OVERALL SUMMARY In response to RFA-AI-17-042, Centers of Excellence in Translational Research, we propose to develop small molecule therapeutics for the treatment of emerging viral infections under the umbrella of the Antiviral Drug Discovery and Development Center. We are a team of scientists experienced in virology, viral immunology, pathogenesis, medicinal chemistry, and translation to human disease. We have established four Projects – each of which addresses infections identified as high priority by the National Institute of Allergy and Infectious Diseases (NIAID). Members of several genera of RNA viruses will be studied as they are major causes of human disease, bioterrorist threats, or emerging infectious diseases. Pharmacological control of these viruses remains limited. Our Projects will focus on (1) coronaviruses that cause SARS and MERS, (2) alphaviruses including Venezuelan equine encephalitis virus and chikungunya, 3) flaviviruses including dengue, West Nile virus, and Zika and 4) influenza A virus. We will utilize lead molecules identified in recent years by AD3C to perform therapeutic proof of principle studies in animal models within the first two years of the grant. Importantly, we will additionally evaluate a limited number of novel compounds provided by our collaborators, the Emory Institute for Drug Discovery (EIDD) and Gilead Sciences in order to have back-up platforms to address the potential development of resistance. Expertise exists in the AD3C for IND enabling studies, IND preparation and filing as well as Phase I studies, should suitable candidates be identified. The projects are supported by three Cores: the Administrative Core (Core A), the Assay Core (Core B), and the Medicinal Chemistry and Lead Development Core (Core C). The organization and interaction between all Projects and Cores will be monitored by the Administrative Core. An Executive Committee (EC) will consist of all Project and Core Leads to review data on monthly conference calls, in order to provide further direction and foster project interactions. An external Scientific Advisory Committee (SAC) will be established to provide evaluation of the project progress and facilitate “Go/No-Go” decisions on a regular basis. Since its inception, AD3C has already contributed significant data to an IND filed for MERS and two patent applications for compounds with activity against chikungunya, illustrating the success of our collaborative model.