The goal of our Fluomics Next Generation U19 program is to collect multidimensional systems biology measurements in influenza virus infected cells, animals and humans to understand virus host-pathogen interactions that underlie disease pathogenesis and provide novel targets for therapeutic intervention. As part of the Fluomics U19 program, our labs have developed and implemented a pipeline consisting of high throughput genome-wide screens to identify host factors involved in virus replication, followed by functional validation in vivo in a mouse model of infection. This pipeline will be applied to rapidly respond to the emergency caused by the recent human outbreak of a novel coronavirus known as SARS-CoV-2 that causes in many infected patients a severe, sometimes lethal, respiratory disease named COVID-19. Specifically, we will use our established high throughput screen tools to rapidly evaluate the potential antiviral activity against SARS-CoV-2 of a chemical library, the ReFRAME collection, that includes nearly all small molecules that have reached clinical development or have undergone significant profiling including optimized pharmacokinetics, safety profiles, and annotations of human dosing. Compounds showing best antiviral activities and known safety profiles will be evaluated in human ACE2 transgenic mice, known to support SARS-CoV-2 replication. By the end of this project, we expect to have at least 1-2 compounds or combination therapies that exhibit SARS-CoV-2 antiviral activity in vivo, which can be immediately moved into the clinic.