2. Academic Validation
  3. Discovery, Optimization, and Evaluation of Non-Nucleoside SARS-CoV-2 NSP14 Inhibitors

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

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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