{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T03:21:24Z","timestamp":1790824884165,"version":"4.1.0"},"update-to":[{"DOI":"10.1371\/journal.ppat.1011993","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2024,2,13]],"date-time":"2024-02-13T00:00:00Z","timestamp":1707782400000}}],"reference-count":54,"publisher":"Public Library of Science (PLoS)","issue":"2","license":[{"start":{"date-parts":[[2024,2,1]],"date-time":"2024-02-01T00:00:00Z","timestamp":1706745600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100015691","name":"Division of Microbiology and Infectious Diseases, National Institute of Allergy and Infectious Diseases","doi-asserted-by":"publisher","award":["AI141222"],"award-info":[{"award-number":["AI141222"]}],"id":[{"id":"10.13039\/100015691","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100015691","name":"Division of Microbiology and Infectious Diseases, National Institute of Allergy and Infectious Diseases","doi-asserted-by":"publisher","award":["AI171403"],"award-info":[{"award-number":["AI171403"]}],"id":[{"id":"10.13039\/100015691","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plospathogens.org"],"crossmark-restriction":false},"short-container-title":["PLoS Pathog"],"abstract":"<jats:p>Pre-existing or rapidly emerging resistance of influenza viruses to approved antivirals makes the development of novel therapeutics to mitigate seasonal influenza and improve preparedness against future influenza pandemics an urgent priority. We have recently identified the chain-terminating broad-spectrum nucleoside analog clinical candidate 4\u2019-fluorouridine (4\u2019-FlU) and demonstrated oral efficacy against seasonal, pandemic, and highly pathogenic avian influenza viruses in the mouse and ferret model. Here, we have resistance-profiled 4\u2019-FlU against a pandemic A\/CA\/07\/2009 (H1N1) (CA09). <jats:italic>In vitro<\/jats:italic> viral adaptation yielded six independently generated escape lineages with distinct mutations that mediated moderate resistance to 4\u2019-FlU in the genetically controlled background of recombinant CA09 (recCA09). Mutations adhered to three distinct structural clusters that are all predicted to affect the geometry of the active site of the viral RNA-dependent RNA polymerase (RdRP) complex for phosphodiester bond formation. Escape could be achieved through an individual causal mutation, a combination of mutations acting additively, or mutations functioning synergistically. Fitness of all resistant variants was impaired in cell culture, and all were attenuated in the mouse model. Oral 4\u2019-FlU administered at lowest-efficacious (2 mg\/kg) or elevated (10 mg\/kg) dose overcame moderate resistance when mice were inoculated with 10 LD<jats:sub>50<\/jats:sub> units of parental or resistant recCA09, demonstrated by significantly reduced virus load and complete survival. In the ferret model, invasion of the lower respiratory tract by variants representing four adaptation lineages was impaired. Resistant variants were either transmission-incompetent, or spread to untreated sentinels was fully blocked by therapeutic treatment of source animals with 4\u2019-FlU.<\/jats:p>","DOI":"10.1371\/journal.ppat.1011993","type":"journal-article","created":{"date-parts":[[2024,2,1]],"date-time":"2024-02-01T18:51:14Z","timestamp":1706813474000},"page":"e1011993","update-policy":"https:\/\/doi.org\/10.1371\/journal.ppat.corrections_policy","source":"Crossref","is-referenced-by-count":21,"title":["Influenza A virus resistance to 4\u2019-fluorouridine coincides with viral attenuation in vitro and in vivo"],"prefix":"10.1371","volume":"20","author":[{"given":"Carolin M.","family":"Lieber","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hae-Ji","family":"Kang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Megha","family":"Aggarwal","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicole A.","family":"Lieberman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elizabeth B.","family":"Sobolik","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeong-Joong","family":"Yoon","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael G.","family":"Natchus","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert 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and Phylogeny-Trait Analyses.","volume":"14","author":"JCD Costa","year":"2022","journal-title":"Viruses"},{"issue":"12","key":"ppat.1011993.ref010","doi-asserted-by":"crossref","first-page":"1080","DOI":"10.1016\/S1474-4422(19)30361-8","article-title":"Antiviral amantadine.","volume":"18","author":"T Nisar","year":"2019","journal-title":"Lancet Neurol"},{"issue":"9","key":"ppat.1011993.ref011","doi-asserted-by":"crossref","DOI":"10.3390\/v10090454","article-title":"Neuraminidase Inhibitors in Influenza Treatment and Prevention-Is It Time to Call It a Day?","volume":"10","author":"C Parra-Rojas","year":"2018","journal-title":"Viruses"},{"issue":"4","key":"ppat.1011993.ref012","first-page":"Cd008965","article-title":"Neuraminidase inhibitors for preventing and treating influenza in adults and children.","volume":"2014","author":"T Jefferson","year":"2014","journal-title":"Cochrane Database Syst 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