<i>S</i> -Adenosylhomocysteine Analogs Selectively Suppress Pan-Coronavirus Replication by Inhibition of nsp14 Methyltransferase
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 <i>S</i>-adenosylhomocysteine. Two analogs, designated <b>4h</b> and <b>4p</b>, inhibit both mouse hepatitis virus and SARS-CoV-2 replication. Compound <b>4p</b> was 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 <b>4p</b> occupies both the <i>S</i>-adenosylmethione and Gppp binding pockets of nsp14 and nsp16. Selectivity of <b>4p</b> for nsp14 is likely due to 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.
Authors
- Thomas J. Hope (ORCID: https://orcid.org/0000-0001-7183-8319)
- K.J.F. Satchell (ORCID: https://orcid.org/0000-0003-3274-7611)
- Irene Chau (ORCID: https://orcid.org/0000-0002-2313-973X)
- J.S. Brunzelle (ORCID: https://orcid.org/0000-0001-9197-0018)
- Arvind Ramanathan (ORCID: https://orcid.org/0000-0002-1622-5488)
- Patrick Grudzien
- Mónica Rosas‐Lemus (ORCID: https://orcid.org/0000-0002-6243-0271)
- G. Minasov (ORCID: https://orcid.org/0000-0001-5460-3462)
- Sudhakar Athe (ORCID: https://orcid.org/0000-0003-0002-9498)
- Jeffrey E. Montgomery (ORCID: https://orcid.org/0000-0003-0477-5498)
- Hazem Abdelkarim (ORCID: https://orcid.org/0000-0001-7180-0177)
- Mark E. Becker (ORCID: https://orcid.org/0000-0002-5992-2806)
- Vadim Gaponenko (ORCID: https://orcid.org/0000-0002-7891-9223)
- Raymond E. Moellering (ORCID: https://orcid.org/0000-0002-3982-9276)
- Viresh H. Rawal (ORCID: https://orcid.org/0000-0003-4606-0239)
- Heng Ma (ORCID: https://orcid.org/0000-0002-7667-922X)
- Fengling Li (ORCID: https://orcid.org/0000-0001-9530-2068)
- Masoud Vedadi
- Jason A. Pattie
Institutions
- Northwestern University (US)
- Argonne National Laboratory (US)
- University of Illinois Urbana-Champaign (US)
- Illinois College (US)
- University of Toronto (CA)
- Structural Genomics Consortium (CA)
- University of Illinois Chicago (US)
- University of Chicago (US)
- Joint Center for Structural Genomics (US)
- Laboratory of Molecular Genetics (PL)
- Stanford Synchrotron Radiation Lightsource (US)
- Institute of Molecular Genetics (RU)
- National Center for Infectious Diseases (US)
Publication Details
- Journal
- ACS Medicinal Chemistry Letters
- Published
- 2025-11-05
- DOI
- https://doi.org/10.1021/acsmedchemlett.5c00510
- Primary Topic
- HIV/AIDS drug development and treatment
- Type
- article
- Field-Weighted Citation Impact
- 0.00