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

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

Nature, 2025, vol. 637, issue 8048, 1178-1185

Abstract: Abstract 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.

Date: 2025
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DOI: 10.1038/s41586-024-08320-0

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