During this period, the Early Translation Branch and the collaborative team worked to design and optimize a high-throughput amenable RABV assay using two recombinant rabies viruses (ERA) expressing luciferase and GFP reporters, enabling primary screening for Rabies inhibitors. Approximately 22,000 compounds were screened and several hundred hits were identified. Hit molecules were further triaged using a HepG2 toxicity assay and a GFP orthogonal assay. Small molecules with ideal profiles in this assay panel were advanced for further characterization in viral and mechanistic assays. A subset of compounds identified as efficacious against RABV have previously been advanced to clinical trials for other diseases/indications and have a favorable biological and PK profile. These compounds will serve as the basis for a drug repurposing study. We have recently advanced several of these compounds to preliminary mouse PK studies, followed by efficacy studies in a rabies hamster model at the CDC. The mechanism of action for this series is also being investigated. Novel hits from the HTS efforts are being used in a quantitative structure activity relationship study (QSAR) to identify additional active compounds and chemotypes. These results will inspire a medicinal chemistry campaign, where we seek to develop novel small molecule therapeutics for RABV treatment.