An oral non-covalent non-peptidic inhibitor of SARS-CoV-2 Mpro ameliorates viral replication and pathogenesis invivo. Academic Article uri icon

abstract

  • 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 (0.009M IC50) as well as SARS-CoV-2 replication in human lung cell lines (0.008M 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.

published proceedings

  • Cell Rep

author list (cited authors)

  • Zhou, N. E., Tang, S. u., Bian, X., Parai, M. K., Krieger, I. V., Flores, A., ... Sacchettini, J. C.

complete list of authors

  • Zhou, Nian E||Tang, Su||Bian, Xuelin||Parai, Maloy K||Krieger, Inna V||Flores, Armando||Jaiswal, Pradeep K||Bam, Radha||Wood, Jeremy L||Shi, Zhe||Stevens, Laura J||Scobey, Trevor||Diefenbacher, Meghan V||Moreira, Fernando R||Baric, Thomas J||Acharya, Arjun||Shin, Joonyoung||Rathi, Manish M||Wolff, Karen C||Riva, Laura||Bakowski, Malina A||McNamara, Case W||Catanzaro, Nicholas J||Graham, Rachel L||Schultz, David C||Cherry, Sara||Kawaoka, Yoshihiro||Halfmann, Peter J||Baric, Ralph S||Denison, Mark R||Sheahan, Timothy P||Sacchettini, James C