Description (as provided by the applicant): Antiviral drugs on the market today have been developed according to the so-called one bug, one drug strategy. That is, each drug is highly specific for a particular virus. In contrast, treatment of bacterial infections has been revolutionized by the development of broad-spectrum antibiotics, which can act on multiple bacteria. This proposal aims to do the same for virus infections through the discovery of antiviral compounds with broad-spectrum activities against respiratory viruses. The advantages to such drugs are: 1) Eliminating the need to correctly diagnose the cause of the virus infection prior to commencing treatment. 2) The ability to treat infections caused by viruses that are resistant to current drugs. 3) The ability to treat infections caused by viruses for which no specific drugs exist. In the R21 phase the goal is to identify cellular factors that are required for efficient grwth of influenza virus and other respiratory viruses and which possess suitable druggable properties. Candidates will be selected via a process that involves integration of multiple datasets containing RNAi, proteomic and transcriptome information on the interaction of influenza virus with host cells. Those druggable host factors that have the best support for a role in promoting influenza virus replication will undergo further validation and will be assessed for similar roles with other respiratory viruses. Priority will be given to those factors required by te broadest range of viruses. Three cellular targets will be chosen to enter the R33 phase, where small molecule high-throughput screens will be performed to identify specific inhibitors. These host factor inhibitors will be characterized for their ability to inhibit multiple respiratory virues and the most potent will be analyzed for antiviral efficacy in animal models. Through careful selection of well-supported host targets, this proposal aims to identify lead compounds with broad-spectrum antiviral activity. Public Health Relevance: Respiratory viruses, including influenza virus, cause highly contagious, acute infections. For many of these viruses there are no effective antiviral drugs and for influenza, increasing resistance to approved drugs is a growing concern. Here we propose a strategy for developing new host-targeted drugs that have broad-spectrum antiviral activity.