A Novel Chemotype of Orally Active SARS-CoV-2 NSP14 Methyltransferase Inhibitors
Abstract The periodic emergence of human coronaviruses (hCoVs) necessitates direct-acting antivirals targeting underexploited viral proteins with broad-spectrum potential. Building on our discovery of TDI-015051, a first-in-class SARS-CoV-2 mRNA cap guanine-N7 methyltransferase (MTase) NSP14 inhibitor whose translational development was limited by metabolic liabilities, we conducted medicinal chemistry optimization of a structurally distinct high-throughput screening hit. We arrived at MAVDA-K-256, a small-molecule inhibitor with improved pharmacological properties compared to TDI-015051. MAVDA-K-256 engaged NSP14 through the formation of a ternary complex with S-adenosyl-l-homocysteine, potently inhibiting its MTase activity and SARS-CoV-2 replication (EC50 = 24.6 nM). MAVDA-K-256 demonstrated broad-spectrum antiviral activity against diverse hCoVs without targeting the host mRNA cap MTase. Its favorable metabolic stability and pharmacokinetic properties enabled twice-daily oral dosing in a murine SARS-CoV-2 infection model, resulting in a five-log reduction in viral lung burden. These findings validate NSP14 inhibition as a promising antiviral strategy and support further preclinical development of MAVDA-K-256.
Authors
- Cindy Meyer (ORCID: https://orcid.org/0000-0003-3807-8383)
- David S. Perlin (ORCID: https://orcid.org/0000-0002-9503-3184)
- Julius Nitsche
- James M. Balkovec
- 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)
- Madhuvika Murugan (ORCID: https://orcid.org/0000-0002-0706-0730)
- Oleg M. Ganichkin
- Andrew M. Nelson
- Thomas Tuschl (ORCID: https://orcid.org/0000-0002-6483-5678)
- Joel S. Freundlich (ORCID: https://orcid.org/0000-0002-3411-3455)
- Alison W. Ashbrook (ORCID: https://orcid.org/0000-0003-1114-1426)
- Stefan Steinbacher (ORCID: https://orcid.org/0000-0002-4224-8317)
- Neelam Oswal (ORCID: https://orcid.org/0000-0002-3531-5948)
- Matthew Zimmerman (ORCID: https://orcid.org/0000-0002-4390-3555)
- Joseph Fraser Glickman (ORCID: https://orcid.org/0000-0002-6706-4039)
- Enriko Dolgov
- J. Robert Merritt (ORCID: https://orcid.org/0009-0005-7283-5394)
- Suyapa Penalva-Lopez
- Vijeta Sharma (ORCID: https://orcid.org/0000-0003-2760-3365)
- J-A Davis (ORCID: https://orcid.org/0009-0007-3256-8978)
- Julianna Cangialosi
- Ching-Wen Chang
- Pankaj Sharma
Institutions
- Rutgers, The State University of New Jersey (US)
- Hackensack Meridian Health (US)
- Rockefeller University (US)
Publication Details
- Journal
- Journal of Medicinal Chemistry
- Published
- 2026-10-16
- DOI
- https://doi.org/10.1021/acs.jmedchem.6c01763
- Primary Topic
- SARS-CoV-2 and COVID-19 Research
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Rockefeller University
- Stavros Niarchos Foundation
- National Institute of Allergy and Infectious Diseases