{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T09:08:55Z","timestamp":1785402535780,"version":"3.56.0"},"reference-count":18,"publisher":"MDPI AG","issue":"15","license":[{"start":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T00:00:00Z","timestamp":1785369600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>Antiviral drug resistance in SARS-CoV-2 is increasingly limiting treatment efficacy. Four recent studies have revealed two key resistance mechanisms: (1) Mutations in the main protease (Mpro)\u2014including E166V, E166A, and S144-series variants\u2014disrupt drug binding or active-site conformation, reducing nirmatrelvir efficacy. (2) The proofreading exoribonuclease (ExoN) removes incorporated nucleoside analogues (e.g., bemnifosbuvir, sofosbuvir), conferring resistance. Guided by structural and pharmacological insights, three effective countermeasures have been established: structure-based optimization of Mpro inhibitors, rational design of ExoN-evading nucleoside analogues, and synergistic combination therapies. These advances provide a solid framework for developing next-generation antivirals to combat emerging resistant SARS-CoV-2 variants.<\/jats:p>","DOI":"10.3390\/molecules31152655","type":"journal-article","created":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T08:09:42Z","timestamp":1785398982000},"page":"2655","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Novel Mechanisms of SARS-CoV-2 Drug Resistance and Rational Design of Anti-Resistant Antivirals"],"prefix":"10.3390","volume":"31","author":[{"given":"Xianghan","family":"Bai","sequence":"first","affiliation":[{"name":"State Key Laboratory of Discovery and Utilization of Functional Components in Traditional Chinese Medicine, Key Laboratory of Chemical Biology (Ministry of Education), Department of Medicinal Chemistry, School of Pharmaceutical Sciences, Shandong University, Ji\u2019nan 250012, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bing","family":"Ye","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Discovery and Utilization of Functional Components in Traditional Chinese Medicine, Key Laboratory of Chemical Biology (Ministry of Education), Department of Medicinal Chemistry, School of Pharmaceutical Sciences, Shandong University, Ji\u2019nan 250012, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9853-3793","authenticated-orcid":false,"given":"Shenghua","family":"Gao","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Discovery and Utilization of Functional Components in Traditional Chinese Medicine, Key Laboratory of Chemical Biology (Ministry of Education), Department of Medicinal Chemistry, School of Pharmaceutical Sciences, Shandong University, Ji\u2019nan 250012, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9675-6026","authenticated-orcid":false,"given":"Peng","family":"Zhan","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Discovery and Utilization of Functional Components in Traditional Chinese Medicine, Key Laboratory of Chemical Biology (Ministry of Education), Department of Medicinal Chemistry, School of Pharmaceutical Sciences, Shandong University, Ji\u2019nan 250012, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7302-2214","authenticated-orcid":false,"given":"Xinyong","family":"Liu","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Discovery and Utilization of Functional Components in Traditional Chinese Medicine, Key Laboratory of Chemical Biology (Ministry of Education), Department of Medicinal Chemistry, School of Pharmaceutical Sciences, Shandong University, Ji\u2019nan 250012, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,7,30]]},"reference":[{"key":"ref_1","unstructured":"World Health Organization (2020, December 31). 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