Nipah virus is a recently emerged zoonotic paramyxovirus with the ability to cause fatal disease in a wide range of host species, including humans. Infection manifests as a severe respiratory illness with or without febrile encephalitis. There are currently no therapeutics or vaccines available to treat or prevent Nipah virus infection, necessitating its classification as a biological safety level-4 (BSL4) pathogen, and its inclusion as a NIAID Category C priority pathogen. Nipah virus emerged in peninsular Malaysia in 1998-9, passing from infected pigs to humans resulting in more than 100 human fatalities and the slaughter of more than 1 million pigs. Nipah virus has since re-emerged six times in Bangladesh and twice in India totaling more than 130 human fatalities. The defining feature of the Malaysian outbreak was the apparent requirement for an intermediary, replicative host (pigs) prior to human infection. However, the recent Bangladesh outbreaks have indicated direct human to human transmission of Nipah virus is possible with case fatality rates approaching 75%, emphasizing the need for the development of effective antivirals. Our facility;The Australian Animal Health Laboratory (AAHL), a component of the CSIRO, conducts world leading research on a variety of BSL4 agents and has been a key sub-contractor of several recent and on-going NIH funded programs. Here, using our expertise and experience in Nipah virus culture both in vitro and in vivo, we will evaluate a large collection of low molecular weight molecules as a means to discover potential inhibitors of Nipah virus infection and replication. This collection consists of a broad range of structural classes of small molecules that have been developed during targeted drug-discovery projects for human, animal, and crop diseases (including antivirals) at the CSIRO. We anticipate that if successful candidate molecules are identified during this study, we will be well positioned to rapidly evaluate their antiviral potential in animal studies and explore their pharmacokinetic and toxicity characteristics with which we are already well experienced from studies using Nipah-specific peptide fusion inhibitors. Additionally, established collaborative linkages will enable us to elucidate the mechanism of inhibition in detail. Specifically, we will: 1) Develop a monolayer assay for rapid quantitation of Nipah virus infection 2) Screen an existing drug discovery library using this assay 3) Evaluate lead compounds for potential second generation modification and pre-clinical development. PUBLIC HEALTH RELEVANCE In the current climate of bioterrorism preparedness, it is essential that any potential threats to human health and safety be mitigated as much as possible by effective, affordable treatments. Nipah virus continues to be a significant source of human suffering, in addition to a potential tool of bioterrorism. This proposed research will address both these issues by identifying potential antiviral compounds effective against live Nipah virus.