Nian E Zhou, Su Tang, Xuelin Bian, Maloy K Parai, Inna V Krieger, Armando Flores, Pradeep K Jaiswal, Radha Bam, Jeremy L Wood, Zhe Shi, Laura J Stevens, Trevor Scobey, Meghan V Diefenbacher, Fernando R Moreira, Thomas J Baric, Arjun Acharya, Joonyoung Shin, Manish M Rathi, Karen C Wolff, Laura Riva, Malina A Bakowski, Case W McNamara, Nicholas J Catanzaro, Rachel L Graham, David C Schultz, Sara Cherry, Yoshihiro Kawaoka, Peter J Halfmann, Ralph S Baric, Mark R Denison, Timothy P Sheahan, James C Sacchettini
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引用次数: 0
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 (0.009 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.
期刊介绍:
Cell Reports publishes high-quality research across the life sciences and focuses on new biological insight as its primary criterion for publication. The journal offers three primary article types: Reports, which are shorter single-point articles, research articles, which are longer and provide deeper mechanistic insights, and resources, which highlight significant technical advances or major informational datasets that contribute to biological advances. Reviews covering recent literature in emerging and active fields are also accepted.
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