2. Academic Validation
  3. Small-molecule inhibition of SARS-CoV-2 NSP14 RNA cap methyltransferase

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

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. ttuschl@rockefeller.edu.
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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