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Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2026,2,3]]},"abstract":"<jats:p>Emerging and reemerging viruses pose a significant threat to global health. Although direct-acting antivirals have shown success, their efficacy is limited by the rapid emergence of drug-resistant viral variants. Hence, there is an urgent need for additional broad spectrum antiviral therapeutic strategies. Here, we identify by phenotypic screening a set of stereochemically defined photoreactive small molecules (photo-stereoprobes) that stereoselectively suppress SARS-CoV-2 replication in human lung epithelial cells. Structure\u2013activity relationship\u2013guided chemical proteomics identified the eukaryotic translation termination factor 1 (ETF1) as a target of the photo-stereoprobes, and this interaction was recapitulated with recombinant purified ETF1. We found that the photo-stereoprobes modulate programmed ribosomal frameshifting mechanisms essential for SARS-CoV-2 infection without causing ETF1 degradation, thus distinguishing the photo-stereoprobes from other known ETF1-directed small molecules. We finally show that the photo-stereoprobes also inhibit the replication of additional viruses with noncanonical ribosomal frameshifting mechanisms. Our findings identify a mechanistically distinct class of ETF1 ligands that implicate host translation termination processes as a potential drug target for antiviral development.<\/jats:p>","DOI":"10.1073\/pnas.2524108123","type":"journal-article","created":{"date-parts":[[2026,1,28]],"date-time":"2026-01-28T16:58:41Z","timestamp":1769619521000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":0,"title":["Integrated phenotypic screening and chemical proteomics identifies ETF1 ligands that modulate viral translation and replication"],"prefix":"10.1073","volume":"123","author":[{"given":"Arthur S.","family":"Kim","sequence":"first","affiliation":[{"name":"Department of Chemistry, The Scripps Research Institute","place":["La Jolla"]},{"name":"Department of Immunology and Microbiology, The Scripps Research Institute","place":["La 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S. Kim Data for \u201cIntegrated phenotypic screening and chemical proteomics identifies ETF1 ligands that modulate viral translation and replication.\u201d Proteome Exchange. http:\/\/proteomecentral.proteomexchange.org\/cgi\/GetDataset?ID=PXD067975. 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