Discovery, Optimization, and Evaluation of Non-Nucleoside SARS-CoV-2 NSP14 Inhibitors

  • J Med Chem. 2025 Sep 25;68(18):19076-19106. doi: 10.1021/acs.jmedchem.5c01155.
Michael W Miller  1 ,  Cindy Meyer  2 ,  Aitor Garzia  2 ,  Hans-Heinrich Hoffmann  3 ,  Tanweer A Khan  1 ,  Melissa Egbertson  4 ,  Robert W Myers  1 ,  Nigel Liverton  1 ,  Stacia Kargman  1 ,  Jada A Davis  2 ,  Oleg Ganichkin  5 ,  Julius Nitsche  5 ,  Stefan Steinbacher  5 ,  Shlomi Dagan  6 ,  J Fraser Glickman  6 ,  Charles M Rice  3 ,  Thomas Tuschl  2 ,  Peter T Meinke  1  7 ,  David J Huggins  1  8
Affiliations
  • 1. Sanders Tri-Institutional Therapeutics Discovery Institute, The Rockefeller University, 1230 York Avenue, New York, New York 10065, United States.
  • 2. Laboratory for RNA Molecular Biology, The Rockefeller University, 1230 York Avenue, New York, New York 10065, United States.
  • 3. Laboratory of Virology and Infectious Disease, The Rockefeller University, 1230 York Avenue, New York, New York 10065, United States.
  • 4. Melissa Egbertson Consulting LLC, 1232 Lois Road, Ambler, Pennsylvania 19002, United States.
  • 5. PROTEROS Biostructures GmbH, Bunsenstrasse 7a, 82152 Planegg-Martinsried, Germany.
  • 6. Fisher Drug Discovery Resource Center, The Rockefeller University, 1230 York Avenue, New York, New York 10065, United States.
  • 7. Department of Pharmacology, Weill Cornell Medicine, New York, New York 10021, United States.
  • 8. Department of Physiology and Biophysics, Weill Cornell Medical College, 1300 York Ave, New York, New York 10065, United States.
PMID: 40910582 DOI: 10.1021/acs.jmedchem.5c01155
Abstract

We recently reported the discovery of TDI-015051, a first-in-class small-molecule inhibitor of the SARS-CoV-2 guanine-N7 methyltransferase nonstructural protein 14 (NSP14). NSP14 plays a critical role in viral RNA cap synthesis and its inhibition represents a novel Antiviral approach. Utilizing systematic structure-activity relationship studies, potent non-nucleoside-based inhibitors with single-digit nanomolar cellular activity were identified from an HTS hit lacking cellular activity. Thermal shift assay data and available crystal structures led us to develop a model of the novel inhibitory ternary complex (NSP14, SAH, inhibitor), which was validated with a crystal structure of the complex. The advances described here enabled a successful proof-of-concept study that validated SARS-CoV-2 NSP14 as a novel drug target for COVID-19 and represent the first demonstration of pharmacological inhibition of viral methyltransferases as a viable avenue for an Antiviral therapeutic.

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