Development of selective NS5 inhibitors for the broad-spectrum treatment of flaviviruses

This project aims to develop a novel small-molecule inhibitor targeting the highly conserved NS5 protein across flaviviruses, offering broad-spectrum antiviral potential. Using the HS-176 scaffold, which has shown promising in vitro efficacy, this proposal focuses on optimization through a structure-activity relationship (SAR) campaign to derive analogs with greater potency and cross-reactivity across flaviviruses. The two key objectives are: (1) to conduct a SAR campaign to design new analogs with enhanced inhibition of NS5, and (2) to assess the in vitro efficacy, ADME properties, and safety profiles of the lead compounds. The overarching goal is to identify analogs with improved potency against NS5, broad activity against multiple flaviviruses, oral bioavailability, and minimal safety concerns, ultimatly identifing lead candidates that can befurther advanced as broad-spectrum antiviral therapies for flavivirus infections.