{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T15:39:37Z","timestamp":1787067577662,"version":"build-2736575974"},"update-to":[{"DOI":"10.1371\/journal.ppat.1011231","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2023,4,11]],"date-time":"2023-04-11T00:00:00Z","timestamp":1681171200000}}],"reference-count":52,"publisher":"Public Library of Science (PLoS)","issue":"3","license":[{"start":{"date-parts":[[2023,3,27]],"date-time":"2023-03-27T00:00:00Z","timestamp":1679875200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["21H02736, 19K24679"],"award-info":[{"award-number":["21H02736, 19K24679"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["18KT0018; 18H01139; 16H04845"],"award-info":[{"award-number":["18KT0018; 18H01139; 16H04845"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["20H04281"],"award-info":[{"award-number":["20H04281"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["20H05042; 19H04839; 18H05103"],"award-info":[{"award-number":["20H05042; 19H04839; 18H05103"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["20H04841"],"award-info":[{"award-number":["20H04841"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100009619","name":"Japan Agency for Medical Research and Development","doi-asserted-by":"publisher","award":["19gm1310002"],"award-info":[{"award-number":["19gm1310002"]}],"id":[{"id":"10.13039\/100009619","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100009619","name":"Japan Agency for Medical Research and Development","doi-asserted-by":"publisher","award":["JP22gm1610008"],"award-info":[{"award-number":["JP22gm1610008"]}],"id":[{"id":"10.13039\/100009619","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100009619","name":"Japan Agency for Medical Research and Development","doi-asserted-by":"publisher","award":["20wm0225002, JP20he0822006, JP20fk0108264, JP20he0822008, JP20wm0225003, JP20fk0108267, JP20wm0125010"],"award-info":[{"award-number":["20wm0225002, JP20he0822006, JP20fk0108264, JP20he0822008, JP20wm0225003, JP20fk0108267, JP20wm0125010"]}],"id":[{"id":"10.13039\/100009619","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100009619","name":"Japan Agency for Medical Research and Development","doi-asserted-by":"publisher","award":["20wm0325007h0001;20wm0325004s0201; 20wm0325012s0301; 20wm0325015s0301"],"award-info":[{"award-number":["20wm0325007h0001;20wm0325004s0201; 20wm0325012s0301; 20wm0325015s0301"]}],"id":[{"id":"10.13039\/100009619","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100009619","name":"Japan Agency for Medical Research and Development","doi-asserted-by":"publisher","award":["20fk0108401; 20fk010847; 21fk0108617; 20fk0108451"],"award-info":[{"award-number":["20fk0108401; 20fk010847; 21fk0108617; 20fk0108451"]}],"id":[{"id":"10.13039\/100009619","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100009619","name":"Japan Agency for Medical Research and Development","doi-asserted-by":"publisher","award":["19fk0108050h0003; 19fk0108156h0001;20fk0108140s0801; 20fk0108413s0301; 19fk0210036h0502; 19fk0310114h0103;"],"award-info":[{"award-number":["19fk0108050h0003; 19fk0108156h0001;20fk0108140s0801; 20fk0108413s0301; 19fk0210036h0502; 19fk0310114h0103;"]}],"id":[{"id":"10.13039\/100009619","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100020963","name":"Moonshot Research and Development Program","doi-asserted-by":"publisher","award":["JPMJMS2021; JPMJMS2025"],"award-info":[{"award-number":["JPMJMS2021; JPMJMS2025"]}],"id":[{"id":"10.13039\/501100020963","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Mitsui Life Social Welfare Foundation"},{"name":"Shinnihon Foundation of Advanced Medical Research"},{"DOI":"10.13039\/100007434","name":"Suzuken Memorial Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100007434","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100012630","name":"Life Science Foundation of Japan","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100012630","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004298","name":"SECOM Science and Technology Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100004298","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004016","name":"The Japan Prize Foundation","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100004016","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100005928","name":"Daiwa Securities Health Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100005928","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plospathogens.org"],"crossmark-restriction":false},"short-container-title":["PLoS Pathog"],"abstract":"<jats:p>\n                    Mutations continue to accumulate within the SARS-CoV-2 genome, and the ongoing epidemic has shown no signs of ending. It is critical to predict problematic mutations that may arise in clinical environments and assess their properties in advance to quickly implement countermeasures against future variant infections. In this study, we identified mutations resistant to remdesivir, which is widely administered to SARS-CoV-2-infected patients, and discuss the cause of resistance. First, we simultaneously constructed eight recombinant viruses carrying the mutations detected in\n                    <jats:italic>in vitro<\/jats:italic>\n                    serial passages of SARS-CoV-2 in the presence of remdesivir. We confirmed that all the mutant viruses didn\u2019t gain the virus production efficiency without remdesivir treatment. Time course analyses of cellular virus infections showed significantly higher infectious titers and infection rates in mutant viruses than wild type virus under treatment with remdesivir. Next, we developed a mathematical model in consideration of the changing dynamic of cells infected with mutant viruses with distinct propagation properties and defined that mutations detected in in vitro passages canceled the antiviral activities of remdesivir without raising virus production capacity. Finally, molecular dynamics simulations of the NSP12 protein of SARS-CoV-2 revealed that the molecular vibration around the RNA-binding site was increased by the introduction of mutations on NSP12. Taken together, we identified multiple mutations that affected the flexibility of the RNA binding site and decreased the antiviral activity of remdesivir. Our new insights will contribute to developing further antiviral measures against SARS-CoV-2 infection.\n                  <\/jats:p>","DOI":"10.1371\/journal.ppat.1011231","type":"journal-article","created":{"date-parts":[[2023,3,27]],"date-time":"2023-03-27T13:36:39Z","timestamp":1679924199000},"page":"e1011231","update-policy":"https:\/\/doi.org\/10.1371\/journal.ppat.corrections_policy","source":"Crossref","is-referenced-by-count":24,"title":["Increased flexibility of the SARS-CoV-2 RNA-binding site causes resistance to remdesivir"],"prefix":"10.1371","volume":"19","author":[{"given":"Shiho","family":"Torii","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kwang Su","family":"Kim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jun","family":"Koseki","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rigel","family":"Suzuki","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shoya","family":"Iwanami","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yasuhisa","family":"Fujita","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yong Dam","family":"Jeong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jumpei","family":"Ito","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiroyuki","family":"Asakura","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mami","family":"Nagashima","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kenji","family":"Sadamasu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kazuhisa","family":"Yoshimura","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"name":"The Genotype to Phenotype Japan (G2P-Japan) Consortium","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kei","family":"Sato","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9091-8285","authenticated-orcid":true,"given":"Yoshiharu","family":"Matsuura","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Teppei","family":"Shimamura","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shingo","family":"Iwami","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takasuke","family":"Fukuhara","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2023,3,27]]},"reference":[{"issue":"7798","key":"ppat.1011231.ref001","doi-asserted-by":"crossref","first-page":"265","DOI":"10.1038\/s41586-020-2008-3","article-title":"A new coronavirus associated with human respiratory disease in China","volume":"579","author":"F Wu","year":"2020","journal-title":"Nature"},{"key":"ppat.1011231.ref002","unstructured":"WHO. WHO Coronavirus (COVID-19) dashboard. Available from: https:\/\/covid19.who.int\/."},{"key":"ppat.1011231.ref003","unstructured":"National Institutes of Health (NIH). Clinical Spectrum of SARS-CoV-2 infection. Available from: https:\/\/www.covid19treatmentguidelines.nih.gov\/overview\/clinical-spectrum\/."},{"issue":"9","key":"ppat.1011231.ref004","doi-asserted-by":"crossref","first-page":"1043","DOI":"10.1016\/S1473-3099(20)30482-5","article-title":"Clinical characteristics of COVID-19 in 104 people with SARS-CoV-2 infection on the Diamond Princess cruise ship: a retrospective analysis","volume":"20","author":"S Tabata","year":"2020","journal-title":"Lancet Infect Dis"},{"issue":"10","key":"ppat.1011231.ref005","doi-asserted-by":"crossref","first-page":"708","DOI":"10.1016\/S2352-4642(21)00198-X","article-title":"Illness duration and symptom profile in symptomatic UK school-aged children tested for SARS-CoV-2","volume":"5","author":"E Molteni","year":"2021","journal-title":"Lancet Child Adolesc Health"},{"issue":"23","key":"ppat.1011231.ref006","doi-asserted-by":"crossref","first-page":"2212","DOI":"10.1056\/NEJMoa2105000","article-title":"Vaccine Breakthrough Infections with SARS-CoV-2 Variants","volume":"384","author":"E Hacisuleyman","year":"2021","journal-title":"N Engl J Med"},{"issue":"6","key":"ppat.1011231.ref007","doi-asserted-by":"crossref","first-page":"838","DOI":"10.1093\/infdis\/jiq124","article-title":"Cluster of oseltamivir-resistant 2009 pandemic influenza A (H1N1) virus infections on a hospital ward among immunocompromised patients\u2014North Carolina, 2009","volume":"203","author":"LF Chen","year":"2011","journal-title":"J Infect Dis"},{"issue":"7159","key":"ppat.1011231.ref008","doi-asserted-by":"crossref","first-page":"660","DOI":"10.1136\/bmj.317.7159.660","article-title":"Antiviral drug resistance","volume":"317","author":"D Pillay","year":"1998","journal-title":"BMJ"},{"issue":"5","key":"ppat.1011231.ref009","doi-asserted-by":"crossref","first-page":"307","DOI":"10.1056\/NEJM199807303390504","article-title":"Sexual transmission of an HIV-1 variant resistant to multiple reverse-transcriptase and protease inhibitors","volume":"339","author":"FM Hecht","year":"1998","journal-title":"N Engl J Med"},{"issue":"3","key":"ppat.1011231.ref010","doi-asserted-by":"crossref","first-page":"183","DOI":"10.1046\/j.1365-2893.1999.00160.x","article-title":"Mutations in the hepatitis B virus polymerase gene associated with antiviral treatment for hepatitis B","volume":"6","author":"M Hussain","year":"1999","journal-title":"J Viral Hepat"},{"issue":"3","key":"ppat.1011231.ref011","doi-asserted-by":"crossref","first-page":"269","DOI":"10.1038\/s41422-020-0282-0","article-title":"Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro","volume":"30","author":"M Wang","year":"2020","journal-title":"Cell Res"},{"issue":"19","key":"ppat.1011231.ref012","doi-asserted-by":"crossref","first-page":"1813","DOI":"10.1056\/NEJMoa2007764","article-title":"Remdesivir for the Treatment of Covid-19\u2014Final Report","volume":"383","author":"JH Beigel","year":"2020","journal-title":"N Engl J Med"},{"issue":"396","key":"ppat.1011231.ref013","doi-asserted-by":"crossref","first-page":"eaal3653","DOI":"10.1126\/scitranslmed.aal3653","article-title":"Broad-spectrum antiviral GS-5734 inhibits both epidemic and zoonotic coronaviruses","volume":"9","author":"TP Sheahan","year":"2017","journal-title":"Sci Transl Med"},{"issue":"1","key":"ppat.1011231.ref014","doi-asserted-by":"crossref","first-page":"222","DOI":"10.1038\/s41467-019-13940-6","article-title":"Comparative therapeutic efficacy of remdesivir and combination lopinavir, ritonavir, and interferon beta against MERS-CoV","volume":"11","author":"TP Sheahan","year":"2020","journal-title":"Nat Commun"},{"issue":"2","key":"ppat.1011231.ref015","doi-asserted-by":"crossref","first-page":"e00221","DOI":"10.1128\/mBio.00221-18","article-title":"Coronavirus Susceptibility to the Antiviral Remdesivir (GS-5734) Is Mediated by the Viral Polymerase and the Proofreading Exoribonuclease","volume":"9","author":"ML Agostini","year":"2018","journal-title":"mBio"},{"key":"ppat.1011231.ref016","doi-asserted-by":"crossref","first-page":"104541","DOI":"10.1016\/j.antiviral.2019.104541","article-title":"Broad spectrum antiviral remdesivir inhibits human endemic and zoonotic deltacoronaviruses with a highly divergent RNA dependent RNA polymerase","volume":"169","author":"AJ Brown","year":"2019","journal-title":"Antiviral Res"},{"issue":"20","key":"ppat.1011231.ref017","doi-asserted-by":"crossref","first-page":"6785","DOI":"10.1074\/jbc.RA120.013679","article-title":"Remdesivir is a direct-acting antiviral that inhibits RNA-dependent RNA polymerase from severe acute respiratory syndrome coronavirus 2 with high potency","volume":"295","author":"CJ Gordon","year":"2020","journal-title":"J Biol Chem"},{"issue":"7","key":"ppat.1011231.ref018","doi-asserted-by":"crossref","first-page":"e1762","DOI":"10.1093\/cid\/ciaa1474","article-title":"Emerging RNA-Dependent RNA Polymerase Mutation in a Remdesivir-Treated B-cell Immunodeficient Patient With Protracted Coronavirus Disease 2019","volume":"73","author":"M Martinot","year":"2021","journal-title":"Clin Infect Dis"},{"key":"ppat.1011231.ref019","doi-asserted-by":"crossref","first-page":"1547","DOI":"10.1038\/s41467-022-29104-y","article-title":"De novo emergence of a remdesivir resistance mutation during treatment of persistent SARS-CoV-2 infection in an immunocompromised patient: a case report","volume":"13","author":"S Gandhi","year":"2022","journal-title":"Nature commun"},{"issue":"9","key":"ppat.1011231.ref020","doi-asserted-by":"crossref","first-page":"e1009929","DOI":"10.1371\/journal.ppat.1009929","article-title":"In vitro selection of Remdesivir resistance suggests evolutionary predictability of SARS-CoV-2.","volume":"17","author":"AM Szemiel","year":"2021","journal-title":"PLoS Pathog"},{"issue":"3","key":"ppat.1011231.ref021","doi-asserted-by":"crossref","first-page":"109014","DOI":"10.1016\/j.celrep.2021.109014","article-title":"Establishment of a reverse genetics system for SARS-CoV-2 using circular polymerase extension reaction","volume":"35","author":"S Torii","year":"2021","journal-title":"Cell Rep"},{"issue":"7813","key":"ppat.1011231.ref022","doi-asserted-by":"crossref","first-page":"561","DOI":"10.1038\/s41586-020-2294-9","article-title":"Rapid reconstruction of SARS-CoV-2 using a synthetic genomics platform","volume":"582","author":"TTN Thao","year":"2020","journal-title":"Nature"},{"issue":"5","key":"ppat.1011231.ref023","doi-asserted-by":"crossref","first-page":"841","DOI":"10.1016\/j.chom.2020.04.004","article-title":"An Infectious cDNA Clone of SARS-CoV-2","volume":"27","author":"X Xie","year":"2020","journal-title":"Cell Host Microbe"},{"issue":"7","key":"ppat.1011231.ref024","doi-asserted-by":"crossref","first-page":"1124","DOI":"10.1016\/j.chom.2021.06.006","article-title":"SARS-CoV-2 spike L452R variant evades cellular immunity and increases infectivity","volume":"29","author":"C Motozono","year":"2021","journal-title":"Cell Host Microbe"},{"issue":"7896","key":"ppat.1011231.ref025","doi-asserted-by":"crossref","first-page":"300","DOI":"10.1038\/s41586-021-04266-9","article-title":"Enhanced fusogenicity and pathogenicity of SARS-CoV-2 Delta P681R mutation","volume":"602","author":"A Saito","year":"2022","journal-title":"Nature"},{"key":"ppat.1011231.ref026","doi-asserted-by":"crossref","first-page":"115","DOI":"10.1038\/s43587-022-00170-7","article-title":"SARS-CoV-2 infection triggers paracrine senescence and leads to a sustained senescence-associated inflammatory response","volume":"2","author":"S Tsuji","year":"2022","journal-title":"Nature aging"},{"key":"ppat.1011231.ref027","unstructured":"Nextstrain. Genomic epidemiology of novel coronavirus -Global sampling. Available from: https:\/\/nextstrain.org\/ncov\/gisaid\/global. Accessed 8 December 2022."},{"key":"ppat.1011231.ref028","unstructured":"Network for Genomic Surveillance in South Africa (NGS-SA). SARS-CoV-2 Sequencing Update 26 November 2021. Available from: https:\/\/www.nicd.ac.za\/wp-content\/uploads\/2021\/11\/Update-of-SA-sequencing-data-from-GISAID-26-Nov_Final.pdf."},{"key":"ppat.1011231.ref029","doi-asserted-by":"crossref","first-page":"676","DOI":"10.1038\/s41586-021-04388-0","article-title":"Striking Antibody Evasion Manifested by the Omicron Variant of SARS-CoV-2","volume":"602","author":"L Liu","year":"2022","journal-title":"Nature"},{"issue":"7896","key":"ppat.1011231.ref030","doi-asserted-by":"crossref","first-page":"294","DOI":"10.1038\/s41586-021-04245-0","article-title":"The N501Y spike substitution enhances SARS-CoV-2 infection and transmission","volume":"602","author":"Y Liu","year":"2022","journal-title":"Nature"},{"issue":"7902","key":"ppat.1011231.ref031","doi-asserted-by":"crossref","first-page":"700","DOI":"10.1038\/s41586-022-04462-1","article-title":"Attenuated fusogenicity and pathogenicity of SARS-CoV-2 Omicron variant","volume":"603","author":"R Suzuki","year":"2022","journal-title":"Nature"},{"issue":"1","key":"ppat.1011231.ref032","doi-asserted-by":"crossref","first-page":"44","DOI":"10.1016\/j.chom.2020.11.007","article-title":"Complete Mapping of Mutations to the SARS-CoV-2 Spike Receptor-Binding Domain that Escape Antibody Recognition","volume":"29","author":"AJ Greaney","year":"2021","journal-title":"Cell Host Microbe"},{"issue":"7","key":"ppat.1011231.ref033","doi-asserted-by":"crossref","first-page":"409","DOI":"10.1038\/s41579-021-00573-0","article-title":"SARS-CoV-2 variants, spike mutations and immune escape","volume":"19","author":"WT Harvey","year":"2021","journal-title":"Nat Rev Microbiol"},{"issue":"6593","key":"ppat.1011231.ref034","doi-asserted-by":"crossref","first-page":"eabn4947","DOI":"10.1126\/science.abn4947","article-title":"Increased risk of SARS-CoV-2 reinfection associated with emergence of the Omicron variant in South Africa","volume":"376","author":"JRC Pulliam","year":"2022","journal-title":"Science"},{"key":"ppat.1011231.ref035","unstructured":"UK Health Security Agency. SARS-CoV-2 variants of concern and variants under investigation in England. 2021 December 31. Available from: https:\/\/assets.publishing.service.gov.uk\/government\/uploads\/system\/uploads\/attachment_data\/file\/1045619\/Technical-Briefing-31-Dec-2021-Omicron_severity_update.pdf."},{"issue":"5","key":"ppat.1011231.ref036","doi-asserted-by":"crossref","first-page":"494","DOI":"10.1056\/NEJMc2119270","article-title":"Effectiveness of BNT162b2 Vaccine against Omicron Variant in South Africa","volume":"386","author":"S Collie","year":"2022","journal-title":"N Engl J Med"},{"issue":"11","key":"ppat.1011231.ref037","first-page":"12575","article-title":"Phase 3 trial of coronavir (favipiravir) in patients with mild to moderate COVID-19","volume":"13","author":"TA Ruzhentsova","year":"2021","journal-title":"Am J Transl Res"},{"issue":"6","key":"ppat.1011231.ref038","doi-asserted-by":"crossref","first-page":"509","DOI":"10.1056\/NEJMoa2116044","article-title":"Molnupiravir for Oral Treatment of Covid-19 in Nonhospitalized Patients","volume":"386","author":"AJ Bernal","year":"2022","journal-title":"N Engl J Med"},{"issue":"6575","key":"ppat.1011231.ref039","doi-asserted-by":"crossref","first-page":"1586","DOI":"10.1126\/science.abl4784","article-title":"An oral SARS-CoV-2 Mpro inhibitor clinical candidate for the treatment of COVID-19","volume":"374","author":"DR Owen","year":"2021","journal-title":"Science"},{"issue":"7902","key":"ppat.1011231.ref040","doi-asserted-by":"crossref","first-page":"706","DOI":"10.1038\/s41586-022-04474-x","article-title":"Altered TMPRSS2 usage by SARS-CoV-2 Omicron impacts infectivity and fusogenicity","volume":"603","author":"B Meng","year":"2022","journal-title":"Nature"},{"issue":"12","key":"ppat.1011231.ref041","doi-asserted-by":"crossref","first-page":"2103","DOI":"10.1016\/j.cell.2022.04.035","article-title":"Virological characteristics of the SARS-CoV-2 Omicron BA.2 spike","volume":"185","author":"D Yamasoba","year":"2022","journal-title":"Cell"},{"issue":"17","key":"ppat.1011231.ref042","doi-asserted-by":"crossref","first-page":"i884","DOI":"10.1093\/bioinformatics\/bty560","article-title":"fastp: an ultra-fast all-in-one FASTQ preprocessor","volume":"34","author":"S Chen","year":"2018","journal-title":"Bioinfomatics"},{"issue":"14","key":"ppat.1011231.ref043","doi-asserted-by":"crossref","first-page":"1754","DOI":"10.1093\/bioinformatics\/btp324","article-title":"Fast and accurate short read alignment with Burrows-Wheeler transform","volume":"25","author":"H Li","year":"2009","journal-title":"Bioinfomatics"},{"issue":"16","key":"ppat.1011231.ref044","doi-asserted-by":"crossref","first-page":"2078","DOI":"10.1093\/bioinformatics\/btp352","article-title":"The Sequence Alignment\/Map format and SAMtools","volume":"25","author":"H Li","year":"2009","journal-title":"Bioinfomatics"},{"issue":"2","key":"ppat.1011231.ref045","doi-asserted-by":"crossref","first-page":"80","DOI":"10.4161\/fly.19695","article-title":"A program for annotating and predicting the effects of single nucleotide polymorphisms, SnpEff: SNPs in the genome of Drosophila melanogaster strain w1118; iso-2; iso-3.","volume":"6","author":"P Cingolani","year":"2012","journal-title":"Fly (Austin)."},{"issue":"3","key":"ppat.1011231.ref046","first-page":"493","article-title":"A simple method of estimating fifty-percent endpoints","volume":"27","author":"LJ Reed","year":"1938","journal-title":"Am J Hyg"},{"issue":"6","key":"ppat.1011231.ref047","doi-asserted-by":"crossref","first-page":"1560","DOI":"10.1016\/j.cell.2020.07.033","article-title":"Structural Basis for Helicase-Polymerase Coupling in the SARS-CoV-2 Replication-Transcription Complex.","volume":"182","author":"J Chen","year":"2020","journal-title":"Cell"},{"key":"ppat.1011231.ref048","doi-asserted-by":"crossref","first-page":"1499","DOI":"10.1126\/science.abc1560","article-title":"Structural basis for inhibition of the RNA-dependent RNA polymerase from SARS-CoV-2 by remdesivir","volume":"36","author":"W Yin","year":"2020","journal-title":"Science"},{"key":"ppat.1011231.ref049","author":"University of California"},{"issue":"12","key":"ppat.1011231.ref050","doi-asserted-by":"crossref","first-page":"1049","DOI":"10.1002\/1096-987X(200009)21:12<1049::AID-JCC3>3.0.CO;2-F","article-title":"How well does a restrained electrostatic potential (RESP) model perform in calculating conformational energies of organic and biological molecules","volume":"21","author":"JM Wang","year":"2000","journal-title":"J Comput Chem"},{"issue":"9","key":"ppat.1011231.ref051","doi-asserted-by":"crossref","first-page":"1157","DOI":"10.1002\/jcc.20035","article-title":"Development and testing of a general amber force field","volume":"25","author":"J Wang","year":"2004","journal-title":"J Comput Chem"},{"issue":"2","key":"ppat.1011231.ref052","doi-asserted-by":"crossref","first-page":"926","DOI":"10.1063\/1.445869","article-title":"Comparison of simple potential functions for simulating liquid water","volume":"79","author":"WL Jorgensen","year":"1983","journal-title":"The Journal of Chemical Physics"}],"updated-by":[{"DOI":"10.1371\/journal.ppat.1011231","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2023,4,11]],"date-time":"2023-04-11T00:00:00Z","timestamp":1681171200000}}],"container-title":["PLOS Pathogens"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.ppat.1011231","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,4,11]],"date-time":"2023-04-11T13:31:37Z","timestamp":1681219897000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.ppat.1011231"}},"subtitle":[],"editor":[{"given":"Bart L.","family":"Haagmans","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2023,3,27]]},"references-count":52,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2023,3,27]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.ppat.1011231","relation":{},"ISSN":["1553-7374"],"issn-type":[{"value":"1553-7374","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,3,27]]}}}