Discovery, Optimization, and Evaluation of Non-Nucleoside SARS-CoV-2 NSP14 Inhibitors
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.
Authors
- David J. Huggins (ORCID: https://orcid.org/0000-0003-1579-2496)
- Cindy Meyer (ORCID: https://orcid.org/0000-0003-3807-8383)
- Hans-Heinrich Hoffmann (ORCID: https://orcid.org/0000-0003-0554-0244)
- Charles M. Rice (ORCID: https://orcid.org/0000-0003-3087-8079)
- Aitor Garzia (ORCID: https://orcid.org/0000-0002-6270-1369)
- Shlomi Dagan
- Stacia Kargman (ORCID: https://orcid.org/0000-0002-0148-8883)
- Oleg M. Ganichkin
- Peter T. Meinke (ORCID: https://orcid.org/0000-0002-7548-6215)
- Thomas Tuschl (ORCID: https://orcid.org/0000-0002-6483-5678)
- Nigel J. Liverton (ORCID: https://orcid.org/0000-0002-3259-4558)
- Tanweer A. Khan (ORCID: https://orcid.org/0000-0001-8093-8194)
- Stefan Steinbacher (ORCID: https://orcid.org/0000-0002-4224-8317)
- Joseph Fraser Glickman (ORCID: https://orcid.org/0000-0002-6706-4039)
- Robert W. Myers (ORCID: https://orcid.org/0000-0003-2599-1050)
- Melissa S. Egbertson (ORCID: https://orcid.org/0000-0001-7968-676X)
- J-A Davis (ORCID: https://orcid.org/0009-0007-3256-8978)
- Michael W. Miller
- Julius Nitsche
Institutions
- Cornell University (US)
- ProterixBio (United States) (US)
- Tri-Institutional Therapeutics Discovery Institute (US)
- Weill Cornell Medicine (US)
- Rockefeller University (US)
- Egis (France) (FR)
Publication Details
- Journal
- Journal of Medicinal Chemistry
- Published
- 2025-09-05
- DOI
- https://doi.org/10.1021/acs.jmedchem.5c01155
- Citations
- 1
- Primary Topic
- Computational Drug Discovery Methods
- Type
- article
- Field-Weighted Citation Impact
- 1.50
Funders
- Memorial Sloan-Kettering Cancer Center
- Takeda Pharmaceutical Company
- Rockefeller University
- Stavros Niarchos Foundation
- Weill Cornell Medicine
- National Institute of Allergy and Infectious Diseases