{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,9]],"date-time":"2026-09-09T11:11:50Z","timestamp":1788952310377,"version":"build-2803163510"},"reference-count":59,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2026,9,9]],"date-time":"2026-09-09T00:00:00Z","timestamp":1788912000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000001","name":"National Science Foundation","doi-asserted-by":"publisher","award":["2515959"],"award-info":[{"award-number":["2515959"]}],"id":[{"id":"10.13039\/100000001","id-type":"DOI","asserted-by":"publisher"}]},{"award":["2515959"],"award-info":[{"award-number":["2515959"]}],"id":[{"id":"https:\/\/ror.org\/021nxhr62","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Viruses"],"abstract":"<jats:p>Various antiviral drug therapies have been developed for the treatment of coronaviruses, particularly SARS-CoV-2. However, the emergence of drug-resistant mutations is detrimental to clinical efficacy and global public health. Antiviral usage exerts selective pressures on viruses that manufacture an environment for resistant strains to emerge, in some cases at a fitness cost. However, the appearance of a compensatory mutation can restore or improve viral fitness, allowing the strain to persist and spread in a population. Here we evaluate the drug resistance mechanisms of multiple SARS-CoV-2 non-structural proteins, including the main protease (Mpro) and the RNA-dependent RNA polymerase (RdRP), which drive polyprotein processing and viral RNA replication, as well as PLPro, EndoU, and Mac1, which contribute to viral replication and counter host innate immune responses. We also discuss several methods that could be used to avoid drug resistance in the future. By integrating the understanding of molecular mechanisms of antiviral treatment with surveillance of resistance-associated mutations and new drug therapies, appropriate clinical approaches can be developed to reduce the impact of drug resistance.<\/jats:p>","DOI":"10.3390\/v18090993","type":"journal-article","created":{"date-parts":[[2026,9,9]],"date-time":"2026-09-09T10:19:16Z","timestamp":1788949156000},"page":"993","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["SARS-CoV-2 Drug-Resistant Mutations in Non-Structural Proteins"],"prefix":"10.3390","volume":"18","author":[{"given":"Madison","family":"Shaw","sequence":"first","affiliation":[{"name":"Department of Molecular Biosciences, University of Kansas, Lawrence, KS 66045, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1560-1573","authenticated-orcid":false,"given":"Anthony R.","family":"Fehr","sequence":"additional","affiliation":[{"name":"Department of Molecular Biosciences, University of Kansas, Lawrence, KS 66045, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,9,9]]},"reference":[{"key":"ref_1","unstructured":"Centers for Disease Control and Prevention (2026, April 08). 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