Flaviviruses causes a substantial global disease burden, typically presenting as either systemic or hemorrhagic illness or as neurological and encephalitic disease. No licensed, commercially available direct-acting antiviral (DAA) is currently approved to specifically treat human infections caused by members of the genus Flavivirus, including dengue, Zika, West Nile, yellow fever, and Japanese encephalitis viruses. However, preventive vaccines are available for several flaviviral diseases, including dengue, yellow fever, Japanese encephalitis, and tick-borne encephalitis. Management therefore remains primarily supportive. We have identified a novel series of NS2B-NS3 protease inhibitors that show nanomolar Zika and low digit micromolar dengue activity in cells. Current efforts are geared towards improving the broad-spectrum properties of these early compounds.

Existing coronavirus antivirals remain constrained by ritonavir-associated drug–drug interactions, emerging resistance, and incomplete coverage across human coronaviruses. The Baruch S. Blumberg Institute is advancing a Mpro protease inhibitor platform designed to overcome these limitations and provide a foundation for treating the seven circulating human alpha- and beta-coronaviruses while strengthening preparedness for future coronavirus outbreaks. Our macrocyclic, non-covalent inhibitors potently target the main proteases of every alpha- and beta-coronavirus tested and suppress replication of SARS-CoV-2, HCoV-OC43, and HCoV-229E in infected cells. Unlike most other Mpro chemotypes, the program avoids a covalent warhead, retains potency against the nirmatrelvir-resistant SARS-CoV-2 E166V variant, and is being optimized for oral administration without ritonavir.