An oral non-covalent non-peptidic inhibitor of SARS-CoV-2 Mpro ameliorates viral replication and pathogenesis in vivo

Safe, effective, and low-cost oral antiviral therapies are needed to treat those at high risk for developing severe COVID-19. To that end, we performed a high-throughput screen to identify non-peptidic, non-covalent inhibitors of the SARS-CoV-2 main protease (Mpro), an essential enzyme in viral replication. NZ-804 was developed from a screening hit through iterative rounds of structure-guided medicinal chemistry. NZ-804 potently inhibits SARS-CoV-2 Mpro (0.009 μM IC50) as well as SARS-CoV-2 replication in human lung cell lines (0.008 μM EC50) and primary human airway epithelial cell cultures. Antiviral activity is maintained against distantly related sarbecoviruses and endemic human CoV OC43. In SARS-CoV-2 mouse and hamster disease models, NZ-804 therapy given once or twice daily significantly diminished SARS-CoV-2 replication and pathogenesis. NZ-804 synthesis is low cost and uncomplicated, simplifying global production and access. These data support the exploration of NZ-804 as a therapy for COVID-19 and future emerging sarbecovirus infections. [Display omitted] •Non-peptidic, non-covalent NZ-804 potently inhibits SARS-CoV-2 main protease (Mpro)•NZ-804 has a high barrier to resistance as compared to nirmatrelvir•NZ-804 is orally bioavailable and blocks viral replication and pathogenesis in animals•Broad activity, safety, and low-cost synthesis make it a candidate for clinical development Zhou et al. describe NZ-804, a non-peptidic inhibitor of the SARS-CoV-2 Mpro. It shows potent antiviral activity with low-nanomolar IC50 and EC50 in human lung cells and primary airway epithelial cultures. It reduces SARS-CoV-2 replication and disease severity in animal models, positioning NZ-804 as a candidate for clinical development.