Article
作者: Ganichkin, Oleg ; Davis, Jada A ; Hoffmann, Hans-Heinrich ; Larson, Chloe ; Rasheed, Risha ; Molina, Henrik ; Rice, Charles M ; Gonzalez, Irene ; Nitsche, Julius ; Kargman, Stacia ; Zimmerman, Matthew ; Goldgirsh, Kira ; Ashbrook, Alison W ; Dolgov, Enriko ; Cangialosi, Julianna ; Nelson, Andrew M ; Miller, Michael W ; Alvarez, Nadine ; Tuschl, Thomas ; Myers, Robert W ; Ramos-Espiritu, Lavoisier ; Menezes, Miriam-Rose ; Penalva-Lopez, Suyapa ; Meyer, Cindy ; Huggins, David J ; Jannath, Syeda Y ; Steinbacher, Stefan ; Chang, Ching-Wen ; Perlin, David S ; Sharma, Vijeta ; Liverton, Nigel ; Oswal, Neelam ; Meinke, Peter T ; Garzia, Aitor ; Glickman, J Fraser ; Alwaseem, Hanan
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.
