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

  • Nature. 2024 Dec 11. doi: 10.1038/s41586-024-08320-0.
Cindy Meyer  1 ,  Aitor Garzia  1 ,  Michael W Miller  2 ,  David J Huggins  2  3 ,  Robert W Myers  2 ,  Hans-Heinrich Hoffmann  4 ,  Alison W Ashbrook  4 ,  Syeda Y Jannath  4 ,  Nigel Liverton  2 ,  Stacia Kargman  2 ,  Matthew Zimmerman  5 ,  Andrew M Nelson  5 ,  Vijeta Sharma  5 ,  Enriko Dolgov  5 ,  Julianna Cangialosi  5 ,  Suyapa Penalva-Lopez  5 ,  Nadine Alvarez  5 ,  Ching-Wen Chang  4  5  6 ,  Neelam Oswal  5 ,  Irene Gonzalez  5 ,  Risha Rasheed  5 ,  Kira Goldgirsh  5 ,  Jada A Davis  1 ,  Lavoisier Ramos-Espiritu  7 ,  Miriam-Rose Menezes  7 ,  Chloe Larson  7 ,  Julius Nitsche  8 ,  Oleg Ganichkin  8 ,  Hanan Alwaseem  9 ,  Henrik Molina  9 ,  Stefan Steinbacher  8 ,  J Fraser Glickman  7 ,  David S Perlin  5 ,  Charles M Rice  4 ,  Peter T Meinke  2 ,  Thomas Tuschl  10
Affiliations
  • 1. Laboratory for RNA Molecular Biology, The Rockefeller University, New York, NY, USA.
  • 2. Sanders Tri-Institutional Therapeutics Discovery Institute, The Rockefeller University, New York, NY, USA.
  • 3. Department of Physiology and Biophysics, Weill Cornell Medical College, New York, NY, USA.
  • 4. Laboratory of Virology and Infectious Disease, The Rockefeller University, New York, NY, USA.
  • 5. Center for Discovery and Innovation, Hackensack Meridian Health, Nutley, NJ, USA.
  • 6. Department of Medicine, Division of Infectious Diseases, Columbia University, New York, NY, USA.
  • 7. Fisher Drug Discovery Resource Center, The Rockefeller University, New York, NY, USA.
  • 8. PROTEROS Biostructures GmbH, Planegg-Martinsried, Germany.
  • 9. Proteomics Resource Center, The Rockefeller University, New York, NY, USA.
  • 10. Laboratory for RNA Molecular Biology, The Rockefeller University, New York, NY, USA. [email protected].
PMID: 39663451 DOI: 10.1038/s41586-024-08320-0
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.

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