{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,30]],"date-time":"2026-10-30T04:59:06Z","timestamp":1793336346060,"version":"4.5.0"},"update-to":[{"DOI":"10.1371\/journal.ppat.1012522","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2024,9,17]],"date-time":"2024-09-17T00:00:00Z","timestamp":1726531200000}}],"reference-count":105,"publisher":"Public Library of Science (PLoS)","issue":"9","license":[{"start":{"date-parts":[[2024,9,11]],"date-time":"2024-09-11T00:00:00Z","timestamp":1726012800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100002428","name":"Austrian Science Fund","doi-asserted-by":"publisher","award":["P35148"],"award-info":[{"award-number":["P35148"]}],"id":[{"id":"10.13039\/501100002428","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002428","name":"Austrian Science Fund","doi-asserted-by":"publisher","award":["P34376"],"award-info":[{"award-number":["P34376"]}],"id":[{"id":"10.13039\/501100002428","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002428","name":"Austrian Science Fund","doi-asserted-by":"publisher","award":["I5406"],"award-info":[{"award-number":["I5406"]}],"id":[{"id":"10.13039\/501100002428","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100015691","name":"Division of Microbiology and Infectious Diseases, National Institute of Allergy and Infectious Diseases","doi-asserted-by":"publisher","award":["U19-AI171954"],"award-info":[{"award-number":["U19-AI171954"]}],"id":[{"id":"10.13039\/100015691","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Merck Sharp & Dohme LLC"}],"content-domain":{"domain":["www.plospathogens.org"],"crossmark-restriction":false},"short-container-title":["PLoS Pathog"],"abstract":"<jats:p>\n                    Nirmatrelvir was the first protease inhibitor specifically developed against the SARS-CoV-2 main protease (3CL\n                    <jats:sup>pro<\/jats:sup>\n                    \/M\n                    <jats:sup>pro<\/jats:sup>\n                    ) and licensed for clinical use. As SARS-CoV-2 continues to spread, variants resistant to nirmatrelvir and other currently available treatments are likely to arise. This study aimed to identify and characterize mutations that confer resistance to nirmatrelvir. To safely generate M\n                    <jats:sup>pro<\/jats:sup>\n                    resistance mutations, we passaged a previously developed, chimeric vesicular stomatitis virus (VSV-M\n                    <jats:sup>pro<\/jats:sup>\n                    ) with increasing, yet suboptimal concentrations of nirmatrelvir. Using Wuhan-1 and Omicron M\n                    <jats:sup>pro<\/jats:sup>\n                    variants, we selected a large set of mutants. Some mutations are frequently present in GISAID, suggesting their relevance in SARS-CoV-2. The resistance phenotype of a subset of mutations was characterized against clinically available protease inhibitors (nirmatrelvir and ensitrelvir) with cell-based, biochemical and SARS-CoV-2 replicon assays. Moreover, we showed the putative molecular mechanism of resistance based on\n                    <jats:italic>in silico<\/jats:italic>\n                    molecular modelling. These findings have implications on the development of future generation M\n                    <jats:sup>pro<\/jats:sup>\n                    inhibitors, will help to understand SARS-CoV-2 protease inhibitor resistance mechanisms and show the relevance of specific mutations, thereby informing treatment decisions.\n                  <\/jats:p>","DOI":"10.1371\/journal.ppat.1012522","type":"journal-article","created":{"date-parts":[[2024,9,11]],"date-time":"2024-09-11T13:37:43Z","timestamp":1726061863000},"page":"e1012522","update-policy":"https:\/\/doi.org\/10.1371\/journal.ppat.corrections_policy","source":"Crossref","is-referenced-by-count":16,"title":["A comprehensive study of SARS-CoV-2 main protease (Mpro) inhibitor-resistant mutants selected in a VSV-based system"],"prefix":"10.1371","volume":"20","author":[{"given":"Francesco","family":"Costacurta","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrea","family":"Dodaro","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Bante","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Helge","family":"Sch\u00f6ppe","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ju-Yi","family":"Peng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bernhard","family":"Sprenger","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xi","family":"He","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Seyed 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Meeting report: 35th International Conference on Antiviral Research in Seattle, Washington, USA\u2013March 21\u201325, 2022. Antiviral Research. Elsevier B.V.; 2023. p. 105521. doi: 10.1016\/j.antiviral.2022.105521","DOI":"10.1016\/j.antiviral.2022.105521"},{"key":"ppat.1012522.ref013","first-page":"1","article-title":"Pardes Biosciences Announces Top-line Results from Phase 2 Trial Evaluating Pomotrelvir for the Treatment of COVID-19","year":"2023"},{"key":"ppat.1012522.ref014","article-title":"1123. EDP-235, A Potent and Once-daily Oral Antiviral, Demonstrates Excellent Penetration into Macrophages and Monocytes, with the Potential for Mitigation of Cytokine Storm in High-Risk COVID-19 Patients.","volume":"9","author":"Y Li","year":"2022","journal-title":"Open Forum Infect Dis."},{"key":"ppat.1012522.ref015","doi-asserted-by":"crossref","first-page":"54","DOI":"10.1016\/j.bbrc.2022.09.010","article-title":"Hotspot residues and resistance mutations in the nirmatrelvir-binding site of SARS-CoV-2 main protease: Design, identification, and correlation with globally circulating viral genomes","volume":"629","author":"AK Padhi","year":"2022","journal-title":"Biochem Biophys Res Commun"},{"key":"ppat.1012522.ref016","article-title":"Naturally Occurring Mutations of SARS-CoV-2 Main Protease Confer Drug Resistance to Nirmatrelvir.","author":"Y Hu","year":"2023","journal-title":"ACS Cent Sci."},{"key":"ppat.1012522.ref017","article-title":"Integrative Approach to Dissect the Drug Resistance 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