Small-molecule inhibition of SARS-CoV-2 NSP14 RNA cap methyltransferase

• 成果类型: Article
• 署名作者: Meyer, Cindy; Garzia, Aitor; Miller, Michael W.; Huggins, David J.; Myers, Robert W.; Hoffmann, Hans-Heinrich; Ashbrook, Alison W.; Jannath, Syeda Y.; Liverton, Nigel; Kargman, Stacia; Zimmerman, Matthew; Nelson, Andrew M.; Sharma, Vijeta; Dolgov, Enriko; Cangialosi, Julianna; Penalva-Lopez, Suyapa; Alvarez, Nadine; Chang, Ching-Wen; Oswal, Neelam; Gonzalez, Irene; Rasheed, Risha; Goldgirsh, Kira; Davis, Jada A.; Ramos-Espiritu, Lavoisier; Menezes, Miriam-Rose; Larson, Chloe; Nitsche, Julius; Ganichkin, Oleg; Alwaseem, Hanan; Molina, Henrik; Steinbacher, Stefan; Glickman, J. Fraser; Perlin, David S.; Rice, Charles M.; Meinke, Peter T.; Tuschl, Thomas
• 署名单位: Rockefeller University; Rockefeller University; Cornell University; Weill Cornell Medicine; Rockefeller University; Columbia University; Rockefeller University; Rockefeller University
• 刊物名称: Nature
• ISSN/ISSBN: 0028-2295
• DOI: 10.1038/s41586-024-08320-0
• 发表日期: 2025-01-30
• 关键词: messenger-rna; CORONAVIRUS; management; infection; binding

摘要

Coronavirus disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)1. The rapid development of highly effective vaccines2,3 against SARS-CoV-2 has altered the trajectory of the pandemic, and antiviral therapeutics4 have further reduced the number of COVID-19 hospitalizations and deaths. Coronaviruses are enveloped, positive-sense, single-stranded RNA viruses that encode various structural and non-structural proteins, including those critical for viral RNA replication and evasion from innate immunity5. Here we report the discovery and development of a first-in-class non-covalent small-molecule inhibitor of the viral guanine-N7 methyltransferase (MTase) NSP14. High-throughput screening identified RU-0415529, which inhibited SARS-CoV-2 NSP14 by forming a unique ternary S-adenosylhomocysteine (SAH)-bound complex. Hit-to-lead optimization of RU-0415529 resulted in TDI-015051 with a dissociation constant (Kd) of 61 pM and a half-maximal effective concentration (EC50) of 11 nM, inhibiting virus infection in a cell-based system. TDI-015051 also inhibited viral replication in primary small airway epithelial cells and in a transgenic mouse model of SARS CoV-2 infection with an efficacy comparable with the FDA-approved reversible covalent protease inhibitor nirmatrelvir6. The inhibition of viral cap methylases as an antiviral strategy is also adaptable to other pandemic viruses.