{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,11]],"date-time":"2026-06-11T07:27:10Z","timestamp":1781162830116,"version":"3.54.1"},"reference-count":82,"publisher":"Wiley","issue":"9","license":[{"start":{"date-parts":[[2025,8,25]],"date-time":"2025-08-25T00:00:00Z","timestamp":1756080000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000038","name":"Natural Sciences and Engineering Research Council of Canada","doi-asserted-by":"publisher","award":["327028\u201009"],"award-info":[{"award-number":["327028\u201009"]}],"id":[{"id":"10.13039\/501100000038","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000024","name":"Canadian Institutes of Health Research","doi-asserted-by":"publisher","award":["MOP\u201013694"],"award-info":[{"award-number":["MOP\u201013694"]}],"id":[{"id":"10.13039\/501100000024","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000024","name":"Canadian Institutes of Health Research","doi-asserted-by":"publisher","award":["OV3\u2010170644"],"award-info":[{"award-number":["OV3\u2010170644"]}],"id":[{"id":"10.13039\/501100000024","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Protein Science"],"published-print":{"date-parts":[[2025,9]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>The emergence of SARS\u2010CoV\u20102 and other lethal coronaviruses has prompted extensive research into targeted antiviral treatments, particularly focusing on the viral 3C\u2010like protease (3CL<jats:sup>pro<\/jats:sup>) due to its essential role for viral replication. However, the rise of drug resistance mutations poses threats to public health and underscores the need to predict resistance mutations and understand the mechanism of how these mutations confer resistance. The binding of inhibitor to 3CL<jats:sup>pro<\/jats:sup> drives it from the monomeric to the active dimeric form, which can counterintuitively lead to enzyme activation rather than inhibition. Furthermore, we find this allosteric coupling between binding and dimerization is sensitive to mutation, leading to a new mechanism for drug resistance. Understanding the relationship between inhibitor binding and dimerization is important for resistant strain surveillance and development of robust antivirals. Herein, we present a systematic study of drug resistance mediated by inhibitor\u2010induced dimerization of 3CL<jats:sup>pro<\/jats:sup>.<\/jats:p>","DOI":"10.1002\/pro.70275","type":"journal-article","created":{"date-parts":[[2025,8,25]],"date-time":"2025-08-25T10:28:05Z","timestamp":1756117685000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Inhibitor\u2010induced dimerization mediates lufotrelvir resistance in mutants of <scp>SARS<\/scp>\u2010<scp>CoV<\/scp>\u20102 <scp>3C\u2010like protease<\/scp>"],"prefix":"10.1002","volume":"34","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6792-3091","authenticated-orcid":false,"given":"Guanyu","family":"Wang","sequence":"first","affiliation":[{"name":"Department of Chemistry McGill University  Montreal Quebec Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Felipe","family":"Venegas","sequence":"additional","affiliation":[{"name":"Department of Chemistry McGill University  Montreal Quebec Canada"},{"name":"Departamento de Ciencias Biom\u00e9dicas Facultad de Medicina, Universidad Cat\u00f3lica del Norte  Coquimbo Chile"},{"name":"Programa de Doctorado en Ciencias Biom\u00e9dicas, Facultad de Medicina Universidad Cat\u00f3lica del Norte  Coquimbo Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andres","family":"Rueda","sequence":"additional","affiliation":[{"name":"Department of Chemistry McGill University  Montreal Quebec Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8993-9353","authenticated-orcid":false,"given":"Osvaldo","family":"Ya\u00f1ez","sequence":"additional","affiliation":[{"name":"Centro de Modelaci\u00f3n Ambiental y Din\u00e1mica de Sistemas (CEMADIS), Facultad de Ingenier\u00eda y Negocios Universidad de Las Am\u00e9ricas  Santiago Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1297-8351","authenticated-orcid":false,"given":"Manuel I.","family":"Osorio","sequence":"additional","affiliation":[{"name":"Facultad de Odontolog\u00eda Universidad Andres Bello  Santiago Chile"},{"name":"Facultad de Medicina Universidad Diego Portales  Santiago Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-6035-0196","authenticated-orcid":false,"given":"Sibei","family":"Qin","sequence":"additional","affiliation":[{"name":"Department of Chemistry McGill University  Montreal Quebec Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9506-1716","authenticated-orcid":false,"given":"Jos\u00e9 Manuel","family":"P\u00e9rez\u2010Donoso","sequence":"additional","affiliation":[{"name":"BioNanotechnology and Microbiology Laboratory, Center for Bioinformatics and Integrative Biology (CBIB), Facultad de Ciencias de la Vida Universidad Andres Bello  Santiago Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4792-8362","authenticated-orcid":false,"given":"Christopher J.","family":"Thibodeaux","sequence":"additional","affiliation":[{"name":"Department of Chemistry McGill University  Montreal Quebec Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6933-2079","authenticated-orcid":false,"given":"Nicolas","family":"Moitessier","sequence":"additional","affiliation":[{"name":"Department of Chemistry McGill University  Montreal Quebec Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3767-1225","authenticated-orcid":false,"given":"Anthony K.","family":"Mittermaier","sequence":"additional","affiliation":[{"name":"Department of Chemistry McGill University  Montreal Quebec Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,8,25]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1042\/BCJ20230027"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.str.2018.04.014"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-021-26239-2"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M705240200"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.1093\/jb\/mvm246"},{"key":"e_1_2_10_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bpj.2009.12.4272"},{"key":"e_1_2_10_8_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M112.426460"},{"key":"e_1_2_10_9_1","doi-asserted-by":"publisher","DOI":"10.1002\/anie.202010316"},{"key":"e_1_2_10_10_1","unstructured":"FDA.Coronavirus (covid\u201019)|drugs.2023.https:\/\/www.fda.gov\/drugs\/emergency\u2010preparedness\u2010drugs\/coronavirus\u2010covid\u201019\u2010drugs. Accessed 18 Dec 2023"},{"key":"e_1_2_10_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jbc.2022.102023"},{"key":"e_1_2_10_12_1","doi-asserted-by":"publisher","DOI":"10.1002\/(SICI)1096-987X(19980115)19:1<102::AID-JCC9>3.0.CO;2-T"},{"key":"e_1_2_10_13_1","doi-asserted-by":"publisher","DOI":"10.1002\/wcms.1563"},{"key":"e_1_2_10_14_1","unstructured":"FrischMJ TrucksGW SchlegelHB ScuseriaGE RobbMA CheesemanJR et al.Gaussian 16 rev. C.01. Wallingford: Gaussian Inc.2016.https:\/\/gaussian.com\/citation\/."},{"key":"e_1_2_10_15_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gki464"},{"key":"e_1_2_10_16_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.febslet.2006.04.004"},{"key":"e_1_2_10_17_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.virusres.2007.02.015"},{"key":"e_1_2_10_18_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2118542"},{"key":"e_1_2_10_19_1","doi-asserted-by":"publisher","DOI":"10.1021\/ct900275y"},{"key":"e_1_2_10_20_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jcim.3c01269"},{"key":"e_1_2_10_21_1","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.abq7360"},{"key":"e_1_2_10_22_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0144865"},{"key":"e_1_2_10_23_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jmedchem.0c01063"},{"key":"e_1_2_10_24_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M502577200"},{"key":"e_1_2_10_25_1","doi-asserted-by":"publisher","DOI":"10.1021\/acscentsci.3c00538"},{"key":"e_1_2_10_26_1","doi-asserted-by":"publisher","DOI":"10.1016\/0263-7855(96)00018-5"},{"key":"e_1_2_10_27_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-022-05514-2"},{"key":"e_1_2_10_28_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ebiom.2023.104559"},{"key":"e_1_2_10_29_1","doi-asserted-by":"publisher","DOI":"10.1093\/ve\/vew014"},{"key":"e_1_2_10_30_1","doi-asserted-by":"publisher","DOI":"10.1002\/prot.23227"},{"key":"e_1_2_10_31_1","doi-asserted-by":"publisher","DOI":"10.1186\/s43556-023-00134-2"},{"key":"e_1_2_10_32_1","doi-asserted-by":"publisher","DOI":"10.1128\/mbio.02815-22"},{"key":"e_1_2_10_33_1","doi-asserted-by":"publisher","DOI":"10.1097\/01.inf.0000188166.17324.60"},{"key":"e_1_2_10_34_1","first-page":"42","article-title":"The coronaviruses","volume":"28","author":"Kapikian AZ","year":"1975","journal-title":"Dev Biol Stand"},{"key":"e_1_2_10_35_1","doi-asserted-by":"publisher","DOI":"10.46234\/ccdcw2021.255"},{"key":"e_1_2_10_36_1","doi-asserted-by":"publisher","DOI":"10.1007\/s13361-011-0311-9"},{"key":"e_1_2_10_37_1","doi-asserted-by":"publisher","DOI":"10.1021\/bi00865a047"},{"key":"e_1_2_10_38_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jasms.2007.04.002"},{"key":"e_1_2_10_39_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M109.095851"},{"key":"e_1_2_10_40_1","doi-asserted-by":"publisher","DOI":"10.1038\/srep20918"},{"key":"e_1_2_10_41_1","doi-asserted-by":"publisher","DOI":"10.1021\/bi200033z"},{"key":"e_1_2_10_42_1","doi-asserted-by":"publisher","DOI":"10.1128\/iai.38.2.419-423.1982"},{"key":"e_1_2_10_43_1","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.00269-12"},{"key":"e_1_2_10_44_1","doi-asserted-by":"publisher","DOI":"10.1038\/s42003-020-01577-x"},{"key":"e_1_2_10_45_1","doi-asserted-by":"publisher","DOI":"10.1126\/sciadv.ade8778"},{"key":"e_1_2_10_46_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0022-2836(65)80285-6"},{"key":"e_1_2_10_47_1","doi-asserted-by":"publisher","DOI":"10.1016\/0005-2744(69)90420-3"},{"key":"e_1_2_10_48_1","doi-asserted-by":"publisher","DOI":"10.1007\/978-1-4899-1531-3_18"},{"key":"e_1_2_10_49_1","doi-asserted-by":"publisher","DOI":"10.1038\/s42003-022-03084-7"},{"key":"e_1_2_10_50_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jbc.2023.103004"},{"key":"e_1_2_10_51_1","doi-asserted-by":"publisher","DOI":"10.3390\/ph15080986"},{"key":"e_1_2_10_52_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms24076062"},{"key":"e_1_2_10_53_1","doi-asserted-by":"publisher","DOI":"10.1038\/srep23748"},{"key":"e_1_2_10_54_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(03)13077-2"},{"key":"e_1_2_10_55_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bpj.2017.04.055"},{"key":"e_1_2_10_56_1","doi-asserted-by":"crossref","unstructured":"RaiDK YurgelonisI McMonagleP RothanHA HaoL GribenkoA et al.Nirmatrelvir an orally active Mpro inhibitor is a potent inhibitor of SARS\u2010CoV\u20102 variants of concern. bioRxiv [Preprint].2022.https:\/\/doi.org\/10.1101\/2022.01.17.476644.","DOI":"10.1101\/2022.01.17.476644"},{"key":"e_1_2_10_57_1","doi-asserted-by":"publisher","DOI":"10.1039\/D2SC06584C"},{"key":"e_1_2_10_58_1","doi-asserted-by":"publisher","DOI":"10.1002\/wcms.1121"},{"key":"e_1_2_10_59_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.biochem.2c00489"},{"key":"e_1_2_10_60_1","doi-asserted-by":"publisher","DOI":"10.1145\/3068335"},{"key":"e_1_2_10_61_1","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.02680-07"},{"key":"e_1_2_10_62_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-021-88630-9"},{"key":"e_1_2_10_63_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejmech.2021.114046"},{"key":"e_1_2_10_64_1","doi-asserted-by":"publisher","DOI":"10.1099\/vir.0.19424-0"},{"key":"e_1_2_10_65_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M115.651463"},{"key":"e_1_2_10_66_1","doi-asserted-by":"publisher","DOI":"10.1136\/bmj.1.5448.1467"},{"key":"e_1_2_10_67_1","unstructured":"U.S. Food & Drug Administration.Fact sheet for healthcare providers: Emergency use authorization for paxlovid.2023.https:\/\/www.fda.gov\/media\/155050\/download. Accessed 29 Nov 2023."},{"key":"e_1_2_10_68_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41579-020-00468-6"},{"key":"e_1_2_10_69_1","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.01819-20"},{"key":"e_1_2_10_70_1","doi-asserted-by":"publisher","DOI":"10.1002\/pro.4857"},{"key":"e_1_2_10_71_1","unstructured":"World Health Organization.Who coronavirus (covid\u201019) dashboard.2024.https:\/\/covid19.who.int\/. Accessed 3 Sep 2024"},{"key":"e_1_2_10_72_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.analchem.3c02459"},{"key":"e_1_2_10_73_1","doi-asserted-by":"publisher","DOI":"10.1107\/S0907444913001315"},{"key":"e_1_2_10_74_1","doi-asserted-by":"publisher","DOI":"10.1110\/ps.8.8.1702"},{"key":"e_1_2_10_75_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jmb.2006.11.073"},{"key":"e_1_2_10_76_1","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.02114-07"},{"key":"e_1_2_10_77_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.biopha.2021.111764"},{"key":"e_1_2_10_78_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.abb3405"},{"key":"e_1_2_10_79_1","doi-asserted-by":"publisher","DOI":"10.1186\/s40249-021-00853-0"},{"key":"e_1_2_10_80_1","doi-asserted-by":"publisher","DOI":"10.1021\/ac034089d"},{"key":"e_1_2_10_81_1","doi-asserted-by":"publisher","DOI":"10.1007\/s13238-010-0044-8"},{"key":"e_1_2_10_82_1","doi-asserted-by":"publisher","DOI":"10.1126\/sciadv.add7197"},{"key":"e_1_2_10_83_1","doi-asserted-by":"publisher","DOI":"10.1099\/0022-1317-81-4-853"}],"container-title":["Protein Science"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/pro.70275","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,9,24]],"date-time":"2025-09-24T14:28:08Z","timestamp":1758724088000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/pro.70275"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,8,25]]},"references-count":82,"journal-issue":{"issue":"9","published-print":{"date-parts":[[2025,9]]}},"alternative-id":["10.1002\/pro.70275"],"URL":"https:\/\/doi.org\/10.1002\/pro.70275","archive":["Portico"],"relation":{},"ISSN":["0961-8368","1469-896X"],"issn-type":[{"value":"0961-8368","type":"print"},{"value":"1469-896X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,8,25]]},"assertion":[{"value":"2025-04-22","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-08-07","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-08-25","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e70275"}}