S2 subunits, which is processed during biogenesis and sets this virus apart from SARS-CoV and other SARS-related CoVs. We determined a cryo-electron microscopy structure of the SARS-CoV-2 S ectodomain trimer, demonstrating spontaneous opening of the receptor-binding domain, and providing a blueprint for the design of vaccines and inhibitors of viral entry. Finally, we demonstrate that SARS-CoV S murine polyclonal sera potently inhibited SARS-CoV-2 S-mediated entry into target cells, thereby indicating that cross-neutralizing antibodies targeting conserved S epitopes can be elicited upon vaccination.
yaow639d
yaow639d
2020-02-20
10.1101/2020.02.19.956581
2
Predicting the angiotensin converting enzyme 2 (ACE2) utilizing capability as the receptor of SARS-CoV-2
Abstract SARS-CoV-2, the newly identified human coronavirus causing severe pneumonia pandemic, was probably originated from Chinese horseshoe bats. However, direct transmission of the virus from bats to humans is unlikely due to lack of direct contact, implying the existence of unknown intermediate hosts. Angiotensin converting enzyme 2 (ACE2) is the receptor of SARS-CoV-2, but only ACE2s of certain species can be utilized by SARS-CoV-2. Here, we evaluated and ranked the receptor-utilizing capability of ACE2s from various species by phylogenetic clustering and sequence alignment with the currently known ACE2s utilized by SARS-CoV-2. As a result, we predicted that SARS-CoV-2 tends to utilize ACE2s of various mammals, except murines, and some birds, such as pigeon. This prediction may help to screen the intermediate hosts of SARS-CoV-2.
yaspd6l7
yaspd6l7
2020-03-19
10.1016/j.micinf.2020.03.003
1
SARS-CoV-2 infection in health care workers: a retrospective analysis and a model study
Background There had been a preliminary occurrence of human-to-human transmissions between healthcare workers (HCWs), but risk factors in the susceptibility for COVID-19, and infection patterns among HCWs have largely remained unknown. Methods Retrospective data collection on demographics, lifestyles, contact status with infected subjects for 118 HCWs (include 12 COVID-19 HCWs) from a single-center. Sleep quality and working pressure were evaluated by Pittsburgh Sleep Quality Index (PSQI) and The Nurse Stress Index (NSI), respectively. Follow-up duration was from Dec 25, 2019, to Feb 15, 2020. Risk factors and transmission models of COVID-19 among HCWs were analyzed and constructed. Findings A high proportion of COVID-19 HCWs had engaged in night shift-work (75.0% vs. 40.6%) and felt they were working under pressure (66.7% vs. 32.1%) than uninfected HCWs. COVID-19 HCWs had higher total scores of PSQI and NSI than uninfected HCWs. Furthermore, these scores were both positively associated with COVID-19 risk. An individual-based model (IBM) estimated the outbreak duration among HCWs in a non-typical COVID-19 ward at 62-80 days and the basic reproduction number =1.27 [1.06, 1.61]. By reducing the average contact rate per HCW by a 1.35 factor and susceptibility by a 1.40 factor, we can avoid an outbreak of the basic case among HCWs. Interpretation Poor sleep quality and high working pressure were positively associated with high risks of COVID-19. A novel IBM of COVID-19 transmission is suitable for simulating different outbreak patterns in a hospital setting.
ybwgza0f
ybwgza0f
2020-04-01
10.1101/2020.03.29.20047159
1
Role of the Spike Glycoprotein of Human Middle East Respiratory Syndrome Coronavirus (MERS-CoV) in Virus Entry and Syncytia Formation
Little is known about the biology of the emerging human group c betacoronavirus, Middle East Respiratory Syndrome coronavirus (MERS-CoV). Because coronavirus spike glycoproteins (S) mediate virus entry, affect viral host range, and elicit neutralizing antibodies, analyzing the functions of MERS-CoV S protein is a high research priority. MERS-CoV S on lentivirus pseudovirions mediated entry into a variety of cell types including embryo cells from New World Eptesicus fuscus bats. Surprisingly, a polyclonal antibody to the S protein of MHV, a group a murine betacoronavirus, cross-reacted in immunoblots with the S2 domain of group c MERS-CoV spike protein. MERS pseudovirions released from 293T cells contained only uncleaved S, and pseudovirus entry was blocked by lysosomotropic reagents NH(4)Cl and bafilomycin and inhibitors of cathepsin L. However, when MERS pseudovirions with uncleaved S protein were adsorbed at 4°C to Vero E6 cells, brief trypsin treatment at neutral pH triggered virus entry at the plasma membrane and syncytia formation. When 293T cells producing MERS pseudotypes co-expressed serine proteases TMPRSS-2 or -4, large syncytia formed at neutral pH, and the pseudovirions produced were non-infectious and deficient in S protein. These experiments show that if S protein on MERS pseudovirions is uncleaved, then viruses enter by endocytosis in a cathepsin L-dependent manner, but if MERS-CoV S is cleaved, either during virus maturation by serine proteases or on pseudovirions by trypsin in extracellular fluids, then viruses enter at the plasma membrane at neutral pH and cause massive syncytia formation even in cells that express little or no MERS-CoV receptor. Thus, whether MERS-CoV enters cells within endosomes or at the plasma membrane depends upon the host cell type and tissue, and is determined by the location of host proteases that cleave the viral spike glycoprotein and activate membrane fusion.
yc8q62z8
yc8q62z8
2013-10-03
10.1371/journal.pone.0076469
1.5
Covid-19: what treatments are being investigated?
ycgz54i3
ycgz54i3
2020-03-26
10.1136/bmj.m1252
3.5
Human monoclonal IgG selection of Plasmodium falciparum for the expression of placental malaria-specific variant surface antigens
Pregnancy-associatedPlasmodium falciparum malaria (PAM) is a major cause of morbidity and mortality in African women and their offspring. PAM is characterized by accumulation of infected erythrocytes (IEs) that adhere to chondroitin sulphate A (CSA) in the placental intervillous space. We show here that human monoclonal IgG antibodies with specificity for variant surface antigens (VSA) specifically expressed by CSA-adhering IEs (VSA(PAM)) can be used in vitro to select parasites from nonpregnant donors to express VSA(PAM) and that this selection for VSA(PAM) expression results in preferential transcription of var2csa. The results corroborate current efforts to develop PAM-specific vaccines based on VAR2CSA.
yci0a6bt
yci0a6bt
2009-06-16
10.1111/j.1365-3024.2009.01097.x
4.5
Rapid selection of a human monoclonal antibody that potently neutralizes SARS-CoV-2 in two animal models
Effective therapies are urgently needed for the SARS-CoV-2/COVID19 pandemic. We identified panels of fully human monoclonal antibodies (mAbs) from eight large phage-displayed Fab, scFv and VH libraries by panning against the receptor binding domain (RBD) of the SARS-CoV-2 spike (S) glycoprotein. One high affinity mAb, IgG1 ab1, specifically neutralized replication competent SARS-CoV-2 with exceptional potency as measured by two different assays. There was no enhancement of pseudovirus infection in cells expressing Fcγ receptors at any concentration. It competed with human angiotensin-converting enzyme 2 (hACE2) for binding to RBD suggesting a competitive mechanism of virus neutralization. IgG1 ab1 potently neutralized mouse ACE2 adapted SARS-CoV-2 in wild type BALB/c mice and native virus in hACE2 expressing transgenic mice. The ab1 sequence has relatively low number of somatic mutations indicating that ab1-like antibodies could be quickly elicited during natural SARS-CoV-2 infection or by RBD-based vaccines. IgG1 ab1 does not have developability liabilities, and thus has potential for therapy and prophylaxis of SARS-CoV-2 infections. The rapid identification (within 6 days) of potent mAbs shows the value of large antibody libraries for response to public health threats from emerging microbes.
ycuiso0g
ycuiso0g
2020-06-02
10.1101/2020.05.13.093088
4
In Vitro Antiviral Activity and Projection of Optimized Dosing Design of Hydroxychloroquine for the Treatment of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2)
BACKGROUND: The Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) first broke out in Wuhan (China) and subsequently spread worldwide. Chloroquine has been sporadically used in treating SARS-CoV-2 infection. Hydroxychloroquine shares the same mechanism of action as chloroquine, but its more tolerable safety profile makes it the preferred drug to treat malaria and autoimmune conditions. We propose that the immunomodulatory effect of hydroxychloroquine also may be useful in controlling the cytokine storm that occurs late-phase in critically ill SARS-CoV-2 infected patients. Currently, there is no evidence to support the use of hydroxychloroquine in SARS-CoV-2 infection. METHODS: The pharmacological activity of chloroquine and hydroxychloroquine was tested using SARS-CoV-2 infected Vero cells. Physiologically-based pharmacokinetic models (PBPK) were implemented for both drugs separately by integrating their in vitro data. Using the PBPK models, hydroxychloroquine concentrations in lung fluid were simulated under 5 different dosing regimens to explore the most effective regimen whilst considering the drug's safety profile. RESULTS: Hydroxychloroquine (EC50=0.72 µM) was found to be more potent than chloroquine (EC50=5.47 µM) in vitro. Based on PBPK models results, a loading dose of 400 mg twice daily of hydroxychloroquine sulfate given orally, followed by a maintenance dose of 200 mg given twice daily for 4 days is recommended for SARS-CoV-2 infection, as it reached three times the potency of chloroquine phosphate when given 500 mg twice daily 5 days in advance. CONCLUSIONS: Hydroxychloroquine was found to be more potent than chloroquine to inhibit SARS-CoV-2 in vitro.
ycwur2vi
ycwur2vi
2020
5
Respiratory disease and virus shedding in rhesus macaques inoculated with SARS-CoV-2
An outbreak of a novel coronavirus, now named SARS-CoV-2, causing respiratory disease and a ∼2% case fatality rate started in Wuhan, China in December 2019. Following unprecedented rapid global spread, the World Health Organization declared COVID-19 a pandemic on March 11, 2020. Although data on disease in humans are emerging at a steady pace, certain aspects of the pathogenesis of SARS-CoV-2 can only be studied in detail in animal models, where repeated sampling and tissue collection is possible. Here, we show that SARS-CoV-2 causes respiratory disease in infected rhesus macaques, with disease lasting 8-16 days. Pulmonary infiltrates, a hallmark of human disease, were visible in lung radiographs of all animals. High viral loads were detected in swabs from the nose and throat of all animals as well as in bronchoalveolar lavages; in one animal we observed prolonged rectal shedding. Taken together, the rhesus macaque recapitulates moderate disease observed in the majority of human cases. The establishment of the rhesus macaque as a model of COVID-19 will increase our understanding of the pathogenesis of this disease and will aid development and testing of medical countermeasures.
ydm77mhk
ydm77mhk
2020-03-21
10.1101/2020.03.21.001628
1
Animal models for the study of influenza pathogenesis and therapy
Influenza A viruses causes a variety of illnesses in humans. The most common infection, seasonal influenza, is usually a mild, self-limited febrile syndrome, but it can be more severe in infants, the elderly, and immunodeficient persons, in whom it can progress to severe viral pneumonitis or be complicated by bacterial superinfection, leading to pneumonia and sepsis. Seasonal influenza also occasionally results in neurologic complications. Rarely, viruses that have spread from wild birds to domestic poultry can infect humans; such “avian influenza” can range in severity from mild conjunctivitis through the rapidly lethal disease seen in persons infected with the H5N1 virus that first emerged in Hong Kong in 1997. To develop effective therapies for this wide range of diseases, it is essential to have laboratory animal models that replicate the major features of illness in humans. This review describes models currently in use for elucidating influenza pathogenesis and evaluating new therapeutic agents.
ydmvugdw
ydmvugdw
2009-05-01
10.1016/j.antiviral.2008.12.014
1
Androgen Regulates SARS-CoV-2 Receptor Levels and Is Associated with Severe COVID-19 Symptoms in Men
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has led to a global health crisis, and yet our understanding of the disease pathophysiology and potential treatment options remains limited. SARS-CoV-2 infection occurs through binding and internalization of the viral spike protein to angiotensin converting enzyme 2 (ACE2) on the host cell membrane. Lethal complications are caused by damage and failure of vital organs that express high levels of ACE2, including the lungs, the heart and the kidneys. Here, we established a high-throughput drug screening strategy to identify therapeutic candidates that reduce ACE2 levels in human embryonic stem cell (hESC) derived cardiac cells. Drug target analysis of validated hit compounds, including 5 alpha reductase inhibitors, revealed androgen signaling as a key modulator of ACE2 levels. Treatment with the 5 alpha reductase inhibitor dutasteride reduced ACE2 levels and internalization of recombinant spike receptor binding domain (Spike-RBD) in hESC-derived cardiac cells and human alveolar epithelial cells. Finally, clinical data on coronavirus disease 2019 (COVID-19) patients demonstrated that abnormal androgen states are significantly associated with severe disease complications and cardiac injury as measured by blood troponin T levels. These findings provide important insights on the mechanism of increased disease susceptibility in male COVID-19 patients and identify androgen receptor inhibition as a potential therapeutic strategy.
ye15hb3y
ye15hb3y
2020-05-15
10.1101/2020.05.12.091082
3.5
SARS-CoV-2 Spike Glycoprotein and ACE2 interaction reveals modulation of viral entry in different hosts
Background SARS-CoV-2 is a viral pathogen causing life threatening disease in human. Interaction between spike protein of SARS-CoV-2 and ACE2 receptor on the cells is a potential factor in the infectivity of a host. The interaction of SARS-CoV-2 spike receptor-binding domain with its receptor - ACE2, in different hosts was evaluated to understand and predict viral entry. The protein and nucleotide sequences of ACE2 were initially compared across different species to identify key differences among them. The ACE2 receptor of various species was homology modeled (6LZG as a reference) and its binding ability to the spike receptor-binding domain of SARS-CoV-2 was assessed. Initially, the spike binding properties of ACE2 of known infected and uninfected species was compared with each Order (of animals) as a group. Finally, a logistic regression model vis-a-vis the spike binding properties of ACE2 (Interaction energy, entropy sidechain and entropy mainchain) was constructed to predict the probability of viral entry in different hosts. Results Phylogeny and alignment comparison did not lead to any meaningful conclusion on viral entry in different hosts. Out of several spike binding properties of ACE2, a significant difference between the known infected and uninfected species was observed for five spike binding properties of ACE2. However, these parameters did not specifically categorize the animals into infected or uninfected, for all the Orders (of animals). The logistic regression model constructed revealed that in the mammalian class, most of the species of Carnivores, Artiodactyls, Perissodactyls, Pholidota, and Primates had high probability of viral entry. However, among the primates, baboons have very low probability of viral entry. Among rodents, hamsters were highly probable for viral entry with rats and mice having a very low probability. Rabbits have a medium probability of viral entry. In Birds, ducks have a very low probability, while chickens seemed to have medium probability and turkey showed the highest probability of viral entry. Conclusions Most of the species considered in this study showed high probability of viral entry. This study would prompt us to closely follow certain species of animals for determining pathogenic insult by SARS-CoV-2 and for determining their ability to act as a carrier and/or disseminator.
ye570v9g
ye570v9g
2020-06-13
10.1101/2020.05.08.084327
4
Is the use of RAS inhibitors safe in the current era of COVID-19 pandemic?
Antihypertensive drugs are one of the most widely used pharmacologic agent in the world and it is predominantly used in the elderly subjects. Pneumonia is the most common cause of death in the extremely old subject. During infection and its complication such as sepsis, hypotension could be exacerbated by antihypertensive drugs because homeostasis mechanisms such as sodium balance, renin angiotensin aldosterone system and/or sympathetic nervous system can be mitigated by antihypertensive drug therapy. Severe Acute Respiratory Syndrome-Coronavirus-1 and 2 viral surface protein is known to attach angiotensin converting enzyme 2 (ACE2) on the cell membrane to facilitate viral entry into the cytoplasm. Despite the theoretical concerns of increased ACE2 expression by Renin-Angiotensin-Aldosterone system (RAS) blockade, there is no evidence that RAS inhibitors are harmful during COVID-19 infection and have in fact been shown to be beneficial in animal studies. Therefore, it is recommended to maintain RAS blockade during the current corona virus pandemic.
ye5v8t3j
ye5v8t3j
2020-05-07
10.1186/s40885-020-00144-0
3.5
SARS-CoV-2 RNA dependent RNA polymerase (RdRp) targeting: an in silico perspective
New treatment against SARS-CoV-2 now is a must. Nowadays, the world encounters a huge health crisis by the COVID-19 viral infection. Nucleotide inhibitors gave a lot of promising results in terms of its efficacy against different viral infections. In this work, molecular modeling, docking, and dynamics simulations are used to build a model for the viral protein RNA-dependent RNA polymerase (RdRp) and test its binding affinity to some clinically approved drugs and drug candidates. Molecular dynamics is used to equilibrate the system upon binding calculations to ensure the successful reproduction of previous results, to include the dynamics of the RdRp, and to understand how it affects the binding. The results show the effectiveness of Sofosbuvir, Ribavirin, Galidesivir, Remdesivir, Favipiravir, Cefuroxime, Tenofovir, and Hydroxychloroquine, in binding to SARS-CoV-2 RdRp. Additionally, Setrobuvir, YAK, and IDX-184, show better results, while four novel IDX-184 derivatives show promising results in attaching to the SARS-CoV-2 RdRp. There is an urgent need to specify drugs that can selectively bind and subsequently inhibit SARS-CoV-2 proteins. The availability of a punch of FDA-approved anti-viral drugs can help us in this mission, aiming to reduce the danger of COVID-19. The compounds 2 and 3 may tightly bind to the SARS-CoV-2 RdRp and so may be successful in the treatment of COVID-19.
yehp3xp7
yehp3xp7
2020
3.5
From SARS to MERS: 10 years of research on highly pathogenic human coronaviruses
Abstract This article introduces a series of invited papers in Antiviral Research marking the 10th anniversary of the outbreak of severe acute respiratory syndrome (SARS), caused by a novel coronavirus that emerged in southern China in late 2002. Until that time, coronaviruses had not been recognized as agents causing severe disease in humans, hence, the emergence of the SARS-CoV came as a complete surprise. Research during the past ten years has revealed the existence of a diverse pool of coronaviruses circulating among various bat species and other animals, suggesting that further introductions of highly pathogenic coronaviruses into the human population are not merely probable, but inevitable. The recent emergence of another coronavirus causing severe disease, Middle East respiratory syndrome (MERS), in humans, has made it clear that coronaviruses pose a major threat to human health, and that more research is urgently needed to elucidate their replication mechanisms, identify potential drug targets, and develop effective countermeasures. In this series, experts in many different aspects of coronavirus replication and disease will provide authoritative, up-to-date reviews of the following topics: – clinical management and infection control of SARS; – reservoir hosts of coronaviruses; – receptor recognition and cross-species transmission of SARS-CoV; – SARS-CoV evasion of innate immune responses; – structures and functions of individual coronaviral proteins; – anti-coronavirus drug discovery and development; and – the public health legacy of the SARS outbreak. Each article will be identified in the last line of its abstract as belonging to the series “From SARS to MERS: 10years of research on highly pathogenic human coronaviruses.”
yev38f0k
yev38f0k
2013-10-31
10.1016/j.antiviral.2013.08.015
2.5
Teicoplanin: an alternative drug for the treatment of coronavirus COVID-19?
In December 2019, a new coronavirus, named SARS-CoV-2, has emerged from China causing pneumonia outbreaks first in the Wuhan region and have now spread worldwide because of its probable high transmission efficiency. Due to the lack of efficient and specific treatments and the need to contain the epidemic, drug repurposing appears to be the best tool to find therapeutic solution. Chloroquine, remdesivir, lopinavir, ribavirin or ritonavir have shown efficacy to inhibit coronavirus in vitro. Teicoplanin, an antibiotic used to treat staphylococci infection, previously showed efficacy to inhibit the first stage of MERS-coronarivus viral cycle in human cells. This activity is conserved on the SARS-Cov-2, thus placing teicoplanin as a potential treatment for patients with this virus.
yf5g53a9
yf5g53a9
2020-03-13
10.1016/j.ijantimicag.2020.105944
1
COVID-19 infection results in alterations of the kynurenine pathway and fatty acid metabolism that correlate with IL-6 levels and renal status
Previous studies suggest a role for systemic reprogramming of host metabolism during viral pathogenesis to fuel rapidly expanding viral proliferation, for example by providing free amino acids and fatty acids as building blocks. In addition, general alterations in metabolism can provide key understanding of pathogenesis. However, little is known about the specific metabolic effects of SARS-COV-2 infection. The present study evaluated the serum metabolism of COVID-19 patients (n=33), identified by a positive nucleic acid test of a nasopharyngeal swab, as compared to COVID-19-negative control patients (n=16). Targeted and untargeted metabolomics analyses specifically identified alterations in the metabolism of tryptophan into the kynurenine pathway, which is well-known to be involved in regulating inflammation and immunity. Indeed, the observed changes in tryptophan metabolism correlated with serum interleukin-6 (IL-6) levels. Metabolomics analysis also confirmed widespread dysregulation of nitrogen metabolism in infected patients, with decreased circulating levels of most amino acids, except for tryptophan metabolites in the kynurenine pathway, and increased markers of oxidant stress (e.g., methionine sulfoxide, cystine), proteolysis, and kidney dysfunction (e.g., creatine, creatinine, polyamines). Increased circulating levels of glucose and free fatty acids were also observed, consistent with altered carbon homeostasis in COVID-19 patients. Metabolite levels in these pathways correlated with clinical laboratory markers of inflammation and disease severity (i.e., IL-6 and C-reactive protein) and renal function (i.e., blood urea nitrogen). In conclusion, this initial observational study of the metabolic consequences of COVID-19 infection in a clinical cohort identified amino acid metabolism (especially kynurenine and cysteine/taurine) and fatty acid metabolism as correlates of COVID-19, providing mechanistic insights, potential markers of clinical severity, and potential therapeutic targets.
yflng8m3
yflng8m3
2020-05-16
10.1101/2020.05.14.20102491
3.5
A deductive approach to modeling the spread of COVID-19
Severe acute respiratory syndrome coronavirus 2 (SARS-COV-2), previously known as 2019-nCoV, is responsible for the atypical pneumonia pandemic designated as Coronavirus Disease 2019 (COVID-19). The confirmed number of cases continues to grow exponentially reaching 492,000 people in 175 countries as of March 25, 2020. 22,169 people (~4.5%) infected with SARS-COV-2 virus have died. We have developed an exponential regression model using the COVID-19 case data (Jan 22 - Mar 22, 2020). Our primary model uses designated Phase 1 countries, who exceed 2500 cases on Mar 22. The model is then applied to Phase 2 countries: those that escaped the initial Phase 1 global expansion of COVID-19. With the exception of stabilizing countries (South Korea, Japan, and Iran) all Phase 1 countries are growing exponentially, as per I2500(t)=120.4 × e0.238t, with a rate, r = 0.238 ± 0.068. Excluding China, the BRICS developing nations and Australia are in Phase 2. Case data from Phase 2 countries are following the model derived from Phase 1 countries. In the absence of measures employed to flatten the curve including social distancing, quarantine, and healthcare expansion, our model projects over 274,000 cases and 12,300 deaths in the US by Mar 31. India can expect 123,000 cases by April 16. By flattening the curve to the growth rate of stabilizing countries (r = 0.044 ± 0.062), the US would prevent 8,500 deaths by Mar 31, and India would prevent 5,500 deaths by April 16.
yg5posts
yg5posts
2020-03-30
10.1101/2020.03.26.20044651
1
Diagnosis of severe acute respiratory syndrome (SARS) by detection of SARS coronavirus nucleocapsid antibodies in an antigen-capturing enzyme-linked immunosorbent assay.
Recombinant severe acute respiratory syndrome (SARS) coronavirus nucleocapsid protein was employed to establish an antigen-capturing enzyme-linked immunosorbent assay (ELISA). Antinucleocapsid protein antibodies could be detected in 68.4% of probable SARS patients 6 to 10 days after illness and in 89.6% of the patients 11 to 61 days after illness. No false-positive results were observed in 20 non-SARS fever patients, 24 non-SARS respiratory illness patients, and 20 health care workers. Among 940 other non-SARS clinical serum samples, only 1 was found to be weakly positive. This method provides a new, sensitive, and specific approach for SARS diagnosis.
ygkwdrxl
ygkwdrxl
2003
3.5
Immunization with the receptor–binding domain of SARS-CoV-2 elicits antibodies cross-neutralizing SARS-CoV-2 and SARS-CoV without antibody-dependent enhancement
Recently emerged severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the pathogen responsible for the ongoing coronavirus disease 2019 (COVID-19) pandemic. Currently, there is no vaccine available for preventing SARS-CoV-2 infection. Like closely related severe acute respiratory syndrome coronavirus (SARS-CoV), SARS-CoV-2 also uses its receptor-binding domain (RBD) on the spike (S) protein to engage the host receptor, human angiotensin-converting enzyme 2 (ACE2), facilitating subsequent viral entry. Here we report the immunogenicity and vaccine potential of SARS-CoV-2 RBD (SARS2-RBD)-based recombinant proteins. Immunization with SARS2-RBD recombinant proteins potently induced a multi-functional antibody response in mice. The resulting antisera could efficiently block the interaction between SARS2-RBD and ACE2, inhibit S-mediated cell-cell fusion, and neutralize both SARS-CoV-2 pseudovirus entry and authentic SARS-CoV-2 infection. In addition, the anti-RBD sera also exhibited cross binding, ACE2-blockade, and neutralization effects towards SARS-CoV. More importantly, we found that the anti-RBD sera did not promote antibody-dependent enhancement of either SARS-CoV-2 pseudovirus entry or authentic virus infection of Fc receptor-bearing cells. These findings provide a solid foundation for developing RBD-based subunit vaccines for SARS-CoV2.
ygwdldae
ygwdldae
2020-05-21
10.1101/2020.05.21.107565
4.5
Remdesivir, lopinavir, emetine, and homoharringtonine inhibit SARS-CoV-2 replication in vitro
An escalating pandemic by the novel SARS-CoV-2 virus is impacting global health and effective therapeutic options are urgently needed. We evaluated the in vitro antiviral effect of compounds that were previously reported to inhibit coronavirus replication and compounds that are currently under evaluation in clinical trials for SARS-CoV-2 patients. We report the antiviral effect of remdesivir, lopinavir, homorringtonine, and emetine against SARS-CoV-2 virus in Vero E6 cells with the estimated 50% effective concentration at 23.15 µM, 26.63 µM, 2.55 µM and 0.46 µM, respectively. Ribavirin or favipiravir that are currently evaluated under clinical trials showed no inhibition at 100 µM. Synergy between remdesivir and emetine was observed, and remdesivir at 6.25 µM in combination with emetine at 0.195 µM may achieve 64.9% inhibition in viral yield. Combinational therapy may help to reduce the effective concentration of compounds below the therapeutic plasma concentrations and provide better clinical benefits.
ygygnmgm
ygygnmgm
2020
5
Investigation of ACE2 N-terminal fragments binding to SARS-CoV-2 Spike RBD
Coronavirus disease 19 (COVID-19) is an emerging global health crisis. With over 7 million confirmed cases to date, this pandemic continues to expand, spurring research to discover vaccines and therapies. SARS-CoV-2 is the novel coronavirus responsible for this disease. It initiates entry into human cells by binding to angiotensin-converting enzyme 2 (ACE2) via the receptor binding domain (RBD) of its spike protein (S). Disrupting the SARS-CoV-2-RBD binding to ACE2 with designer drugs has the potential to inhibit the virus from entering human cells, presenting a new modality for therapeutic intervention. Peptide-based binders are an attractive solution to inhibit the RBD-ACE2 interaction by adequately covering the extended protein contact interface. Using molecular dynamics simulations based on the recently solved cryo-EM structure of ACE2 in complex with SARS-CoV-2-RBD, we observed that the ACE2 peptidase domain (PD) α1 helix is important for binding SARS-CoV-2-RBD. Using automated fast-flow peptide synthesis, we chemically synthesized a 23-mer peptide fragment of the ACE2 PD α1 helix (SBP1) composed entirely of proteinogenic amino acids. Chemical synthesis of SBP1 was complete in 1.5 hours, and after work up and isolation >20 milligrams of pure material was obtained. Bio-layer interferometry (BLI) revealed that SBP1 associates with micromolar affinity to insect-derived SARS-CoV-2-RBD protein obtained from Sino Biological. Association of SBP1 was not observed to an appreciable extent to HEK cell-expressed SARS-CoV-2-RBD proteins and insect-derived variants acquired from other vendors. Moreover, competitive BLI assays showed SBP1 does not outcompete ACE2 binding to Sino Biological insect-derived SARS-CoV-2-RBD. Further investigations are ongoing to gain insight into the molecular and structural determinants of the variable binding behavior to different SARS-CoV-2-RBD protein variants.
yi6yu5l1
yi6yu5l1
2020-06-17
10.1101/2020.03.19.999318
1.5
It is too soon to attribute ADE to COVID-19
yinweejd
yinweejd
2020-04-05
10.1016/j.micinf.2020.03.005
1
Reduction and Functional Exhaustion of T Cells in Patients with Coronavirus Disease 2019 (COVID-19)
BACKGROUND The outbreak of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has posed great threat to human health, which has been declared a public health emergency of international concern (PHEIC) by the WHO. T cells play a critical role in antiviral immunity but their numbers and functional state in COVID-19 patients remain largely unclear. METHODS We retrospectively reviewed the counts of total T cells, CD4+, CD8+ T cell subsets, and serum cytokine concentration from inpatient data of 522 patients with laboratory-confirmed COVID-19, admitted into two hospitals in Wuhan from December 2019 to January 2020, and 40 healthy controls, who came to the hospitals for routine physical examination. In addition, the expression of T cell exhaustion markers PD-1 and Tim-3 were measured by flow cytometry in the peripheral blood of 14 COVID-19 cases. RESULTS The number of total T cells, CD4+ and CD8+ T cells were dramatically reduced in COVID-19 patients, especially among elderly patients (≥60 years of age) and in patients requiring Intensive Care Unit (ICU) care. Counts of total T cells, CD8+T cells or CD4+T cells lower than 800/μL, 300/μL, or 400/μL, respectively, are negatively correlated with patient survival. Statistical analysis demonstrated that T cell numbers are negatively correlated to serum IL-6, IL-10 and TNF-α concentration, with patients in decline period showing reduced IL-6, IL-10 and TNF-α concentrations and restored T cell counts. Finally, T cells from COVID-19 patients have significantly higher levels of the exhausted marker PD-1 as compared to health controls. Moreover, increasing PD-1 and Tim-3 expression on T cells could be seen as patients progressed from prodromal to overtly symptomatic stages, further indicative of T cell exhaustion. CONCLUSIONS T cell counts are reduced significantly in COVID-19 patients, and the surviving T cells appear functionally exhausted. Non-ICU patients, with total T cells, CD8+T cells CD4+T cells counts lower than 800/μL, 300/μL, and 400/μL, respectively, may still require aggressive intervention even in the immediate absence of more severe symptoms due to a high risk for further deterioration in condition.
yj25zkx6
yj25zkx6
2020-02-20
10.1101/2020.02.18.20024364
1
SARS-coronavirus-2 replication in Vero E6 cells: replication kinetics, rapid adaptation and cytopathology
The sudden emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) at the end of 2019 from the Chinese province of Hubei and its subsequent pandemic spread highlight the importance of understanding the full molecular details of coronavirus infection and pathogenesis. Here, we compared a variety of replication features of SARS-CoV-2 and SARS-CoV and analysed the cytopathology caused by the two closely related viruses in the commonly used Vero E6 cell line. Compared to SARS-CoV, SARS-CoV-2 generated higher levels of intracellular viral RNA, but strikingly about 50-fold less infectious viral progeny was recovered from the culture medium. Immunofluorescence microscopy of SARS-CoV-2-infected cells established extensive cross-reactivity of antisera previously raised against a variety of nonstructural proteins, membrane and nucleocapsid protein of SARS-CoV. Electron microscopy revealed that the ultrastructural changes induced by the two SARS viruses are very similar and occur within comparable time frames after infection. Furthermore, we determined that the sensitivity of the two viruses to three established inhibitors of coronavirus replication (Remdesivir, Alisporivir and chloroquine) is very similar, but that SARS-CoV-2 infection was substantially more sensitive to pre-treatment of cells with pegylated interferon alpha. An important difference between the two viruses is the fact that - upon passaging in Vero E6 cells - SARS-CoV-2 apparently is under strong selection pressure to acquire adaptive mutations in its spike protein gene. These mutations change or delete a putative ‘furin-like cleavage site’ in the region connecting the S1 and S2 domains and result in a very prominent phenotypic change in plaque assays.
yk60ol95
yk60ol95
2020-04-20
10.1101/2020.04.20.049924
2.5
COVID-19 and intracerebral haemorrhage: causative or coincidental?
Pneumonia appears to be the most common manifestation of coronavirus disease 2019 (COVID-19), but some extrapulmonary involvement, such as gastrointestinal, cardiac and renal, has been reported. The limited clinical data about the virus's behavior to date, especially extrapulmonary symptoms, suggest that we should be aware of the possibility of initial cerebrovascular manifestations of COVID-19.
ylr2b8ck
ylr2b8ck
2020-03-27
10.1016/j.nmni.2020.100669
1.5
Multi-Channel Transfer Learning of Chest X-ray Images for Screening of COVID-19
The 2019 novel coronavirus (COVID-19) has spread rapidly all over the world and it is affecting the whole society. The current gold standard test for screening COVID-19 patients is the polymerase chain reaction test. However, the COVID-19 test kits are not widely available and time-consuming. Thus, as an alternative, chest X-rays are being considered for quick screening. Since the presentation of COVID-19 in chest X-rays is varied in features and specialization in reading COVID-19 chest X-rays are required thus limiting its use for diagnosis. To address this challenge of reading chest X-rays by radiologists quickly, we present a multi-channel transfer learning model based on ResNet architecture to facilitate the diagnosis of COVID-19 chest X-ray. Three ResNet-based models (Models a, b, and c) were retrained using Dataset_A (1579 normal and 4429 diseased), Dataset_B (4245 pneumonia and 1763 non-pneumonia), and Dataset_C (184 COVID-19 and 5824 Non-COVID19), respectively, to classify (a) normal or diseased, (b) pneumonia or non-pneumonia, and (c) COVID-19 or non-COVID19. Finally, these three models were ensembled and fine-tuned using Dataset_D (1579 normal, 4245 pneumonia, and 184 COVID-19) to classify normal, pneumonia, and COVID-19 cases. Our results show that the ensemble model is more accurate than the single ResNet model, which is also re-trained using Dataset_D as it extracts more relevant semantic features for each class. Our approach provides a precision of 94 % and a recall of 100%. Thus, our method could potentially help clinicians in screening patients for COVID-19, thus facilitating immediate triaging and treatment for better outcomes.
ymz7z76i
ymz7z76i
2020-05-12
3.5
Probable Pangolin Origin of SARS-CoV-2 Associated with the COVID-19 Outbreak
An outbreak of coronavirus disease 2019 (COVID-19) caused by the 2019 novel coronavirus (SARS-CoV-2) began in the city of Wuhan in China and has widely spread worldwide. Currently, it is vital to explore potential intermediate hosts of SARS-CoV-2 to control COVID-19 spread. Therefore, we reinvestigated published data from pangolin lung samples from which SARS-CoV-like CoVs were detected by Liu et al. [1]. We found genomic and evolutionary evidence of the occurrence of a SARS-CoV-2-like CoV (named Pangolin-CoV) in dead Malayan pangolins. Pangolin-CoV is 91.02% and 90.55% identical to SARS-CoV-2 and BatCoV RaTG13, respectively, at the whole-genome level. Aside from RaTG13, Pangolin-CoV is the most closely related CoV to SARS-CoV-2. The S1 protein of Pangolin-CoV is much more closely related to SARS-CoV-2 than to RaTG13. Five key amino acid residues involved in the interaction with human ACE2 are completely consistent between Pangolin-CoV and SARS-CoV-2, but four amino acid mutations are present in RaTG13. Both Pangolin-CoV and RaTG13 lost the putative furin recognition sequence motif at S1/S2 cleavage site that can be observed in the SARS-CoV-2. Conclusively, this study suggests that pangolin species are a natural reservoir of SARS-CoV-2-like CoVs.
yn8nzezq
yn8nzezq
2020-03-19
10.1016/j.cub.2020.03.022
1.5
Automated detection of COVID-19 cases using deep neural networks with X-ray images
Abstract The novel coronavirus 2019 (COVID-2019), which first appeared in Wuhan city of China in December 2019, spread rapidly around the world and became a pandemic. It has caused a devastating effect on both daily lives, public health, and the global economy. It is critical to detect the positive cases as early as possible so as to prevent the further spread of this epidemic and to quickly treat affected patients. The need for auxiliary diagnostic tools has increased as there are no accurate automated toolkits available. Recent findings obtained using radiology imaging techniques suggest that such images contain salient information about the COVID-19 virus. Application of advanced artificial intelligence (AI) techniques coupled with radiological imaging can be helpful for the accurate detection of this disease, and can also be assistive to overcome the problem of a lack of specialized physicians in remote villages. In this study, a new model for automatic COVID-19 detection using raw chest X-ray images is presented. The proposed model is developed to provide accurate diagnostics for binary classification (COVID vs. No-Findings) and multi-class classification (COVID vs. No-Findings vs. Pneumonia). Our model produced a classification accuracy of 98.08% for binary classes and 87.02% for multi-class cases. The DarkNet model was used in our study as a classifier for the you only look once (YOLO) real time object detection system. We implemented 17 convolutional layers and introduced different filtering on each layer. Our model (available at (https://github.com/muhammedtalo/COVID-19)) can be employed to assist radiologists in validating their initial screening, and can also be employed via cloud to immediately screen patients.
yolo8bb3
yolo8bb3
2020-04-28
10.1016/j.compbiomed.2020.103792
2
Chapter 38 Animal Models of Human Viral Diseases
Abstract As the threat of exposure to emerging and reemerging viruses within a naive population increases, it is vital that the basic mechanisms of pathogenesis and immune response be thoroughly investigated. By using animal models in this endeavor, the response to viruses can be studied in a more natural context to identify novel drug targets, and assess the efficacy and safety of new products. This is especially true in the advent of the Food and Drug Administration's animal rule. Although no one animal model is able to recapitulate all the aspects of human disease, understanding the current limitations allows for a more targeted experimental design. Important facets to be considered before an animal study are the route of challenge, species of animals, biomarkers of disease, and a humane endpoint. This chapter covers the current animal models for medically important human viruses, and demonstrates where the gaps in knowledge exist.
yp9ofhi8
yp9ofhi8
2013-12-31
10.1016/b978-0-12-415894-8.00038-5
1
Lithium chloride inhibits the coronavirus infectious bronchitis virus in cell culture
The avian coronavirus infectious bronchitis virus (IBV) is a major economic pathogen of domestic poultry that, despite vaccination, causes mortality and significant losses in production. During replication of the RNA genome there is a high frequency of mutation and recombination, which has given rise to many strains of IBV and results in the potential for new and emerging strains. Currently the live-attenuated vaccine gives poor cross-strain immunity. Effective antiviral agents may therefore be advantageous in the treatment of IBV. Lithium chloride (LiCl) is a potent inhibitor of the DNA virus herpes simplex virus but not RNA viruses. The effect of LiCl on the replication of IBV was examined in cell culture using two model cell types; Vero cells, an African Green monkey kidney-derived epithelial cell line; and DF-1 cells, an immortalized chicken embryo fibroblast cell line. When treated with a range of LiCl concentrations, IBV RNA and protein levels and viral progeny production were reduced in a dose-dependent manner in both cell types, and the data indicated that inhibition was a cellular rather than a virucidal effect. Host cell protein synthesis still took place in LiCl-treated cells and the level of a standard cellular housekeeping protein remained unchanged, indicating that the effect of LiCl was specifically against IBV.
ypv2a9yr
ypv2a9yr
2007-05-02
10.1080/03079450601156083
5
Severe acute respiratory syndrome and dentistry A retrospective view
ABSTRACT Background Severe acute respiratory syndrome, or SARS, which has created panic in Asia and in some parts of North America, is the first epidemic of the new century. Although it has been well-contained, sporadic cases continue to emerge. Objectives The authors trace the emergence of the SARS outbreak from southern China and its spread worldwide, discuss the viral etiology of the infection and its clinical features, and review the infection control guidelines issued during the outbreak by the health authorities in Hong Kong, the Centers for Disease Control and Prevention, the World Health Organization and the American Dental Association. They also review the prospects for a new outbreak and preventive measures. Overview The disease, which is caused by a novel coronavirus termed the “SARS coronavirus,” or SARS-CoV, essentially spreads through droplet infection and affects people of any age. It has a mortality rate ranging from 10 to 15 percent. A major hallmark of this disease has been the rate at which it has affected health care workers through nosocomial transmission; in some countries, up to one-fourth to one-third of those infected were in this category. However, no dental health care worker has been affected by SARS in a nosocomial or dental setting. Conclusions and Clinical Implications Researchers believe that a combination of factors, including the universal infection control measures that the dental community has implemented and/or the low degree of viral shedding in the prodromal phase of SARS, may have obviated the spread of the disease in dental settings. The dental community should reflect on this outbreak to reinforce the currently applied infection control measures.
yq4dtf8n
yq4dtf8n
2004-09-30
10.14219/jada.archive.2004.0405
0.5
The emerging utility of neopterin?
yq4kn8ip
yq4kn8ip
2005-04-22
10.1016/j.clim.2005.03.008
1.5
Comparison of SARS-CoV-2 spike protein binding to human, pet, farm animals, and putative intermediate hosts ACE2 and ACE2 receptors
The emergence of a novel coronavirus, SARS-CoV-2, resulted in a pandemic. Here, we used recently released X-ray structures of human ACE2 bound to the receptor-binding domain (RBD) of the spike protein (S) from SARS-CoV-2 to predict its binding to ACE2 proteins from different animals, including pets, farm animals, and putative intermediate hosts of SARS-CoV-2. Comparing the interaction sites of ACE2 proteins known to serve or not serve as receptor allows to define residues important for binding. From the 20 amino acids in ACE2 that contact S up to seven can be replaced and ACE2 can still function as the SARS-CoV-2 receptor. These variable amino acids are clustered at certain positions, mostly at the periphery of the binding site, while changes of the invariable residues prevent S-binding or infection of the respective animal. Some ACE2 proteins even tolerate the loss or the acquisition of N-glycosylation sites located near the S-interface. Of note, pigs and dogs which are not or not effectively infected, respectively, have only a few changes in the binding site have relatively low levels of ACE2 in the respiratory tract. Comparison of the RBD of S of SARS-CoV-2 with viruses from bat and pangolin revealed that the latter contains only one substitution, whereas the bat virus exhibits five. However, ACE2 of pangolin exhibit seven changes relative to human ACE2, a similar number of substitutions is present in ACE2 of bats, raccoon, and civet suggesting that SARS-CoV-2 may not especially adapted to ACE2 of any of its putative intermediate hosts. These analyses provide new insight into the receptor usage and animal source/origin of SARS-COV-2. IMPORTANCE SARS-CoV-2 is threatening people worldwide and there are no drugs or vaccines available to mitigate its spread. The origin of the virus is still unclear and whether pets and livestock can be infected and transmit SARS-CoV-2 are important and unknown scientific questions. Effective binding to the host receptor ACE2 is the first prerequisite for infection of cells and determines the host range. Our analysis provides a framework for the prediction of potential hosts of SARS-CoV-2. We found that ACE2 from species known to support SARS-CoV-2 infection tolerate many amino acid changes indicating that the species barrier might be low. However, the lower expression of ACE2 in the upper respiratory tract of some pets and livestock means more research and monitoring should be done to explore the animal source of infection and the risk of potential cross-species transmission. Finally, the analysis also showed that SARS-CoV-2 may not specifically adapted to any of its putative intermediate hosts.
yqeifpoy
yqeifpoy
2020-05-08
10.1101/2020.05.08.084061
3.5
Pharmacologic Treatments for Coronavirus Disease 2019 (COVID-19): A Review
Importance: The pandemic of coronavirus disease 2019 (COVID-19) caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) presents an unprecedented challenge to identify effective drugs for prevention and treatment. Given the rapid pace of scientific discovery and clinical data generated by the large number of people rapidly infected by SARS-CoV-2, clinicians need accurate evidence regarding effective medical treatments for this infection. Observations: No proven effective therapies for this virus currently exist. The rapidly expanding knowledge regarding SARS-CoV-2 virology provides a significant number of potential drug targets. The most promising therapy is remdesivir. Remdesivir has potent in vitro activity against SARS-CoV-2, but it is not US Food and Drug Administration approved and currently is being tested in ongoing randomized trials. Oseltamivir has not been shown to have efficacy, and corticosteroids are currently not recommended. Current clinical evidence does not support stopping angiotensin-converting enzyme inhibitors or angiotensin receptor blockers in patients with COVID-19. Conclusions and Relevance: The COVID-19 pandemic represents the greatest global public health crisis of this generation and, potentially, since the pandemic influenza outbreak of 1918. The speed and volume of clinical trials launched to investigate potential therapies for COVID-19 highlight both the need and capability to produce high-quality evidence even in the middle of a pandemic. No therapies have been shown effective to date.
yth9hh5q
yth9hh5q
2020
4.5
Mechanism of thrombocytopenia in COVID-19 patients
Since December 2019, a novel coronavirus has spread throughout China and across the world, causing a continuous increase in confirmed cases within a short period of time. Some studies reported cases of thrombocytopenia, but hardly any studies mentioned how the virus causes thrombocytopenia. We propose several mechanisms by which coronavirus disease 2019 causes thrombocytopenia to better understand this disease and provide more clinical treatment options.
yti2nukb
yti2nukb
2020-04-15
10.1007/s00277-020-04019-0
3.5
Prediction and analysis of Coronavirus Disease 2019
In December 2019, a novel coronavirus was found in a seafood wholesale market in Wuhan, China. WHO officially named this coronavirus as COVID-19. Since the first patient was hospitalized on December 12, 2019, China has reported a total of 78,824 confirmed CONID-19 cases and 2,788 deaths as of February 28, 2020. Wuhan's cumulative confirmed cases and deaths accounted for 61.1% and 76.5% of the whole China mainland , making it the priority center for epidemic prevention and control. Meanwhile, 51 countries and regions outside China have reported 4,879 confirmed cases and 79 deaths as of February 28, 2020. COVID-19 epidemic does great harm to people's daily life and country's economic development. This paper adopts three kinds of mathematical models, i.e., Logistic model, Bertalanffy model and Gompertz model. The epidemic trends of SARS were first fitted and analyzed in order to prove the validity of the existing mathematical models. The results were then used to fit and analyze the situation of COVID-19. The prediction results of three different mathematical models are different for different parameters and in different regions. In general, the fitting effect of Logistic model may be the best among the three models studied in this paper, while the fitting effect of Gompertz model may be better than Bertalanffy model. According to the current trend, based on the three models, the total number of people expected to be infected is 49852-57447 in Wuhan,12972-13405 in non-Hubei areas and 80261-85140 in China respectively. The total death toll is 2502-5108 in Wuhan, 107-125 in Non-Hubei areas and 3150-6286 in China respetively. COVID-19 will be over p robably in late-April, 2020 in Wuhan and before late-March, 2020 in other areas respectively.
ytu39uvk
ytu39uvk
2020-03-11
2
Potentially repurposable drugs for COVID-19 identified from SARS-CoV-2 Host Protein Interactome
We previously presented the protein-protein interaction network - the ‘HoP’ or the host protein interactome - of 332 host proteins that were identified to interact with 27 nCoV19 viral proteins by Gordon et al. Here, we studied drugs targeting the proteins in this interactome to identify whether any of them may potentially be repurposable against SARS-CoV-2. We studied each of the drugs using the BaseSpace Correlation Engine and identified those that induce gene expression profiles negatively correlated with SARS-associated expression profile. This analysis resulted in 20 drugs whose differential gene expression (drug versus normal) had an anti-correlation with differential expression for SARS (viral infection versus normal). These included drugs that were already being tested for their clinical activity against SARS-CoV-2, those with proven activity against SARS-CoV/MERS-CoV, broad-spectrum antiviral drugs, and those identified/prioritized by other computational re-purposing studies. In summary, our integrated computational analysis of the HoP interactome in conjunction with drug-induced transcriptomic data resulted in drugs that may be repurposable for COVID-19.
yv2gjjzg
yv2gjjzg
2020-05-28
10.21203/rs.3.rs-30363/v1
5
Structural and molecular modelling studies reveal a new mechanism of action of chloroquine and hydroxychloroquine against SARS-CoV-2 infection
The recent emergence of the novel pathogenic SARS-coronavirus 2 (SARS-CoV-2) is responsible for a worldwide pandemic. Given the global health emergency, drug repositioning is the most reliable option to design an efficient therapy for infected patients without delay. The first step of the viral replication cycle [i.e. attachment to the surface of respiratory cells, mediated by the spike (S) viral protein] offers several potential therapeutic targets. The S protein uses the angiotension-converting enzyme-2 (ACE-2) receptor for entry, but also sialic acids linked to host cell surface gangliosides. Using a combination of structural and molecular modelling approaches, this study showed that chloroquine (CLQ), one of the drugs currently under investigation for SARS-CoV-2 treatment, binds sialic acids and gangliosides with high affinity. A new type of ganglioside-binding domain at the tip of the N-terminal domain of the SARS-CoV-2 S protein was identified. This domain (111-158), which is fully conserved among clinical isolates worldwide, may improve attachment of the virus to lipid rafts and facilitate contact with the ACE-2 receptor. This study showed that, in the presence of CLQ [or its more active derivative, hydroxychloroquine (CLQ-OH)], the viral S protein is no longer able to bind gangliosides. The identification of this new mechanism of action of CLQ and CLQ-OH supports the use of these repositioned drugs to cure patients infected with SARS-CoV-2. The in-silico approaches used in this study might also be used to assess the efficiency of a broad range of repositioned and/or innovative drug candidates before clinical evaluation.
yvmbzfmp
yvmbzfmp
2020
5
SARS
Abstract Severe acute respiratory syndrome (SARS) emerged in southern China in late 2002. It first spread within Guangdong Province and then to other parts of China. Via air travelers, it quickly reached various countries around the globe, causing several major hospital outbreaks. Within weeks, the causative agent, a previously unknown coronavirus (SARS-CoV), was identified, thanks to an unprecedented international effort led by the World Health Organization (WHO). Its origin was quickly traced to wild animals traded locally for culinary purposes. Masked palm civet and some other species seem to have acted as intermediate hosts. Since then, SARS-like coronaviruses were found in different bat species in China and elsewhere, and bats are now regarded as the wildlife reservoir for SARS-CoV. Fortunately, the SARS outbreak could be contained within months. Until July 2003, it had caused 8096 cases, with 774 deaths. Once adequate measures such as isolating patients and quarantining their contacts were strictly adhered to, further transmission between human beings could be interrupted. SARS is an example of how rapidly an infectious agent can spread in the modern world. At the same time, it should serve as a showcase of how international cooperation and modern science can help to combat the spread of infectious diseases.
yvsyo4l9
yvsyo4l9
2011-12-31
10.1016/b978-0-444-63951-6.00624-0
0.5
Search for SARS-CoV-2 inhibitors in currently approved drugs to tackle COVID-19 pandemia
Different treatments are currently used for clinical management of SARS-CoV-2 infection, but little is known about their efficacy yet. Here we present ongoing results to compare currently available drugs for a variety of diseases to find out if they counteract SARS-CoV-2-induced cytopathic effect in vitro. Our goal is to prioritize antiviral activity to provide a solid evidence-driven rationale for forthcoming clinical trials. Since the most effective antiviral approaches are usually based on combined therapies that tackle the viral life cycle at different stages, we are also testing combinations of drugs that may be critical to reduce the emergence of resistant viruses. We will provide results as soon as they become available, so data should be interpreted with caution, clearly understanding the limitations of the in vitro model, that may not always reflect what could happen in vivo. Thus, our goal is to test the most active antivirals identified in adequate animal models infected with SARS-CoV-2, to add more information about possible in vivo efficacy. In turn, successful antivirals could be tested in clinical trials as treatments for infected patients, but also as pre-exposure prophylaxis to avoid novel infections until an effective and safe vaccine is developed.
ywaefpe8
ywaefpe8
2020-04-24
10.1101/2020.04.23.055756
2
8 INFECTIOUS DISEASES
Publisher Summary The emergence of new pathogens, or the concern about bioterrorism, has brought an added urgency to the development of more efficient and rapid methods to detect pathogens and predict their potential virulence. Till date, DNA testing in microbiology has been directed predominantly to the detection of organisms that are difficult to culture in vitro, or for various reasons the growth is unlikely. DNA analysis can be used successfully in infections in which there is a mix of pathogens. Apart from the straightforward diagnostic applications, DNA microbiological testing has been used to detect antimicrobial resistance or toxigenic forms of E. coli. More recently, the availability of DNA technology to quantitate HCV and HIV has been useful in planning and monitoring treatment. The pathogenesis of many infections, particularly viral ones, can also be realized from experimental strategies based on light and electron microscopy, cell culture and immunoassay. The advantages that are provided by DNA techniques include the ability to detect latent (non-replicating) viruses and to localize their genomes to nuclear or cytoplasmic regions within cells. Nucleic acid probe techniques (NAT) can also be manipulated to enable a broad spectrum of serotypes to be detectable. This is particularly valuable in those emerging infections where the underlying serotypes are unknown.
yxawoasz
yxawoasz
2005-12-31
10.1016/b978-012699057-7/50008-4
0.5
Coronavirus Disease (COVID-19): A primer for emergency physicians
INTRODUCTION: Rapid worldwide spread of Coronavirus Disease 2019 (COVID-19) has resulted in a global pandemic. OBJECTIVE: This review article provides emergency physicians with an overview of the most current understanding of COVID-19 and recommendations on the evaluation and management of patients with suspected COVID-19. DISCUSSION: Severe Acute Respiratory Syndrome coronavirus 2 (SARS-CoV-2), the virus responsible for causing COVID-19, is primarily transmitted from person-to-person through close contact (approximately 6 ft) by respiratory droplets. Symptoms of COVID-19 are similar to other viral upper respiratory illnesses. Three major trajectories include mild disease with upper respiratory symptoms, non-severe pneumonia, and severe pneumonia complicated by acute respiratory distress syndrome (ARDS). Emergency physicians should focus on identifying patients at risk, isolating suspected patients, and informing hospital infection prevention and public health authorities. Patients with suspected COVID-19 should be asked to wear a facemask. Respiratory etiquette, hand washing, and personal protective equipment are recommended for all healthcare personnel caring for suspected cases. Disposition depends on patient symptoms, hemodynamic status, and patient ability to self-quarantine. CONCLUSION: This narrative review provides clinicians with an updated approach to the evaluation and management of patients presenting to the emergency department with suspected COVID-19.
yy7abob9
yy7abob9
2020-03-24
10.1016/j.ajem.2020.03.036
1
The SARS-CoV-2 receptor ACE2 expression of maternal-fetal interface and fetal organs by single-cell transcriptome study
The new type of pneumonia caused by the SARS-CoV-2 (Severe acute respiratory syndrome coronavirus 2) has been declared as a global public health concern by WHO. As of April 3, 2020, more than 1,000,000 human infections have been diagnosed around the world, which exhibited apparent person-to-person transmission characteristics of this virus. The capacity of vertical transmission in SARS-CoV-2 remains controversial recently. Angiotensin-converting enzyme 2 (ACE2) is now confirmed as the receptor of SARS-CoV-2 and plays essential roles in human infection and transmission. In present study, we collected the online available single-cell RNA sequencing (scRNA-seq) data to evaluate the cell specific expression of ACE2 in maternal-fetal interface as well as in multiple fetal organs. Our results revealed that ACE2 was highly expressed in maternal-fetal interface cells including stromal cells and perivascular cells of decidua, and cytotrophoblast and syncytiotrophoblast in placenta. Meanwhile, ACE2 was also expressed in specific cell types of human fetal heart, liver and lung, but not in kidney. And in a study containing series fetal and post-natal mouse lung, we observed ACE2 was dynamically changed over the time, and ACE2 was extremely high in neonatal mice at post-natal day 1~3. In summary, this study revealed that the SARS-CoV-2 receptor was widely spread in specific cell types of maternal-fetal interface and fetal organs. And thus, both the vertical transmission and the placenta dysfunction/abortion caused by SARS-CoV-2 need to be further carefully investigated in clinical practice.
yz9yhnbx
yz9yhnbx
2020-04-16
10.1371/journal.pone.0230295
2.5
A systematic review of antibody mediated immunity to coronaviruses: antibody kinetics, correlates of protection, and association of antibody responses with severity of disease
The duration and nature of immunity generated in response to SARS-CoV-2 infection is unknown. Many public health responses and modeled scenarios for COVID-19 outbreaks caused by SARSCoV-2 assume that infection results in an immune response that protects individuals from future infections or illness for some amount of time. The timescale of protection is a critical determinant of the future impact of the pathogen. The presence or absence of protective immunity due to infection or vaccination (when available) will affect future transmission and illness severity. The dynamics of immunity and nature of protection are relevant to discussions surrounding therapeutic use of convalescent sera as well as efforts to identify individuals with protective immunity. Here, we review the scientific literature on antibody immunity to coronaviruses, including SARS-CoV-2 as well as the related SARS-CoV-1, MERS-CoV and human endemic coronaviruses (HCoVs). We reviewed 1281 abstracts and identified 322 manuscripts relevant to 5 areas of focus: 1) antibody kinetics, 2) correlates of protection, 3) immunopathogenesis, 4) antigenic diversity and cross-reactivity, and 5) population seroprevalence. While studies of SARS-CoV-2 are necessary to determine immune responses to it, evidence from other coronaviruses can provide clues and guide future research.
yzffm05r
yzffm05r
2020-04-17
10.1101/2020.04.14.20065771
3.5
Emerging Influenza and Psychosis: An Important Story in Psychological Medicine
yzloau0d
yzloau0d
2013
10.4103/0253-7176.116269
4
The continued epidemic threat of SARS-CoV-2 and implications for the future of global public health
A new coronavirus (CoV) called SARS-CoV-2 emerged in Wuhan, China in December 2019 as the etiological agent of a viral pneumonia called COVID-19. The global spread of SARS-CoV-2 has been so extensive that the WHO declared COVID-19 a pandemic on March 11, 2020. Below, we discuss the emergence of SARS-CoV-2 and provide the historical context, which strongly suggests emerging CoVs provide an immediate threat to global public health and will continue to do so in the future.
yztlb0fn
yztlb0fn
2020-06-04
10.1016/j.coviro.2020.05.010
4.5
The Anticoagulant Nafamostat Potently Inhibits SARS-CoV-2 S Protein-Mediated Fusion in a Cell Fusion Assay System and Viral Infection In Vitro in a Cell-Type-Dependent Manner
Although infection by SARS-CoV-2, the causative agent of coronavirus pneumonia disease (COVID-19), is spreading rapidly worldwide, no drug has been shown to be sufficiently effective for treating COVID-19. We previously found that nafamostat mesylate, an existing drug used for disseminated intravascular coagulation (DIC), effectively blocked Middle East respiratory syndrome coronavirus (MERS-CoV) S protein-mediated cell fusion by targeting transmembrane serine protease 2 (TMPRSS2), and inhibited MERS-CoV infection of human lung epithelium-derived Calu-3 cells. Here we established a quantitative fusion assay dependent on severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) S protein, angiotensin I converting enzyme 2 (ACE2) and TMPRSS2, and found that nafamostat mesylate potently inhibited the fusion while camostat mesylate was about 10-fold less active. Furthermore, nafamostat mesylate blocked SARS-CoV-2 infection of Calu-3 cells with an effective concentration (EC)50 around 10 nM, which is below its average blood concentration after intravenous administration through continuous infusion. On the other hand, a significantly higher dose (EC50 around 30 mM) was required for VeroE6/TMPRSS2 cells, where the TMPRSS2-independent but cathepsin-dependent endosomal infection pathway likely predominates. Together, our study shows that nafamostat mesylate potently inhibits SARS-CoV-2 S protein-mediated fusion in a cell fusion assay system and also inhibits SARS-CoV-2 infection in vitro in a cell-type-dependent manner. These findings, together with accumulated clinical data regarding nafamostat's safety, make it a likely candidate drug to treat COVID-19.
z0h32jyu
z0h32jyu
2020
4
Repurposing of clinically approved drugs for treatment of coronavirus disease 2019 in a 2019-novel coronavirus-related coronavirus model
BACKGROUND: Medicines for the treatment of 2019-novel coronavirus (2019-nCoV) infections are urgently needed. However, drug screening using live 2019-nCoV requires high-level biosafety facilities, which imposes an obstacle for those institutions without such facilities or 2019-nCoV. This study aims to repurpose the clinically approved drugs for the treatment of coronavirus disease 2019 (COVID-19) in a 2019-nCoV-related coronavirus model. METHODS: A 2019-nCoV-related pangolin coronavirus GX_P2V/pangolin/2017/Guangxi was described. Whether GX_P2V uses angiotensin-converting enzyme 2 (ACE2) as the cell receptor was investigated by using small interfering RNA (siRNA) -mediated silencing of ACE2. The pangolin coronavirus model was used to identify drug candidates for treating 2019-nCoV infection. Two libraries of 2406 clinically approved drugs were screened for their ability to inhibit cytopathic effects on Vero E6 cells by GX_P2V infection. The anti-viral activities and anti-viral mechanisms of potential drugs were further investigated. Viral yields of RNAs and infectious particles were quantified by quantitative real-time polymerase chain reaction (qRT-PCR) and plaque assay, respectively. RESULTS: The spike protein of coronavirus GX_P2V shares 92.2% amino acid identity with that of 2019-nCoV isolate Wuhan-hu-1, and uses ACE2 as the receptor for infection just like 2019-nCoV. Three drugs, including cepharanthine (CEP), selamectin, and mefloquine hydrochloride, exhibited complete inhibition of cytopathic effects in cell culture at 10 μmol/L. CEP demonstrated the most potent inhibition of GX_P2V infection, with a concentration for 50% of maximal effect [EC(50)] of 0.98 μmol/L. The viral RNA yield in cells treated with 10 μmol/L CEP was 15,393-fold lower than in cells without CEP treatment ([6.48 ± 0.02] × 10(−4)vs. 1.00 ± 0.12, t = 150.38, P < 0.001) at 72 h post-infection (p.i.). Plaque assays found no production of live viruses in media containing 10 μmol/L CEP at 48 h p.i. Furthermore, we found CEP had potent anti-viral activities against both viral entry (0.46 ± 0.12, vs.1.00 ± 0.37 t = 2.42, P < 0.05) and viral replication ([6.18 ± 0.95] × 10(−4)vs. 1.00 ± 0.43, t = 3.98, P < 0.05). CONCLUSIONS: Our pangolin coronavirus GX_P2V is a workable model for 2019-nCoV research. CEP, selamectin, and mefloquine hydrochloride are potential drugs for treating 2019-nCoV infection. Our results strongly suggest that CEP is a wide-spectrum inhibitor of pan-betacoronavirus, and further study of CEP for treatment of 2019-nCoV infection is warranted.
z0qzgu5m
z0qzgu5m
2020-03-06
10.1097/cm9.0000000000000797
2
Complete genome sequence of bat coronavirus HKU2 from Chinese horseshoe bats revealed a much smaller spike gene with a different evolutionary lineage from the rest of the genome
Abstract Apart from bat-SARS-CoV, we have identified a novel group 1 coronavirus, bat-CoV HKU2, in Rhinolophus sinicus (Chinese horseshoe bats). Since it has been suggested that the receptor-binding motif (RBM) of SARS-CoV may have been acquired from a group 1 coronavirus, we conducted a surveillance study and identified bat-SARS-CoV and bat-CoV HKU2 in 8.7% and 7.5% respectively of R. sinicus in Hong Kong and Guangdong. Complete genome sequencing of four strains of bat-CoV HKU2 revealed the smallest coronavirus genome (27164 nucleotides) and a unique spike protein evolutionarily distinct from the rest of the genome. This spike protein, sharing similar deletions with other group 2 coronaviruses in its C-terminus, also contained a 15-amino acid peptide homologous to a corresponding peptide within the RBM of spike protein of SARS-CoV, which was absent in other coronaviruses except bat-SARS-CoV. These suggest a common evolutionary origin in the spike protein of bat-CoV HKU2, bat-SARS-CoV, and SARS-CoV.
z2kgcjtp
z2kgcjtp
2007-10-25
10.1016/j.virol.2007.06.009
3.5
COVID19 inhibitors: A prospective therapeutics
Abstract The inhibition of viral targets might provide new therapies for coronavirus disease abbreviated as COVID-19. The rational drug design identified as much of the recent discoveries of potent drugs molecule against any targets. This results in an improvement in bindings for better potency and selectivity. The drugs containing ethanolamine/propylamine fragments along with heterocycles have shown potential antiviral results. Similarly, there is the possibility of controlling the COVID-19 infection by nucleotide analogues. Here we also highlight drugs ACEIs/ARBs inhibitory discussing both their advantages and disadvantages. The class of compounds/antibodies inhibiting interleukin-6 works in antirheumatoid drugs are found useful in alleviating overactive inflammatory responses in the lungs of the patient. These inclusion based approaches counter some of the side-effects associated with the heterocycles and also potentiate the efficacy of the molecules. In this review article, design strategies for some of the drugs effective against SARS-CoV-2 are represented. The review also focuses on the listing of drugs that are currently testing under clinical trials for the COVID-19 virus with their mechanism of action. This conversation undertakes the opportunity to do a bit for the newer researchers working in this arena.
z4hc9yhb
z4hc9yhb
2020-06-17
10.1016/j.bioorg.2020.104027
4
Positive rate of RT-PCR detection of SARS-CoV-2 infection in 4880 cases from one hospital in Wuhan, China, from Jan to Feb 2020
Abstract Background There’s an outbreak of a novel coronavirus (SARS-CoV-2) infection since December 2019, first in China, and currently with more than 80 thousand confirmed infection globally in 29 countries till March 2, 2020. Identification, isolation and caring for patients early are essential to limit human-to-human transmission including reducing secondary infections among close contacts and health care workers, preventing transmission amplification events. The RT-PCR detection of viral nucleic acid test (NAT) was one of the most quickly established laboratory diagnosis method in a novel viral pandemic, just as in this COVID-19 outbreak. Methods 4880 cases that had respiratory infection symptoms or close contact with COVID-19 patients in hospital in Wuhan, China, were tested for SARS-CoV-2 infection by use of quantitative RT-PCR (qRT-PCR) on samples from the respiratory tract. Positive rates were calculated in groups divided by genders or ages. Results The positive rate was about 38% for the total 4880 specimens. Male and older population had a significant higher positive rates. However, 57% was positive among the specimens from the Fever Clinics. Binary logistic regression analysis showed that age, not gender, was the risk factor for SARS-CoV-2 infection in fever clinics. Conclusions Therefore, we concluded that viral NAT played an important role in identifying SARS-CoV-2 infection.
z4l3pk23
z4l3pk23
2020-06-30
10.1016/j.cca.2020.03.009
1.5
Short peptides derived from the interaction domain of SARS coronavirus nonstructural protein nsp10 can suppress the 2′-O-methyltransferase activity of nsp10/nsp16 complex
Abstract Coronaviruses are the etiological agents of respiratory and enteric diseases in humans and livestock, exemplified by the life-threatening severe acute respiratory syndrome (SARS) caused by SARS coronavirus (SARS-CoV). However, effective means for combating coronaviruses are still lacking. The interaction between nonstructural protein (nsp) 10 and nsp16 has been demonstrated and the crystal structure of SARS-CoV nsp16/10 complex has been revealed. As nsp10 acts as an essential trigger to activate the 2′-O-methyltransferase activity of nsp16, short peptides derived from nsp10 may have inhibitory effect on viral 2′-O-methyltransferase activity. In this study, we revealed that the domain of aa 65–107 of nsp10 was sufficient for its interaction with nsp16 and the region of aa 42–120 in nsp10, which is larger than the interaction domain, was needed for stimulating the nsp16 2′-O-methyltransferase activity. We further showed that two short peptides derived from the interaction domain of nsp10 could inhibit the 2′-O-methyltransferase activity of SARS-CoV nsp16/10 complex, thus providing a novel strategy and proof-of-principle study for developing peptide inhibitors against SARS-CoV.
z5109axc
z5109axc
2012-08-31
10.1016/j.virusres.2012.05.017
0.5
The role of α4 integrin in Theiler’s murine encephalomyelitis virus (TMEV)-induced demyelinating disease: an infectious animal model for multiple sclerosis (MS)
Natalizumab, which is an antibody against α4 integrin, has been used for the treatment of multiple sclerosis (MS). In the present study, we investigated both the role of α4 integrin and the therapeutic effect of HCA3551, a newly synthesized orally active small-molecule α4 integrin antagonist, in the development of TMEV-induced demyelinating disease (TMEV-IDD). The mRNA levels of α4 integrins were significantly up-regulated in the CNS of mice with TMEV-IDD as compared with naïve mice (*p<0.05). HCA3551 treatment in the effector phase significantly suppressed both the clinical and histological development of TMEV-IDD. The number of infiltrating mononuclear inflammatory cells in the CNS was significantly decreased in the mice treated with HCA3551 (**p<0.01). The labeling indices for CD68 antigen and the absolute cell numbers of TNF-α-producing CD4(+) T cells and IFN-γ-producing CD8(+) T cells were significantly decreased in the CNS of mice treated with HCA3551 (*p<0.05). HCA3551 treatment in the effector phase might inhibit the binding of α4 integrin to VCAM-1, thereby decreasing the number of MNCs in the CNS.
z5lv81bi
z5lv81bi
2016-11-01
10.1093/intimm/dxw045
5
Natural product-derived phytochemicals as potential agents against coronaviruses: a review
Abstract Coronaviruses are responsible for a growing economic, social and mortality burden, as the causative agent of diseases such as severe acute respiratory syndrome (SARS), Middle East respiratory syndrome (MERS), avian infectious bronchitis virus (IBV) and COVID-19. However, there is a lack of effective antiviral agents for many coronavirus strains. Naturally existing compounds provide a wealth of chemical diversity, including antiviral activity, and thus may have utility as therapeutic agents against coronaviral infections. The PubMed database was searched for papers including the keywords coronavirus, SARS or MERS, as well as traditional medicine, herbal, remedy or plants, with 55 primary research articles identified. The overwhelming majority of publications focussed on polar compounds. Compounds that show promise for the inhibition of coronavirus in humans include scutellarein, silvestrol, tryptanthrin, saikosaponin B2, quercetin, myricetin, caffeic acid, psoralidin, isobavachalcone, and lectins such as griffithsin. Other compounds such as lycorine may be suitable if a therapeutic level of antiviral activity can be achieved without exceeding toxic plasma concentrations. It was noted that the most promising small molecules identified as coronavirus inhibitors contained a conjugated fused ring structure with the majority being classified as being polyphenols.
z6kiee09
z6kiee09
2020-04-30
10.1016/j.virusres.2020.197989
3.5
Potential therapies for coronaviruses
Coronavirus replication offers several attractive targets for chemotherapy. These include: viral entry (inhibited by chloroquine and peptides); viral RNA (targeted by antisense approaches/RNAi); the main protease 3CLpro (inhibited by peptidic molecules such as HIV-1 protease inhibitors and miscellaneous compounds); the accessory protease(s) PLpro(s) (inhibited by zinc ions); RNA-dependent RNA polymerase (inhibited by aurintricarboxylic acid and antisense approaches); and helicase (inhibited by bananins). Chloroquine and HIV-1 protease inhibitors (with well-known toxicity profiles) should be considered for clinical tests if severe acute respiratory syndrome (SARS) re-emerges; however, there are other attractive compounds. Lessons should be learnt from AIDS research for choosing the best strategies.
z739ifu5
z739ifu5
2006-08-31
10.1517/13543776.16.9.1269
0.5
A model for 2019-nCoV infection with treatment
The current emergence of coronavirus (2019-nCoV or COVID-19) puts the world in threat. 2019-nCoV remains the outbreak of SARS-CoV 2002-2003. The structural research on the receptor recognition by SARS-CoV has identified the key interactions between SARS-CoV spike protein and its host receptor, also known as angiotensin converting enzyme 2 (ACE2). It controls both the cross-species and human-to-human transmissions of SARS-CoV. In this article, we have considered the infection dynamics of SARS-CoV-2 infection in the acute stage. Our aim is to propose and analyse a mathematical model for investigating the effect of CTL responses over the viral mutation to control the viral infection when a post-infection vaccine is administered at regular intervals. Dynamics of the system with and without impulses have been analysed using qualitative theory. Main findings are supported through numerical simulations.
z73q22v3
z73q22v3
2020-04-29
10.1101/2020.04.24.20077958
2.5
Associations between immune-suppressive and stimulating drugs and novel COVID-19—a systematic review of current evidence
BACKGROUND: Cancer and transplant patients with COVID-19 have a higher risk of developing severe and even fatal respiratory diseases, especially as they may be treated with immune-suppressive or immune-stimulating drugs. This review focuses on the effects of these drugs on host immunity against COVID-19. METHODS: Using Ovid MEDLINE, we reviewed current evidence for immune-suppressing or -stimulating drugs: cytotoxic chemotherapy, low-dose steroids, tumour necrosis factorα (TNFα) blockers, interlukin-6 (IL-6) blockade, Janus kinase (JAK) inhibitors, IL-1 blockade, mycophenolate, tacrolimus, anti-CD20 and CTLA4-Ig. RESULTS: 89 studies were included. Cytotoxic chemotherapy has been shown to be a specific inhibitor for severe acute respiratory syndrome coronavirus in in vitro studies, but no specific studies exist as of yet for COVID-19. No conclusive evidence for or against the use of non-steroidal anti-inflammatory drugs (NSAIDs) in the treatment of COVID-19 patients is available, nor is there evidence indicating that TNFα blockade is harmful to patients in the context of COVID-19. COVID-19 has been observed to induce a pro-inflammatory cytokine generation and secretion of cytokines, such as IL-6, but there is no evidence of the beneficial impact of IL-6 inhibitors on the modulation of COVID-19. Although there are potential targets in the JAK-STAT pathway that can be manipulated in treatment for coronaviruses and it is evident that IL-1 is elevated in patients with a coronavirus, there is currently no evidence for a role of these drugs in treatment of COVID-19. CONCLUSION: The COVID-19 pandemic has led to challenging decision-making about treatment of critically unwell patients. Low-dose prednisolone and tacrolimus may have beneficial impacts on COVID-19. The mycophenolate mofetil picture is less clear, with conflicting data from pre-clinical studies. There is no definitive evidence that specific cytotoxic drugs, low-dose methotrexate for auto-immune disease, NSAIDs, JAK kinase inhibitors or anti-TNFα agents are contraindicated. There is clear evidence that IL-6 peak levels are associated with severity of pulmonary complications.
za3qypgg
za3qypgg
2020-03-27
10.3332/ecancer.2020.1022
1.5
Animal Models for Target Diseases in Gene Therapy — using DNA and siRNA Delivery Strategies
Nanoparticles, including lipopolyamines leading to lipoplexes, liposomes, and polyplexes are targeted drug carrier systems in the current search for a successful delivery system for polynucleic acids. This review is focused on the impact of gene and siRNA delivery for studies of efficacy, pharmacodynamics, and pharmacokinetics within the setting of the wide variety of in vivo animal models now used. This critical appraisal of the recent literature sets out the different models that are currently being investigated to bridge from studies in cell lines through towards clinical reality. Whilst many scientists will be familiar with rodent (murine, fecine, cricetine, and musteline) models, few probably think of fish as a clinically relevant animal model, but zebrafish, madake, and rainbow trout are all being used. Larger animal models include rabbit, cat, dog, and cow. Pig is used both for the prevention of foot-and-mouth disease and human diseases, sheep is a model for corneal transplantation, and the horse naturally develops arthritis. Non-human primate models (macaque, common marmoset, owl monkey) are used for preclinical gene vector safety and efficacy trials to bridge the gap prior to clinical studies. We aim for the safe development of clinically effective delivery systems for DNA and RNAi technologies.
zaro1a2m
zaro1a2m
2008-10-08
10.1007/s11095-008-9646-8
1
Comparative tropism, replication kinetics, and cell damage profiling of SARS-CoV-2 and SARS-CoV with implications for clinical manifestations, transmissibility, and laboratory studies of COVID-19: an observational study
Summary Background Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was reported from China in January, 2020. SARS-CoV-2 is efficiently transmitted from person to person and, in 2 months, has caused more than 82 000 laboratory-confirmed cases of coronavirus disease 2019 (COVID-19) and 2800 deaths in 46 countries. The total number of cases and deaths has surpassed that of the 2003 severe acute respiratory syndrome coronavirus (SARS-CoV). Although both COVID-19 and severe acute respiratory syndrome (SARS) manifest as pneumonia, COVID-19 is associated with apparently more efficient transmission, fewer cases of diarrhoea, increased mental confusion, and a lower crude fatality rate. However, the underlying virus–host interactive characteristics conferring these observations on transmissibility and clinical manifestations of COVID-19 remain unknown. Methods We systematically investigated the cellular susceptibility, species tropism, replication kinetics, and cell damage of SARS-CoV-2 and compared findings with those for SARS-CoV. We compared SARS-CoV-2 and SARS-CoV replication in different cell lines with one-way ANOVA. For the area under the curve comparison between SARS-CoV-2 and SARS-CoV replication in Calu3 (pulmonary) and Caco2 (intestinal) cells, we used Student's t test. We analysed cell damage induced by SARS-CoV-2 and SARS-CoV with one-way ANOVA. Findings SARS-CoV-2 infected and replicated to comparable levels in human Caco2 cells and Calu3 cells over a period of 120 h (p=0·52). By contrast, SARS-CoV infected and replicated more efficiently in Caco2 cells than in Calu3 cells under the same multiplicity of infection (p=0·0098). SARS-CoV-2, but not SARS-CoV, replicated modestly in U251 (neuronal) cells (p=0·036). For animal species cell tropism, both SARS-CoV and SARS-CoV-2 replicated in non-human primate, cat, rabbit, and pig cells. SARS-CoV, but not SARS-CoV-2, infected and replicated in Rhinolophus sinicus bat kidney cells. SARS-CoV-2 consistently induced significantly delayed and milder levels of cell damage than did SARS-CoV in non-human primate cells (VeroE6, p=0·016; FRhK4, p=0·0004). Interpretation As far as we know, our study presents the first quantitative data for tropism, replication kinetics, and cell damage of SARS-CoV-2. These data provide novel insights into the lower incidence of diarrhoea, decreased disease severity, and reduced mortality in patients with COVID-19, with respect to the pathogenesis and high transmissibility of SARS-CoV-2 compared with SARS-CoV. Funding May Tam Mak Mei Yin, The Shaw Foundation Hong Kong, Richard Yu and Carol Yu, Michael Seak-Kan Tong, Respiratory Viral Research Foundation, Hui Ming, Hui Hoy and Chow Sin Lan Charity Fund, Chan Yin Chuen Memorial Charitable Foundation, Marina Man-Wai Lee, The Hong Kong Hainan Commercial Association South China Microbiology Research Fund, The Jessie & George Ho Charitable Foundation, Perfect Shape Medical, The Consultancy Service for Enhancing Laboratory Surveillance of Emerging Infectious Diseases and Research Capability on Antimicrobial Resistance for the Department of Health of the Hong Kong Special Administrative Region Government, The Theme-Based Research Scheme of the Research Grants Council, Sanming Project of Medicine in Shenzhen, and The High Level-Hospital Program, Health Commission of Guangdong Province, China.
zawf4jzm
zawf4jzm
2020-04-21
10.1016/s2666-5247(20)30004-5
2
Predicting commercially available antiviral drugs that may act on the novel coronavirus (SARS-CoV-2) through a drug-target interaction deep learning model
Abstract The infection of a novel coronavirus found in Wuhan of China (SARS-CoV-2) is rapidly spreading, and the incidence rate is increasing worldwide. Due to the lack of effective treatment options for SARS-CoV-2, various strategies are being tested in China, including drug repurposing. In this study, we used our pre-trained deep learning-based drug-target interaction model called Molecule Transformer-Drug Target Interaction (MT-DTI) to identify commercially available drugs that could act on viral proteins of SARS-CoV-2. The result showed that atazanavir, an antiretroviral medication used to treat and prevent the human immunodeficiency virus (HIV), is the best chemical compound, showing an inhibitory potency with Kd of 94.94 nM against the SARS-CoV-2 3C-like proteinase, followed by remdesivir (113.13 nM), efavirenz (199.17 nM), ritonavir (204.05 nM), and dolutegravir (336.91 nM). Interestingly, lopinavir, ritonavir, and darunavir are all designed to target viral proteinases. However, in our prediction, they may also bind to the replication complex components of SARS-CoV-2 with an inhibitory potency with Kd < 1,000 nM. In addition, we also found that several antiviral agents, such as Kaletra (lopinavir/ritonavir), could be used for the treatment of SARS-CoV-2. Overall, we suggest that the list of antiviral drugs identified by the MT-DTI model should be considered, when establishing effective treatment strategies for SARS-CoV-2.
zb434ve3
zb434ve3
2020-03-30
10.1016/j.csbj.2020.03.025
0.5
Discovery of Synergistic and Antagonistic Drug Combinations against SARS-CoV-2 In Vitro
COVID-19 is undoubtedly the most impactful viral disease of the current century, afflicting millions worldwide. As yet, there is not an approved vaccine, as well as limited options from existing drugs for treating this disease. We hypothesized that combining drugs with independent mechanisms of action could result in synergy against SARS-CoV-2. Using in silico approaches, we prioritized 73 combinations of 32 drugs with potential activity against SARS-CoV-2 and then tested them in vitro. Overall, we identified 16 synergistic and 8 antagonistic combinations, 4 of which were both synergistic and antagonistic in a dose-dependent manner. Among the 16 synergistic cases, combinations of nitazoxanide with three other compounds (remdesivir, amodiaquine and umifenovir) were the most notable, all exhibiting significant synergy against SARS-CoV-2. The combination of nitazoxanide, an FDA-approved drug, and remdesivir, FDA emergency use authorization for the treatment of COVID-19, demonstrate a strong synergistic interaction. Notably, the combination of remdesivir and hydroxychloroquine demonstrated strong antagonism. Overall, our results emphasize the importance of both drug repurposing and preclinical testing of drug combinations for potential therapeutic use against SARS-CoV-2 infections.
zbpk7sh0
zbpk7sh0
2020-06-30
10.1101/2020.06.29.178889
5
Remdesivir: A Review of Its Discovery and Development Leading to Emergency Use Authorization for Treatment of COVID-19
[Image: see text] The global pandemic of SARS-CoV-2, the causative viral pathogen of COVID-19, has driven the biomedical community to action—to uncover and develop antiviral interventions. One potential therapeutic approach currently being evaluated in numerous clinical trials is the agent remdesivir, which has endured a long and winding developmental path. Remdesivir is a nucleotide analogue prodrug that perturbs viral replication, originally evaluated in clinical trials to thwart the Ebola outbreak in 2014. Subsequent evaluation by numerous virology laboratories demonstrated the ability of remdesivir to inhibit coronavirus replication, including SARS-CoV-2. Here, we provide an overview of remdesivir’s discovery, mechanism of action, and the current studies exploring its clinical effectiveness.
zdfx3zo3
zdfx3zo3
2020-05-04
10.1021/acscentsci.0c00489
3.5
scRNA-seq reveals ACE2 and TMPRSS2 expression in TROP2+ Liver Progenitor Cells: Implications in COVID-19 associated Liver Dysfunction
The recent pandemic of coronavirus disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). COVID-19 was first reported in China (December 2019) and now prevalent in ∼170 countries across the globe. Entry of SARS-CoV-2 into mammalian cells require the binding of viral Spike (S) proteins to the ACE2 (angiotensin converting enzyme 2) receptor. Once entered the S protein is primed by a specialised serine protease, TMPRSS2 (Transmembrane Serine Protease 2) in the host cell. Importantly, beside respiratory symptoms, consistent with other common respiratory virus infection when patients become viraemic, a significant number of COVID-19 patients also develop liver comorbidities. We explored if specific target cell-type in the mammalian liver, could be implicated in disease pathophysiology other than the general deleterious response to cytokine storms. Here we employed single-cell RNA-seq (scRNA-seq) to survey the human liver and identified potentially implicated liver cell-type for viral ingress. We report the co-expression of ACE2 and TMPRSS2 in a TROP2+ liver progenitor population. Importantly, we fail to detect the expression of ACE2 in hepatocyte or any other liver (immune and stromal) cell types. These results indicated that in COVID-19 associated liver dysfunction and cell death, viral infection of TROP2+ progenitors in liver may significantly impaired liver regeneration and could lead to pathology. Highlights - EPCAM+ Liver progenitors co-express ACE2 and TMPRSS2 - ACE2 and TMPRSS2 expression is highest in TROP2high progenitors - ACE2 and TMPRSS2 cells express cholangiocyte biased fate markers - ACE2 and TMPRSS2 positive cells are absent in human fetal liver
zdog6ddu
zdog6ddu
2020-03-25
10.1101/2020.03.23.002832
1
COVID-19 preclinical models: human angiotensin-converting enzyme 2 transgenic mice
Coronavirus disease 2019 (COVID-19) is a declared pandemic that is spreading all over the world at a dreadfully fast rate. Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), the pathogen of COVID-19, infects the human body using angiotensin-converting enzyme 2 (ACE2) as a receptor identical to the severe acute respiratory syndrome (SARS) pandemic that occurred in 2002-2003. SARS-CoV-2 has a higher binding affinity to human ACE2 than to that of other species. Animal models that mimic the human disease are highly essential to develop therapeutics and vaccines against COVID-19. Here, we review transgenic mice that express human ACE2 in the airway and other epithelia and have shown to develop a rapidly lethal infection after intranasal inoculation with SARS-CoV, the pathogen of SARS. This literature review aims to present the importance of utilizing the human ACE2 transgenic mouse model to better understand the pathogenesis of COVID-19 and develop both therapeutics and vaccines.
zebz0gns
zebz0gns
2020
4.5
COVID-19 spreading: a model
This communication describes a recursive mathematical model of the spreading COVID-19 infection, which allows estimating the effectiveness of quarantine measures. The model was used to analyze the situation in eight countries and to find the viral transmissibility, which made it possible to give a brief prediction of the COVID-19 spreading.
zec7hphk
zec7hphk
2020-04-28
10.1101/2020.04.23.20076562
2
VereFlu™: an integrated multiplex RT-PCR and microarray assay for rapid detection and identification of human influenza A and B viruses using lab-on-chip technology
Threatening sporadic outbreaks of avian influenza and the H1N1 pandemic of 2009 highlight the need for rapid and accurate detection and typing of influenza viruses. In this paper, we describe the validation of the VereFlu™ Lab-on-Chip Influenza Assay, which is based on the integration of two technologies: multiplex reverse transcription (RT)-PCR followed by microarray amplicon detection. This assay simultaneously detects five influenza virus subtypes, including the 2009 pandemic influenza A (H1N1), seasonal H1N1, H3N2, H5N1 and influenza B virus. The VereFlu™ assay was clinically validated in Singapore and compared against reference methods of real-time PCR, virus detection by immunofluorescence of cell cultures and sequencing. A sensitivity and specificity of 96.8% and 92.8%, respectively, was demonstrated for pandemic H1N1; 95.7% and 100%, respectively, for seasonal H1N1; 91.2% and 97.6%, respectively, for seasonal H3N2; 95.2% and 100%, respectively, for influenza B. Additional evaluations carried out at the World Health Organization (WHO) Collaborating Centre, Melbourne, Australia, confirmed that the test was able to reliably detect H5N1. This portable, fast time-to-answer (3 hours) device is particularly suited for diagnostic applications of detection, differentiation and identification of human influenza virus subtypes.
zfbu9646
zfbu9646
2011-04-19
10.1007/s00705-011-0999-7
3.5
Identification of Candidate COVID-19 Therapeutics using hPSC-derived Lung Organoids
The SARS-CoV-2 virus has caused already over 3.5 million COVID-19 cases and 250,000 deaths globally. There is an urgent need to create novel models to study SARS-CoV-2 using human disease-relevant cells to understand key features of virus biology and facilitate drug screening. As primary SARS-CoV-2 infection is respiratory-based, we developed a lung organoid model using human pluripotent stem cells (hPSCs) that could be adapted for drug screens. The lung organoids, particularly aveolar type II cells, express ACE2 and are permissive to SARS-CoV-2 infection. Transcriptomic analysis following SARS-CoV-2 infection revealed a robust induction of chemokines and cytokines with little type I/III interferon signaling, similar to that observed amongst human COVID-19 pulmonary infections. We performed a high throughput screen using hPSC-derived lung organoids and identified FDA-approved drug candidates, including imatinib and mycophenolic acid, as inhibitors of SARS-CoV-2 entry. Pre- or post-treatment with these drugs at physiologically relevant levels decreased SARS-CoV-2 infection of hPSC-derived lung organoids. Together, these data demonstrate that hPSC-derived lung cells infected by SARS-CoV-2 can model human COVID-19 disease and provide a valuable resource to screen for FDA-approved drugs that might be repurposed and should be considered for COVID-19 clinical trials.
zg2u7fwx
zg2u7fwx
2020-05-05
10.1101/2020.05.05.079095
3.5
Nelfinavir was predicted to be a potential inhibitor of 2019-nCov main protease by an integrative approach combining homology modelling, molecular docking and binding free energy calculation
2019-nCov has caused more than 80 deaths as of 27 January 2020 in China, and infection cases have been reported in more than 10 countries. However, there is no approved drug to treat the disease. 2019-nCov Mpro is a potential drug target to combat the virus. We built homology models based on SARS Mpro structures, and docked 1903 small molecule drugs to the models. Based on the docking score and the 3D similarity of the binding mode to the known Mpro ligands, 4 drugs were selected for binding free energy calculations. Both MM/GBSA and SIE methods voted for nelfinavir, with the binding free energy of −24.69±0.52 kcal/mol and −9.42±0.04 kcal/mol, respectively. Therefore, we suggested that nelfinavir might be a potential inhibitor against 2019-nCov Mpro.
zgdbvfi4
zgdbvfi4
2020-01-28
10.1101/2020.01.27.921627
1.5
Fight against novel coronavirus: A perspective of medicinal chemists
The ongoing novel coronavirus disease (COVID-19) pandemic makes us painfully perceive that our bullet shells are blank so far for fighting against severe human coronavirus (HCoV). In spite of vast research work, it is crystal clear that the evident does not warrant the commercial blossoming of anti-HCoV drugs. In this circumstance, drug repurposing and/or screening of databases are the only fastest option. This study is an initiative to recapitulate the medicinal chemistry of severe acute respiratory syndrome (SARS)-CoV-2 (SARS-CoV-2). The aim is to present an exquisite delineation of the current research from the perspective of a medicinal chemist to allow the rapid development of anti-SARS-CoV-2 agents.
zgrtux7i
zgrtux7i
2020-06-12
10.1016/j.ejmech.2020.112559
4
COVID-19, SARS and MERS: are they closely related?
Abstract Background The 2019 novel coronavirus (SARS-CoV-2) is a new human coronavirus which is spreading with epidemic features in China and other Asian countries; cases have also been reported worldwide. This novel coronavirus disease (COVID-19) is associated with a respiratory illness that may lead to severe pneumonia and acute respiratory distress syndrome (ARDS). Although related to the severe acute respiratory syndrome (SARS) and the Middle East respiratory syndrome (MERS), COVID-19 shows some peculiar pathogenetic, epidemiological and clinical features which to date are not completely understood. Aims To provide a review of the differences in pathogenesis, epidemiology and clinical features of COVID-19, SARS and MERS. Sources The most recent literature in the English language regarding COVID-19 has been reviewed, and extracted data have been compared with the current scientific evidence about SARS and MERS epidemics. Content COVID-19 seems not to be very different from SARS regarding its clinical features. However, it has a fatality rate of 2.3%, lower than that of SARS (9.5%) and much lower than that of MERS (34.4%). The possibility cannot be excluded that because of the less severe clinical picture of COVID-19 it can spread in the community more easily than MERS and SARS. The actual basic reproductive number (R0) of COVID-19 (2.0–2.5) is still controversial. It is probably slightly higher than the R0 of SARS (1.7–1.9) and higher than that of MERS (<1). A gastrointestinal route of transmission for SARS-CoV-2, which has been assumed for SARS-CoV and MERS-CoV, cannot be ruled out and needs further investigation. Implications There is still much more to know about COVID-19, especially as concerns mortality and its capacity to spread on a pandemic level. Nonetheless, all of the lessons we learned in the past from the SARS and MERS epidemics are the best cultural weapons with which to face this new global threat.
zi98dq1v
zi98dq1v
2020-03-28
10.1016/j.cmi.2020.03.026
2
Thiopurine analogs and mycophenolic acid synergistically inhibit the papain-like protease of Middle East respiratory syndrome coronavirus
Abstract Middle East respiratory syndrome coronavirus (MERS-CoV) is a new highly pathogenic human coronaviruses that emerged in Jeddah and Saudi Arabia and has quickly spread to other countries in Middle East, Europe and North Africa since 2012. Up to 17 December 2014, it has infected at least 938 people with a fatality rate of about 36% globally. This has resulted in an urgent need to identify antiviral drugs that are active against MERS-CoV. The papain-like protease (PLpro) of MERS-CoV represents an important antiviral target as it is not only essential for viral maturation, but also antagonizes interferon stimulation of the host via its deubiquitination activity. Here, we report the discovery that two SARS-CoV PLpro inhibitors, 6-mercaptopurine (6MP) and 6-thioguanine (6TG), as well as the immunosuppressive drug mycophenolic acid, are able to inhibit MERS-CoV PLpro. Their inhibition mechanisms and mutually binding synergistic effect were also investigated. Our results identify for the first time three inhibitors targeting MERS-CoV PLpro and these can now be used as lead compounds for further antiviral drug development.
zj34cb6f
zj34cb6f
2015-03-31
10.1016/j.antiviral.2014.12.011
3.5
Evolutionary history, potential intermediate animal host, and cross‐species analyses of SARS‐CoV‐2
To investigate the evolutionary history of the recent outbreak of severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) in China, a total of 70 genomes of virus strains from China and elsewhere with sampling dates between 24 December 2019 and 3 February 2020 were analyzed. To explore the potential intermediate animal host of the SARS‐CoV‐2 virus, we reanalyzed virome data sets from pangolins and representative SARS‐related coronaviruses isolates from bats, with particular attention paid to the spike glycoprotein gene. We performed phylogenetic, split network, transmission network, likelihood‐mapping, and comparative analyses of the genomes. Based on Bayesian time‐scaled phylogenetic analysis using the tip‐dating method, we estimated the time to the most recent common ancestor and evolutionary rate of SARS‐CoV‐2, which ranged from 22 to 24 November 2019 and 1.19 to 1.31 × 10(−3) substitutions per site per year, respectively. Our results also revealed that the BetaCoV/bat/Yunnan/RaTG13/2013 virus was more similar to the SARS‐CoV‐2 virus than the coronavirus obtained from the two pangolin samples (SRR10168377 and SRR10168378). We also identified a unique peptide (PRRA) insertion in the human SARS‐CoV‐2 virus, which may be involved in the proteolytic cleavage of the spike protein by cellular proteases, and thus could impact host range and transmissibility. Interestingly, the coronavirus carried by pangolins did not have the RRAR motif. Therefore, we concluded that the human SARS‐CoV‐2 virus, which is responsible for the recent outbreak of COVID‐19, did not come directly from pangolins.
zknmfgsh
zknmfgsh
2020-03-11
10.1002/jmv.25731
1
Lipid-lowering therapy and renin-angiotensin-aldosterone system inhibitors in the era of the COVID-19 pandemic
zlc0dv0a
zlc0dv0a
2020-04-14
10.5114/aoms.2020.94503
3.5
Validation and verification of the Abbott RealTime SARS-CoV-2 assay analytical and clinical performance.
BACKGROUND High-throughput assays for the SARS-CoV-2 virus are critical to increasing test capacity and slowing the spread of COVID-19. Abbott Molecular developed and received emergency use authorization (EUA) to deploy the new RealTime SARS-CoV-2 assay, run on the automated m2000sp/rt system. OBJECTIVE To evaluate analytical and clinical performance of the RealTime SARS-CoV-2 assay compared to the SARS-CoV-2 CDC-based laboratory developed test (LDT) in clinical use by the University of Washington Clinical Virology Laboratory (UW Virology). METHODS RealTime SARS-CoV-2 assay limit of detection (LOD) was evaluated by testing two dilution panels of 60 replicates each. Cross-reactivity was evaluated by testing 24 clinical samples positive for various non‒SARS-CoV-2 respiratory viruses. Clinical performance was evaluated using 30 positive and 30 negative SARS-CoV-2 clinical samples previously tested using the UW Virology SARS-CoV-2 LDT. RESULTS Exceeding the 100 copies/mL LOD reported in the RealTime SARS-CoV-2 assay EUA product insert, 19 of 20 replicates were detected at 50 copies/mL and 16 of 20 replicates were detected at 25 copies/mL. All clinical samples positive for 24 non‒SARS-CoV-2 respiratory viruses were SARS-CoV-2 negative on the RealTime SARS-CoV-2 assay. The assay had high sensitivity (93%) and specificity (100%) for detecting SARS-CoV-2 in clinical samples. Two positive samples that tested negative with the RealTime SARS-CoV-2 assay had cycle numbers of 35.94 or greater and required dilution prior to testing. One of these samples was also inconclusive on the SARS-CoV-2 LDT. CONCLUSION The RealTime SARS-CoV-2 assay is acceptable for clinical use. With the high-throughput, fully automated m2000 system, this assay will accelerate the pace of SARS-CoV-2 testing.
zmmatkka
zmmatkka
2020-05-28
10.1016/j.jcv.2020.104474
4.5
Hydroxychloroquine, a less toxic derivative of chloroquine, is effective in inhibiting SARS-CoV-2 infection in vitro
zn87f1lk
zn87f1lk
2020-03-18
10.1038/s41421-020-0156-0
3.5
Coronavirus Disease 2019 (COVID-19) and pregnancy: what obstetricians need to know
Coronavirus disease 2019 is an emerging disease with a rapid increase in cases and deaths since its first identification in Wuhan, China, in December 2019. Limited data are available about coronavirus disease 2019 during pregnancy; however, information on illnesses associated with other highly pathogenic coronaviruses (ie, severe acute respiratory syndrome and the Middle East respiratory syndrome) might provide insights into coronavirus disease 2019’s effects during pregnancy. Coronaviruses cause illness ranging in severity from the common cold to severe respiratory illness and death. Currently the primary epidemiologic risk factors for coronavirus disease 2019 include travel from mainland China (especially Hubei Province) or close contact with infected individuals within 14 days of symptom onset. Data suggest an incubation period of ∼5 days (range, 2–14 days). Average age of hospitalized patients has been 49–56 years, with a third to half with an underlying illness. Children have been rarely reported. Men were more frequent among hospitalized cases (54–73%). Frequent manifestations include fever, cough, myalgia, headache, and diarrhea. Abnormal testing includes abnormalities on chest radiographic imaging, lymphopenia, leukopenia, and thrombocytopenia. Initial reports suggest that acute respiratory distress syndrome develops in 17–29% of hospitalized patients. Overall case fatality rate appears to be ∼1%; however, early data may overestimate this rate. In 2 reports describing 18 pregnancies with coronavirus disease 2019, all were infected in the third trimester, and clinical findings were similar to those in nonpregnant adults. Fetal distress and preterm delivery were seen in some cases. All but 2 pregnancies were cesarean deliveries and no evidence of in utero transmission was seen. Data on severe acute respiratory syndrome and Middle East respiratory syndrome in pregnancy are sparse. For severe acute respiratory syndrome, the largest series of 12 pregnancies had a case-fatality rate of 25%. Complications included acute respiratory distress syndrome in 4, disseminated intravascular coagulopathy in 3, renal failure in 3, secondary bacterial pneumonia in 2, and sepsis in 2 patients. Mechanical ventilation was 3 times more likely among pregnant compared with nonpregnant women. Among 7 first-trimester infections, 4 ended in spontaneous abortion. Four of 5 women with severe acute respiratory syndrome after 24 weeks’ gestation delivered preterm. For Middle East respiratory syndrome, there were 13 case reports in pregnant women, of which 2 were asymptomatic, identified as part of a contact investigation; 3 patients (23%) died. Two pregnancies ended in fetal demise and 2 were born preterm. No evidence of in utero transmission was seen in severe acute respiratory syndrome or Middle East respiratory syndrome. Currently no coronavirus-specific treatments have been approved by the US Food and Drug Administration. Because coronavirus disease 2019 might increase the risk for pregnancy complications, management should optimally be in a health care facility with close maternal and fetal monitoring. Principles of management of coronavirus disease 2019 in pregnancy include early isolation, aggressive infection control procedures, oxygen therapy, avoidance of fluid overload, consideration of empiric antibiotics (secondary to bacterial infection risk), laboratory testing for the virus and coinfection, fetal and uterine contraction monitoring, early mechanical ventilation for progressive respiratory failure, individualized delivery planning, and a team-based approach with multispecialty consultations. Information on coronavirus disease 2019 is increasing rapidly. Clinicians should continue to follow the Centers for Disease Control and Prevention website to stay up to date with the latest information (https://www.cdc.gov/coronavirus/2019-nCoV/hcp/index.html).
zndtddty
zndtddty
2020-02-24
10.1016/j.ajog.2020.02.017
1.5
Preliminary evaluation of voluntary event cancellation as a countermeasure against the COVID-19 outbreak in Japan as of 11 March, 2020
Background: To control COVID−19 outbreak in Japan, sports and entertainment events were canceled in Japan for two weeks from 26 February to 11 March. It has been designated as voluntary event cancellation (VEC). Object: This study predicts the effectiveness of VEC enduring and after its implementation. Method: We applied a simple susceptible−infected−recovery model to data of patients with symptoms in Japan during 14 January to VEC introduction and after VEC introduction to 8 March. We adjusted the reporting delay in the latest few days. Results: Results suggest that the basic reproduction number, R0, before VEC introduced as 2.50 with a 95% confidence interval (CI) was [2.43, 2.55] and the effective reproduction number, Rv, after VEC introduced as 1. 88; its 95% CI was [1.68,2.02]. Discussion and Conclusion: Results demonstrated that VEC can reduce COVID−19 infectiousness by 35%, but R0 remains higher than one.
zowo5ojd
zowo5ojd
2020-03-16
10.1101/2020.03.12.20035220
1.5
COVID-19: Knowns, Unknowns, and Questions
The recent emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) from the Hubei province in China in late 2019 demonstrates the epidemic potential of coronaviruses. The rapid spread of this virus across the world in only 2 months highlights the transmissibility of this family of viruses and the significant morbidity and mortality that they can cause. We highlight the current state of knowledge of coronavirus biology while answering questions concerning the current outbreak of SARS-CoV-2.
zpaqd5vd
zpaqd5vd
2020-03-18
10.1128/msphere.00203-20
1
Animal models and antibody assays for evaluating candidate SARS vaccines: Summary of a technical meeting 25–26 August 2005, London, UK
Severe acute respiratory syndrome (SARS) emerged in the Guangdong province of China in late 2002 and spread to 29 countries. By the end of the outbreak in July 2003, the CDC and WHO reported 8437 cases with a 9.6% case fatality rate. The disease was caused by a previously unrecognized coronavirus, SARS-CoV. Drawing on experience with animal coronavirus vaccines, several vaccine candidates have been developed and evaluated in pre-clinical trials. Available data suggest that vaccines should be based on the the 180 kDa viral spike protein, S, the only significant neutralization antigen capable of inducing protective immune responses in animals. In the absence of clinical cases of SARS, candidate vaccines should be evaluated for efficacy in animal models, and although it is uncertain whether the United States Food and Drug Administration's “animal rule” would apply to licensure of a SARS vaccine, it is important to develop standardized animal models and immunological assays in preparation for this eventuality. This report summarizes the recommendations from a WHO Technical Meeting on Animal Models and Antibody Assays for Evaluating Candidate SARS Vaccines held on 25–26 August 2005 in South Mimms, UK, provides guidance on the use of animal models, and outlines the steps to develop standard reagents and assays for immunological evaluation of candidate SARS vaccines.
zpi7uis1
zpi7uis1
2006-11-30
10.1016/j.vaccine.2006.07.009
2.5
Computational screening of antagonists against the SARS-CoV-2 (COVID-19) coronavirus by molecular docking
In the current spread of novel coronavirus (SARS-CoV-2), antiviral drug discovery is of great importance. AutoDock Vina was used to screen potential drugs by molecular docking with the structural protein and non-structural protein sites of new coronavirus. Ribavirin, a common antiviral drug, remdesivir, chloroquine and luteolin were studied. Honeysuckle is generally believed to have antiviral effects in traditional Chinese medicine. In this study, luteolin (the main flavonoid in honeysuckle) was found to bind with a high affinity to the same sites of the main protease of SARS-CoV-2 as the control molecule. Chloroquine has been proved clinically effective and can bind to the main protease; this may be the antiviral mechanism of this drug. The study was restricted to molecular docking without validation by molecular dynamics simulations. Interactions with the main protease may play a key role in fighting against viruses. Luteolin is a potential antiviral molecule worthy of attention.
zqn6s0af
zqn6s0af
2020
4.5
Comparative Pathogenesis Of COVID-19, MERS And SARS In A Non-Human Primate Model
A novel coronavirus, SARS-CoV-2, was recently identified in patients with an acute respiratory syndrome, COVID-19. To compare its pathogenesis with that of previously emerging coronaviruses, we inoculated cynomolgus macaques with SARS-CoV-2 or MERS-CoV and compared with historical SARS-CoV infections. In SARS-CoV-2-infected macaques, virus was excreted from nose and throat in absence of clinical signs, and detected in type I and II pneumocytes in foci of diffuse alveolar damage and mucous glands of the nasal cavity. In SARS-CoV-infection, lung lesions were typically more severe, while they were milder in MERS-CoV infection, where virus was detected mainly in type II pneumocytes. These data show that SARS-CoV-2 can cause a COVID-19-like disease, and suggest that the severity of SARS-CoV-2 infection is intermediate between that of SARS-CoV and MERS-CoV. One Sentence Summary SARS-CoV-2 infection in macaques results in COVID-19-like disease with prolonged virus excretion from nose and throat in absence of clinical signs.
zrbesm5b
zrbesm5b
2020-03-17
10.1101/2020.03.17.995639
1
Investigation of Some Antiviral N-Heterocycles as COVID 19 Drug: Molecular Docking and DFT Calculations
The novel coronavirus, COVID-19, caused by SARS-CoV-2, is a global health pandemic that started in December 2019. The effective drug target among coronaviruses is the main protease M(pro), because of its essential role in processing the polyproteins that are translated from the viral RNA. In this study, the bioactivity of some selected heterocyclic drugs named Favipiravir (1), Amodiaquine (2), 2′-Fluoro-2′-deoxycytidine (3), and Ribavirin (4) was evaluated as inhibitors and nucleotide analogues for COVID-19 using computational modeling strategies. The density functional theory (DFT) calculations were performed to estimate the thermal parameters, dipole moment, polarizability, and molecular electrostatic potential of the present drugs; additionally, Mulliken atomic charges of the drugs as well as the chemical reactivity descriptors were investigated. The nominated drugs were docked on SARS-CoV-2 main protease (PDB: 6LU7) to evaluate the binding affinity of these drugs. Besides, the computations data of DFT the docking simulation studies was predicted that the Amodiaquine (2) has the least binding energy (−7.77 Kcal/mol) and might serve as a good inhibitor to SARS-CoV-2 comparable with the approved medicines, hydroxychloroquine, and remdesivir which have binding affinity −6.06 and −4.96 Kcal/mol, respectively. The high binding affinity of 2 was attributed to the presence of three hydrogen bonds along with different hydrophobic interactions between the drug and the critical amino acids residues of the receptor. Finally, the estimated molecular electrostatic potential results by DFT were used to illustrate the molecular docking findings. The DFT calculations showed that drug 2 has the highest of lying HOMO, electrophilicity index, basicity, and dipole moment. All these parameters could share with different extent to significantly affect the binding affinity of these drugs with the active protein sites.
zsr5zz2k
zsr5zz2k
2020-05-30
10.3390/ijms21113922
4.5
Animal models of mechanisms of SARS-CoV-2 infection and COVID-19 pathology
The coronavirus disease 2019 (COVID-19) pandemic caused by SARS-CoV-2 infections has led to substantial unmet need for treatments, many of which will require testing in appropriate animal models of this disease. Vaccine trials are already underway, but there remains an urgent need to find other therapeutic approaches to either target SARS-CoV-2 or the complications arising from viral infection, particularly the dysregulated immune response and systemic complications which have been associated with progression to severe COVID-19. At the time of writing, in vivo studies of SARS-CoV-2 infection have been described using macaques, cats, ferrets, hamsters, and transgenic mice expressing human angiotensin I converting enzyme 2 (ACE2). These infection models have already been useful for studies of transmission and immunity, but to date only partially model the mechanisms implicated in human severe COVID-19. There is therefore an urgent need for development of animal models for improved evaluation of efficacy of drugs identified as having potential in the treatment of severe COVID-19. These models need to recapitulate key mechanisms of COVID-19 severe acute respiratory distress syndrome and reproduce the immunopathology and systemic sequelae associated with this disease. Here, we review the current models of SARS-CoV-2 infection and COVID-19-related disease mechanisms and suggest ways in which animal models can be adapted to increase their usefulness in research into COVID-19 pathogenesis and for assessing potential treatments.
zw2boiyo
zw2boiyo
2020
5
Quantitative and sensitive detection of the SARS-CoV spike protein using bispecific monoclonal antibody-based enzyme-linked immunoassay
Abstract The severe acute respiratory syndrome coronavirus (SARS-CoV) spike protein is known to mediate receptor interaction and immune recognition and thus it is considered as a major target for vaccine design. The spike protein plays an important role in virus entry, virus receptor interactions, and virus tropism. Sensitive diagnosis of SARS is essential for the control of the disease in humans. Recombinant SARS-CoV S1 antigen was produced and purified for the development of monoclonal and bi-specific monoclonal antibodies. The hybridomas secreting anti-S1 antibodies, F26G18 and P136.8D12, were fused respectively with the YP4 hybridoma to generate quadromas. The sandwich ELISA was formed by using F26G18 as a coating antibody and biotinylated F26G18 as a detection antibody with a detection limit of 0.037μg/ml (p <0.02). The same detection limit was found with P136.8D12 as a coating antibody and biotinylated F26G18 as a detection antibody. The sensitivity was improved (detection limit of 0.019μg/ml), however, when using bi-specific monoclonal antibody (F157) as the detection antibody. In conclusion, the method described in this study allows sensitive detection of a recombinant SARS spike protein by sandwich ELISA with bi-specific monoclonal antibody and could be used for the diagnosis of patients suspected with SARS.
zwhavf4h
zwhavf4h
2013-01-31
10.1016/j.jviromet.2012.09.006
1.5
The battle against SARS and MERS coronaviruses: Reservoirs and Animal Models
In humans, infection with the coronavirus, especially the severe acute respiratory syndrome coronavirus (SARS‐CoV) and the emerging Middle East respiratory syndrome coronavirus (MERS‐CoV), induces acute respiratory failure, resulting in high mortality. Irregular coronavirus related epidemics indicate that the evolutionary origins of these two pathogens need to be identified urgently and there are still questions related to suitable laboratory animal models. Thus, in this review we aim to highlight key discoveries concerning the animal origin of the virus and summarize and compare current animal models.
zy8qjaai
zy8qjaai
2018-07-28
10.1002/ame2.12017
2.5
What to expect from antibody assays of SARS-CoV-2?
zzkgjpnq
zzkgjpnq
2020
5