{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,25]],"date-time":"2026-09-25T15:06:54Z","timestamp":1790348814377,"version":"4.1.0"},"reference-count":57,"publisher":"American Association for the Advancement of Science (AAAS)","issue":"13","content-domain":{"domain":["www.science.org"],"crossmark-restriction":true},"short-container-title":["Sci. Adv."],"published-print":{"date-parts":[[2023,3,31]]},"abstract":"<jats:p>\n                    Vaccines and drugs have helped reduce disease severity and blunt the spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). However, ongoing virus transmission, continuous evolution, and increasing selective pressures have the potential to yield viral variants capable of resisting these interventions. Here, we investigate the susceptibility of natural variants of the main protease [M\n                    <jats:sup>pro<\/jats:sup>\n                    ; 3C-like protease (3CL\n                    <jats:sup>pro<\/jats:sup>\n                    )] of SARS-CoV-2 to protease inhibitors. Multiple single amino acid changes in M\n                    <jats:sup>pro<\/jats:sup>\n                    confer resistance to nirmatrelvir (the active component of Paxlovid). An additional clinical-stage inhibitor, ensitrelvir (Xocova), shows a different resistance mutation profile. Importantly, phylogenetic analyses indicate that several of these resistant variants have pre-existed the introduction of these drugs into the human population and are capable of spreading. These results encourage the monitoring of resistance variants and the development of additional protease inhibitors and other antiviral drugs with different mechanisms of action and resistance profiles for combinatorial therapy.\n                  <\/jats:p>","DOI":"10.1126\/sciadv.ade8778","type":"journal-article","created":{"date-parts":[[2023,4,10]],"date-time":"2023-04-10T10:02:09Z","timestamp":1681120929000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":164,"title":["Transmissible SARS-CoV-2 variants with resistance to clinical protease inhibitors"],"prefix":"10.1126","volume":"9","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6598-8994","authenticated-orcid":true,"given":"Seyed Arad","family":"Moghadasi","sequence":"first","affiliation":[{"name":"Department of Biochemistry, Molecular Biology, and Biophysics, University of Minnesota, Twin Cities, Minneapolis, MN 55455, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8148-9490","authenticated-orcid":true,"given":"Emmanuel","family":"Heilmann","sequence":"additional","affiliation":[{"name":"Institute of Virology, Medical University of Innsbruck, Innsbruck, Austria."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1358-6755","authenticated-orcid":true,"given":"Ahmed Magdy","family":"Khalil","sequence":"additional","affiliation":[{"name":"Texas Biomedical Research Institute, San Antonio, TX 78227, USA."},{"name":"Department of Zoonotic Diseases, Faculty of Veterinary Medicine, Zagazig University, Zagazig 44511, Egypt."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9907-0508","authenticated-orcid":true,"given":"Christina","family":"Nnabuife","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Chemical Biology, Baylor College of 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Hu E.\u00a0M.\u00a0Lewandowski H.\u00a0Tan R.\u00a0T.\u00a0Morgan X.\u00a0Zhang L.\u00a0M.\u00a0C. Jacobs S.\u00a0G.\u00a0Butler M.\u00a0V.\u00a0Mongora J.\u00a0Choy Y.\u00a0Chen J.\u00a0Wang Naturally occurring mutations of SARS-CoV-2 main protease confer drug resistance to nirmatrelvir. bioRxiv 2022.06.28.497978 [ Preprint ]. 6 September 2022. https:\/\/doi.org\/10.1101\/2022.06.28.497978.","DOI":"10.1101\/2022.06.28.497978"},{"key":"e_1_3_2_30_2","doi-asserted-by":"crossref","unstructured":"J. Ou E.\u00a0M.\u00a0Lewandowski Y.\u00a0Hu A.\u00a0A.\u00a0Lipinski R.\u00a0T.\u00a0Morgan L.\u00a0M.\u00a0C. Jacobs X.\u00a0Zhang M.\u00a0J.\u00a0Bikowitz P.\u00a0Langlais H.\u00a0Tan J.\u00a0Wang Y.\u00a0Chen J.\u00a0S.\u00a0Choy A yeast-based system to study SARS-CoV-2 M pro structure and to identify nirmatrelvir resistant mutations. bioRxiv 2022.08.06.503039 [ Preprint ]. 8 August 2022. https:\/\/doi.org\/10.1101\/2022.08.06.503039.","DOI":"10.21203\/rs.3.rs-1942964\/v1"},{"key":"e_1_3_2_31_2","doi-asserted-by":"publisher","DOI":"10.1126\/sciadv.add7197"},{"key":"e_1_3_2_32_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-022-05514-2"},{"key":"e_1_3_2_33_2","doi-asserted-by":"crossref","unstructured":"D. Jochmans C.\u00a0Liu K.\u00a0Donckers A.\u00a0Stoycheva S.\u00a0Boland S.\u00a0K.\u00a0Stevens C.\u00a0De Vita B.\u00a0Vanmechelen P.\u00a0Maes B.\u00a0Tr\u00fceb N.\u00a0Ebert V.\u00a0Thiel S.\u00a0De Jonghe L.\u00a0Vangeel D.\u00a0Bardiot A.\u00a0Jekle L.\u00a0M.\u00a0Blatt L.\u00a0Beigelman J.\u00a0A.\u00a0Symons P.\u00a0Raboisson P.\u00a0Chaltin A.\u00a0Marchand J.\u00a0Neyts J.\u00a0Deval K.\u00a0Vandyck The substitutions L50F E166A and L167F in SARS-CoV-2 3CLpro are selected by a protease inhibitor in vitro and confer resistance to nirmatrelvir. bioRxiv 2022.06.07.495116 [ Preprint ]. 7 June 2022. https:\/\/doi.org\/10.1101\/2022.06.07.495116.","DOI":"10.1101\/2022.06.07.495116"},{"key":"e_1_3_2_34_2","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.abq7360"},{"key":"e_1_3_2_35_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2117142119"},{"key":"e_1_3_2_36_2","unstructured":"www.japic.or.jp\/mail_s\/pdf\/23-11-1-07.pdf."},{"key":"e_1_3_2_37_2","doi-asserted-by":"crossref","unstructured":"G. Dias Noske E.\u00a0de Souza Silva M.\u00a0Ortiz de Godoy I.\u00a0Dolci R.\u00a0Sachetto Fernandes R.\u00a0Vict\u00f3rio Carvalho Guido P.\u00a0Sj\u00f6 G.\u00a0Oliva A.\u00a0Schutzer Godoy Structural basis of nirmatrelvir and ensitrelvir resistance profiles against SARS-CoV-2 main protease naturally occurring polymorphisms. bioRxiv 2022.08.31.506107 [ Preprint ]. 1 September 2022. https:\/\/doi.org\/10.1101\/2022.08.31.506107.","DOI":"10.1101\/2022.08.31.506107"},{"key":"e_1_3_2_38_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-020-20075-6"},{"key":"e_1_3_2_39_2","doi-asserted-by":"publisher","DOI":"10.1002\/hep.27934"},{"key":"e_1_3_2_40_2","first-page":"1333","article-title":"Combating susceptibility to drug resistance: Lessons from HIV-1 protease","volume":"11","author":"King N. M.","year":"2004","unstructured":"N. M.\u00a0King, M.\u00a0Prabu-Jeyabalan, E. A.\u00a0Nalivaika, C. A.\u00a0Schiffer, Combating susceptibility to drug resistance: Lessons from HIV-1 protease. 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Reddy M.\u00a0N.\u00a0Melo S.\u00a0L.\u00a0Seyler J.\u00a0Domanski D.\u00a0L.\u00a0Dotson S.\u00a0Buchoux I.\u00a0M.\u00a0Kenney O.\u00a0Beckstein MDAnalysis: A python package for the rapid analysis of molecular dynamics simulations in Proceedings of the 15th Python in Science Conference (SciPy 2016).","DOI":"10.25080\/Majora-629e541a-00e"},{"key":"e_1_3_2_58_2","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/bty407"}],"container-title":["Science Advances"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.science.org\/doi\/pdf\/10.1126\/sciadv.ade8778","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,1,9]],"date-time":"2024-01-09T16:21:42Z","timestamp":1704817302000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.science.org\/doi\/10.1126\/sciadv.ade8778"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,3,31]]},"references-count":57,"journal-issue":{"issue":"13","published-print":{"date-parts":[[2023,3,31]]}},"alternative-id":["10.1126\/sciadv.ade8778"],"URL":"https:\/\/doi.org\/10.1126\/sciadv.ade8778","relation":{"has-preprint":[{"id-type":"doi","id":"10.1101\/2022.08.07.503099","asserted-by":"object"}]},"ISSN":["2375-2548"],"issn-type":[{"value":"2375-2548","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,3,31]]},"assertion":[{"value":"2022-09-14","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2023-02-28","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2023-03-29","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"eade8778"}}