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

作者：Nian Zhou, Su Tang, Xuelin Bian, Maloy Kumar Parai, Inna V. Krieger, Armando Flores, Parag Jaiswal, Radha Bam, Jeremy P. Wood, Zhe Shi, Laura J. Stevens, Trevor Scobey, Meghan V. Diefenbacher, Fernando R. Moreira, Thomas J. Baric, Arjun Acharya, Joonyoung Shin, Manish Rathi, Karen C. Wolff, Laura Riva, Malina A. Bakowski, Case W. McNamara, Nicholas Catanzaro, Rachel L. Graham, D. Schultz, Sara Cherry, Yoshihiro Kawaoka, Peter Halfmann, Ralph S. Baric, Mark R. Denison, Timothy P. Sheahan, James C. Sacchettini · 发表于：Cell Reports · 年份：2024 · DOI：10.1016/j.celrep.2024.114929 · 被引用次数：12 · 研究领域：SARS-CoV-2 and COVID-19 Research、Viral gastroenteritis research and epidemiology、Influenza Virus Research Studies

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 IC 50 ) as well as SARS-CoV-2 replication in human lung cell lines (0.008 μM EC 50 ) 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.