{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,25]],"date-time":"2026-02-25T06:23:04Z","timestamp":1772000584601,"version":"3.50.1"},"reference-count":34,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2026,2,23]],"date-time":"2026-02-23T00:00:00Z","timestamp":1771804800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Health and Labour Sciences Research","award":["24HA2005"],"award-info":[{"award-number":["24HA2005"]}]},{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"crossref","award":["23K06576"],"award-info":[{"award-number":["23K06576"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100009619","name":"Japan Agency for Medical Research and Development","doi-asserted-by":"crossref","award":["JP223fa627005"],"award-info":[{"award-number":["JP223fa627005"]}],"id":[{"id":"10.13039\/100009619","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Viruses"],"abstract":"<jats:p>Molnupiravir induces mutations that render severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) replication-competent through error catastrophe mechanisms. Previous studies showed no resistant virus emergence during prolonged molnupiravir treatment, with no resistant variants reported. However, these approaches were limited by genetic uniformity at passage initiation. To investigate viral population dynamics under enhanced genetic diversity, we employed mutagenic pre-treatment using 5-fluorouracil (5-FU) and favipiravir to generate diverse quasi-species populations before molnupiravir selection pressure. Viral populations were treated with stepwise increasing molnupiravir concentrations (10 \u03bcM \u27f6 25 \u03bcM \u27f6 40 \u03bcM) over ten serial passages. Viral detectability, plaque morphology, and mutation accumulation were analyzed using molecular and sequencing approaches. Only high-concentration favipiravir (1000 \u03bcM) pre-treatment maintained detectable viral RNA through ten passages under 40 \u03bcM molnupiravir, while favipiravir (500 \u03bcM) and 5-FU groups became undetectable after passage 6. Surviving populations formed extremely small plaques with markedly reduced replication capacity. Next-generation sequencing revealed extensive mutation accumulation across viral proteins, including polymerase proteins. Individual viable virus isolation was unsuccessful, and large-scale propagation could not be achieved. These findings demonstrate apparent survival rather than true resistance to molnupiravir, characterized by severely compromised viral fitness.<\/jats:p>","DOI":"10.3390\/v18020273","type":"journal-article","created":{"date-parts":[[2026,2,23]],"date-time":"2026-02-23T16:22:55Z","timestamp":1771863775000},"page":"273","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["SARS-CoV-2 Error Catastrophe Under Molnupiravir: Mutagenic Enhancement Enables Viral Persistence with Impaired Fitness"],"prefix":"10.3390","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0009-0005-0143-2475","authenticated-orcid":false,"given":"Yuriko","family":"Tomita","sequence":"first","affiliation":[{"name":"Influenza Research Center, National Institute of Infectious Diseases, Japan Institute of Health and Security (JIHS), Tokyo 208-0011, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kaya","family":"Miyazaki","sequence":"additional","affiliation":[{"name":"Department of Respiratory Viruses, National Institute of Infectious Diseases, Japan Institute of Health and Security (JIHS), Tokyo 208-0011, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rika","family":"Mochizuki","sequence":"additional","affiliation":[{"name":"Department of Respiratory Viruses, National Institute of Infectious Diseases, Japan Institute of Health and Security (JIHS), Tokyo 208-0011, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hideki","family":"Hasegawa","sequence":"additional","affiliation":[{"name":"Influenza Research Center, National Institute of Infectious Diseases, Japan Institute of Health and Security (JIHS), Tokyo 208-0011, Japan"},{"name":"Institute for Vaccine Research and Development, Hokkaido University, Sapporo 001-0021, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2026,2,23]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1016\/j.virusres.2006.01.017","article-title":"Nidovirales: Evolving the Largest RNA Virus Genome","volume":"117","author":"Gorbalenya","year":"2006","journal-title":"Virus Res."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"270","DOI":"10.4161\/rna.8.2.15013","article-title":"Coronaviruses: An RNA Proofreading Machine Regulates Replication Fidelity and Diversity","volume":"8","author":"Denison","year":"2011","journal-title":"RNA Biol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1128\/JVI.01031-17","article-title":"Complexities of Viral Mutation Rates","volume":"92","author":"Peck","year":"2018","journal-title":"J. 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