PROJECT SUMMARY Novel therapies for the treatment of chikungunya virus (CHIKV) infections are urgently needed to address the alarming spread of this pathogen across the Americas. We have identified three distinct series of potent, selective, and orally bioavailable inhibitors of CHIKV replication. In this Phase II renewal SBIR project, we will optimize these series of CHIKV inhibitors to Pre-Development stage and advance a first ever CHIKV antiviral candidate to IND-enabling studies. To accomplish this task, we will execute an integrated medicinal chemistry optimization/biological profiling campaign to optimize the potency, drug-like properties and oral exposure of each series. One or more Pre-Development Candidates will be identified and advanced through candidate selection studies into non-GLP repeat-dose tox in both rats and dogs.