Physical Sciences Division
Published November 5, 2025 | Version v1
Journal article Metadata-only

S-Adenosylhomocysteine Analogs Selectively Suppress Pan-Coronavirus Replication by Inhibition of nsp14 Methyltransferase

Creators

  • 1. Northwestern University
  • 2. University of Chicago
  • 3. University of Toronto
  • 4. Argonne National Laboratory
  • 5. University of Illinois-Chicago

Description

To address the ongoing threat of SARS-CoV-2 and potential emergence of novel coronaviruses, we employed a comprehensive strategy to identify and synthesize inhibitors of coronavirus methyltransferases with chemical analogs of S-adenosylhomocysteine (SAH). Two analogs, designated 4h and 4p, inhibit both mouse hepatitis virus and SARS-CoV-2 replication. Compound 4p was the most potent with half-maximal inhibition of biochemical activity at 0.2 μM and antiviral activity at ∼20 μM. This compound also has low cytotoxicity and preferentially inhibits nsp14 over nsp16 and human methyltransferases. Furthermore, molecular docking based on a newly determined crystal structure of the apo nsp16−nsp10 complex predicts that 4p occupies both the S-adenosylmethione and Gppp binding pockets of nsp14 and nsp16. Selectivity of 4p for nsp14 is likely due to the enhanced structural stability of the nsp14 binding pocket relative to nsp16. These findings highlight SAH analogs as scaffolds for pan-coronavirus therapeutics and underscore the value of structure-guided design in antiviral drug discovery.

Additional details

Identifiers

DOI
10.1021/acsmedchemlett.5c00510
Other
oai:uchicago.tind.io:16630

Funding

Janssen (United States)
National Cancer Institute
P30-CA065530
Bayer (United States)
Merck KGaA, Darmstadt (Germany)
Genentech
National Institute of Allergy and Infectious Diseases
75N93022C00035
Takeda (Canada)
Pfizer (United States)
Bristol-Myers Squibb (United States)
Genome Canada
OGI-196
Ontario Genomics
Office of Science
DE-AC02-06CH11357
United States Department of Energy
National Institute of General Medical Sciences
P20GM12117
Boehringer Ingelheim Fonds
U.S. National Science Foundation
ECCS-2025633
Michigan Economic Development Corporation
Michigan Technology Tri-Corridor
Northwestern University
60057467
Structural Genomics Consortium
1097737
European Federation of Pharmaceutical Industries and Associations
875510
National Institute of Allergy and Infectious Diseases
HHSN272201700060C

UChicago Information

Division(s)
Physical Sciences Division
Department(s)
Chemistry