S-adenosylhomocysteine analogs selectively suppress pan-coronavirus replication by inhibition of nsp14 methyltransferase.
| Title: | S-adenosylhomocysteine analogs selectively suppress pan-coronavirus replication by inhibition of nsp14 methyltransferase. |
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| Authors: | Rosas-Lemus M; Department of Microbiology-Immunology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611 USA.; Center for Structural Biology of Infectious Diseases, Northwestern University Feinberg School of Medicine, Chicago, IL 60611 USA.; Athe S; Department of Chemistry, University of Chicago, Chicago, IL 60637 USA.; Minasov G; Department of Microbiology-Immunology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611 USA.; Center for Structural Biology of Infectious Diseases, Northwestern University Feinberg School of Medicine, Chicago, IL 60611 USA.; Pattie JA; Department of Microbiology-Immunology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611 USA.; Center for Structural Biology of Infectious Diseases, Northwestern University Feinberg School of Medicine, Chicago, IL 60611 USA.; Brunzelle JS; Center for Structural Biology of Infectious Diseases, Northwestern University Feinberg School of Medicine, Chicago, IL 60611 USA.; Northwestern Synchrotron Research Center, Life Sciences Collaborative Team, Northwestern University, Argonne, IL, USA.; Chau I; Structural Genomics Consortium, University of Toronto, Toronto ON M5S 1A8 Canada.; Li F; Structural Genomics Consortium, University of Toronto, Toronto ON M5S 1A8 Canada.; Vedadi M; Department of Pharmacology and Toxicology, University of Toronto, Toronto ON M5S 1A8 Canada.; Ma H; Data Science and Learning Division, Argonne National Laboratory, Lemont, IL 60439 USA.; Ramanathan A; Data Science and Learning Division, Argonne National Laboratory, Lemont, IL 60439 USA.; Becker ME; Department of Cell and Developmental Biology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611 USA.; Hope TJ; Department of Cell and Developmental Biology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611 USA.; Abdelkarim H; Department of Biochemistry and Molecular Genetics, College of Medicine, University of Illinois-Chicago, Chicago, IL 60607 USA.; Grudzien P; Department of Biochemistry and Molecular Genetics, College of Medicine, University of Illinois-Chicago, Chicago, IL 60607 USA.; Gaponenko V; Department of Biochemistry and Molecular Genetics, College of Medicine, University of Illinois-Chicago, Chicago, IL 60607 USA.; Montgomery JE; Department of Chemistry, University of Chicago, Chicago, IL 60637 USA.; Moellering RE; Department of Chemistry, University of Chicago, Chicago, IL 60637 USA.; Rawal VH; Department of Chemistry, University of Chicago, Chicago, IL 60637 USA.; Satchell KJF; Department of Microbiology-Immunology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611 USA.; Center for Structural Biology of Infectious Diseases, Northwestern University Feinberg School of Medicine, Chicago, IL 60611 USA. |
| Source: | ACS medicinal chemistry letters [ACS Med Chem Lett] 2025 Nov 05. Date of Electronic Publication: 2025 Nov 05. |
| Publication Model: | Ahead of Print |
| Publication Type: | Journal Article |
| Language: | English |
| Journal Info: | Publisher: American Chemical Society Country of Publication: United States NLM ID: 101521073 Publication Model: Print-Electronic Cited Medium: Print ISSN: 1948-5875 (Print) Linking ISSN: 19485875 NLM ISO Abbreviation: ACS Med Chem Lett |
| Imprint Name(s): | Original Publication: Washington, D.C. : American Chemical Society |
| Abstract: | 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. Two analogs, designated 4h and 4p, inhibit both mouse hepatitis virus and SARS-CoV-2 replication. Compound 4p 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 4p occupies both the S-adenosylmethione and Gppp binding pockets of nsp14 and nsp16. Selectivity of 4p 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. |
| Competing Interests: | This work was conducted under an open science agreement by all researchers and thus all authors declare no competing financial interests. All work was safely conducted in laboratories approved by the institutional research safety offices of their institutions. All work with SARS-CoV-2 and MHV was conducted in Biosafety Level 3 and Biosafety Level 2 approved laboratories, respectively, following protocols approved by the Northwestern University Institutional Biosafety Committee. All chemical reactions were conducted in a certified ventilated chemical fume hood following safety protocols approved by the University of Chicago. |
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| Grant Information: | 75N93022C00035 United States AI NIAID NIH HHS; HHSN272201700060C United States AI NIAID NIH HHS; P20 GM121176 United States GM NIGMS NIH HHS; U01 AI124316 United States AI NIAID NIH HHS |
| Contributed Indexing: | Keywords: Coronavirus; SAH; SARS-CoV-2; methyltransferase; nsp14 |
| Entry Date(s): | Date Created: 20260122 Latest Revision: 20260316 |
| Update Code: | 20260316 |
| PubMed Central ID: | PMC12818953 |
| DOI: | 10.1021/acsmedchemlett.5c00510 |
| PMID: | 41568342 |
| Database: | MEDLINE |
Journal Article