{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,15]],"date-time":"2026-10-15T03:43:21Z","timestamp":1792035801745,"version":"4.4.0"},"reference-count":48,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2026,2,18]],"date-time":"2026-02-18T00:00:00Z","timestamp":1771372800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Gilead Sciences, Inc."},{"name":"Alberta Ministry of Technology and Innovation"},{"name":"National Institute of Allergy and Infectious Diseases of the National Institutes of Health","award":["U19AI171292"],"award-info":[{"award-number":["U19AI171292"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Viruses"],"abstract":"<jats:p>Flaviviruses are arthropod-borne RNA viruses associated with significant human diseases globally. There are no effective direct-acting antivirals approved to treat these viral infections. Given its critical role in viral replication, the RNA-dependent RNA polymerase (RdRp) is a logical target for antiviral drug development. Remdesivir (formerly GS-5734), a 1\u2032-cyano modified C-adenosine monophosphate prodrug, was the first US Food and Drug Administration (FDA) approved antiviral for coronavirus disease 2019 (COVID-19) and was also shown to inhibit flavivirus replication. GS-7682, a 4\u2032-cyano modified C-adenosine prodrug, exhibits a broad-spectrum antiviral activity. Here, we determined the anti-flavivirus potency of both remdesivir and GS-7682 and characterized their active triphosphate forms, GS-443902 and GS-646939, respectively, against a panel of purified flavivirus RdRps. These include dengue, Japanese encephalitis, West Nile, yellow fever, and Zika. Enzyme kinetics demonstrate efficient RNA incorporation of GS-443902 and GS-646939. GS-646939 acts as an immediate chain terminator. Conversely, GS-443902 acts through a template-dependent inhibition mechanism by impeding the incorporation of the complementary UTP. Both mechanisms correlate with anti-flavivirus activity, although remdesivir is generally superior. The data demonstrate that immediate chain termination is not necessarily a preferred mechanism of action of nucleotide analogs. Template-dependent inhibition should also be considered, especially for viruses lacking intrinsic proofreading activities.<\/jats:p>","DOI":"10.3390\/v18020257","type":"journal-article","created":{"date-parts":[[2026,2,18]],"date-time":"2026-02-18T11:45:58Z","timestamp":1771415158000},"page":"257","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["1\u2032- and 4\u2032-Cyano Modified Adenosine Analogs Against Prototypic Flavivirus RNA-Dependent RNA Polymerases"],"prefix":"10.3390","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0009-0000-7231-0663","authenticated-orcid":false,"given":"Simon M.","family":"Walker","sequence":"first","affiliation":[{"name":"Department of Medical Microbiology and Immunology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB T6G 2E1, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8259-6201","authenticated-orcid":false,"given":"Calvin J.","family":"Gordon","sequence":"additional","affiliation":[{"name":"Department of Medical Microbiology and Immunology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB T6G 2E1, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1698-2961","authenticated-orcid":false,"given":"Egor P.","family":"Tchesnokov","sequence":"additional","affiliation":[{"name":"Department of Medical Microbiology and Immunology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB T6G 2E1, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4889-4624","authenticated-orcid":false,"given":"Long","family":"Sun","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX 77555, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing","family":"Zou","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX 77555, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0918-016X","authenticated-orcid":false,"given":"Xuping","family":"Xie","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX 77555, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-5445-0515","authenticated-orcid":false,"given":"Nicholas C.","family":"Riola","sequence":"additional","affiliation":[{"name":"Gilead Sciences, Inc., Foster City, CA 94404, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vincent","family":"Cutillas","sequence":"additional","affiliation":[{"name":"Gilead Sciences, Inc., Foster City, CA 94404, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Venice","family":"Du Pont","sequence":"additional","affiliation":[{"name":"Gilead Sciences, Inc., Foster City, CA 94404, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaofeng","family":"Zhao","sequence":"additional","affiliation":[{"name":"Gilead Sciences, Inc., Foster City, CA 94404, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ting","family":"Wang","sequence":"additional","affiliation":[{"name":"Gilead Sciences, Inc., Foster City, CA 94404, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4080-4321","authenticated-orcid":false,"given":"Jared","family":"Pitts","sequence":"additional","affiliation":[{"name":"Gilead Sciences, Inc., Foster City, CA 94404, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-1365-0287","authenticated-orcid":false,"given":"Dustin S.","family":"Siegel","sequence":"additional","affiliation":[{"name":"Gilead Sciences, Inc., Foster City, CA 94404, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jason K.","family":"Perry","sequence":"additional","affiliation":[{"name":"Gilead Sciences, Inc., Foster City, CA 94404, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joy Y.","family":"Feng","sequence":"additional","affiliation":[{"name":"Gilead Sciences, Inc., Foster City, CA 94404, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4327-1727","authenticated-orcid":false,"given":"John P.","family":"Bilello","sequence":"additional","affiliation":[{"name":"Gilead Sciences, Inc., Foster City, CA 94404, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthias","family":"G\u00f6tte","sequence":"additional","affiliation":[{"name":"Department of Medical Microbiology and Immunology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB T6G 2E1, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,2,18]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Zhao, R., Wang, M., Cao, J., Shen, J., Zhou, X., Wang, D., and Cao, J. (2021). Flavivirus: From Structure to Therapeutics Development. Life, 11.","DOI":"10.3390\/life11070615"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"796","DOI":"10.1038\/s41564-020-0714-0","article-title":"The continued threat of emerging flaviviruses","volume":"5","author":"Pierson","year":"2020","journal-title":"Nat. Microbiol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"504","DOI":"10.1038\/nature12060","article-title":"The global distribution and burden of dengue","volume":"496","author":"Bhatt","year":"2013","journal-title":"Nature"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1895644","DOI":"10.1080\/21645515.2021.1895644","article-title":"Re-thinking yellow fever vaccines: Fighting old foes with new generation vaccines","volume":"18","author":"Rollier","year":"2022","journal-title":"Hum. Vaccines Immunother."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"237","DOI":"10.1016\/j.cll.2010.01.001","article-title":"Yellow fever: A reemerging threat","volume":"30","author":"Gardner","year":"2010","journal-title":"Clin. Lab. Med."},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Shukla, R., Ramasamy, V., Shanmugam, R.K., Ahuja, R., and Khanna, N. (2020). Antibody-Dependent Enhancement: A Challenge for Developing a Safe Dengue Vaccine. Front. Cell Infect. Microbiol., 10.","DOI":"10.3389\/fcimb.2020.572681"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"447","DOI":"10.1038\/nrd4010","article-title":"Advances in the development of nucleoside and nucleotide analogues for cancer and viral diseases","volume":"12","author":"Jordheim","year":"2013","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"6851","DOI":"10.3390\/cimb45080433","article-title":"Recent Advances in Molecular Mechanisms of Nucleoside Antivirals","volume":"45","author":"Kamzeeva","year":"2023","journal-title":"Curr. Issues Mol. Biol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"66","DOI":"10.1016\/j.antiviral.2018.04.004","article-title":"The evolution of nucleoside analogue antivirals: A review for chemists and non-chemists. Part 1: Early structural modifications to the nucleoside scaffold","volume":"154","author":"Yates","year":"2018","journal-title":"Antivir. Res."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1016\/j.antiviral.2014.02.006","article-title":"Polymerases of hepatitis C viruses and flaviviruses: Structural and mechanistic insights and drug development","volume":"105","author":"Lim","year":"2014","journal-title":"Antivir. Res."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"104536","DOI":"10.1016\/j.antiviral.2019.104536","article-title":"Structure of the yellow fever NS5 protein reveals conserved drug targets shared among flaviviruses","volume":"169","author":"Dubankova","year":"2019","journal-title":"Antivir. Res."},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"de Freitas, C.S., Higa, L.M., Sacramento, C.Q., Ferreira, A.C., Reis, P.A., Delvecchio, R., Monteiro, F.L., Barbosa-Lima, G., James Westgarth, H., and Vieira, Y.R. (2019). Yellow fever virus is susceptible to sofosbuvir both in vitro and in vivo. PLoS Negl. Trop. Dis., 13.","DOI":"10.1371\/journal.pntd.0007072"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"134","DOI":"10.1016\/j.antiviral.2016.11.023","article-title":"The FDA-approved drug sofosbuvir inhibits Zika virus infection","volume":"137","author":"Govero","year":"2017","journal-title":"Antivir. Res."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"6345","DOI":"10.1038\/s41598-017-06612-2","article-title":"Evaluation of Sofosbuvir (beta-D-2\u2032-deoxy-2\u2032-alpha-fluoro-2\u2032-beta-C-methyluridine) as an inhibitor of Dengue virus replication","volume":"7","author":"Xu","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"104708","DOI":"10.1016\/j.antiviral.2020.104708","article-title":"Evaluation of sofosbuvir activity and resistance profile against West Nile virus in vitro","volume":"175","author":"Dragoni","year":"2020","journal-title":"Antivir. Res."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"20435","DOI":"10.1073\/pnas.0907010106","article-title":"An adenosine nucleoside inhibitor of dengue virus","volume":"106","author":"Yin","year":"2009","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"113852","DOI":"10.1016\/j.ejmech.2021.113852","article-title":"Design, synthesis and evaluation of 2\u2032-acetylene-7-deaza-adenosine phosphoamidate derivatives as anti-EV71 and anti-EV-D68 agents","volume":"226","author":"Yan","year":"2021","journal-title":"Eur. J. Med. Chem."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"2040206618761299","DOI":"10.1177\/2040206618761299","article-title":"Nucleoside analogs as a rich source of antiviral agents active against arthropod-borne flaviviruses","volume":"26","author":"Eyer","year":"2018","journal-title":"Antivir. Chem. Chemother."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1648","DOI":"10.1021\/acs.jmedchem.6b01594","article-title":"Discovery and Synthesis of a Phosphoramidate Prodrug of a Pyrrolo [2,1-f][triazin-4-amino] Adenine C-Nucleoside (GS-5734) for the Treatment of Ebola and Emerging Viruses","volume":"60","author":"Siegel","year":"2017","journal-title":"J. Med. Chem."},{"key":"ref_20","unstructured":"(2025, December 04). U.S. Food and Drug Administration Approves Gilead\u2019s Antiviral Veklury\u00ae (Remdesivir) for Treatment of COVID-19. Available online: https:\/\/www.gilead.com\/news\/news-details\/2020\/us-food-and-drug-administration-approves-gileads-antiviral-veklury-remdesivir-for-treatment-of-covid-19."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"5001","DOI":"10.1021\/acs.jmedchem.1c00071","article-title":"Prodrugs of a 1\u2032-CN-4-Aza-7,9-dideazaadenosine C-Nucleoside Leading to the Discovery of Remdesivir (GS-5734) as a Potent Inhibitor of Respiratory Syncytial Virus with Efficacy in the African Green Monkey Model of RSV","volume":"64","author":"Mackman","year":"2021","journal-title":"J. Med. Chem."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"43395","DOI":"10.1038\/srep43395","article-title":"GS-5734 and its parent nucleoside analog inhibit Filo-, Pneumo-, and Paramyxoviruses","volume":"7","author":"Lo","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"381","DOI":"10.1038\/nature17180","article-title":"Therapeutic efficacy of the small molecule GS-5734 against Ebola virus in rhesus monkeys","volume":"531","author":"Warren","year":"2016","journal-title":"Nature"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"e00221-18","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":"Agostini","year":"2018","journal-title":"mBio"},{"key":"ref_25","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":"Sheahan","year":"2017","journal-title":"Sci. Transl. Med."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"3131","DOI":"10.1038\/s41598-023-29517-9","article-title":"Expanded profiling of Remdesivir as a broad-spectrum antiviral and low potential for interaction with other medications in vitro","volume":"13","author":"Radoshitzky","year":"2023","journal-title":"Sci. Rep."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"4773","DOI":"10.1074\/jbc.AC120.013056","article-title":"The antiviral compound remdesivir potently inhibits RNA-dependent RNA polymerase from Middle East respiratory syndrome coronavirus","volume":"295","author":"Gordon","year":"2020","journal-title":"J. Biol. Chem."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"101849","DOI":"10.1016\/j.isci.2020.101849","article-title":"Remdesivir Is Effective in Combating COVID-19 because It Is a Better Substrate than ATP for the Viral RNA-Dependent RNA Polymerase","volume":"23","author":"Dangerfield","year":"2020","journal-title":"iScience"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"16156","DOI":"10.1074\/jbc.AC120.015720","article-title":"Template-dependent inhibition of coronavirus RNA-dependent RNA polymerase by remdesivir reveals a second mechanism of action","volume":"295","author":"Tchesnokov","year":"2020","journal-title":"J. Biol. Chem."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"279","DOI":"10.1038\/s41467-020-20542-0","article-title":"Mechanism of SARS-CoV-2 polymerase stalling by remdesivir","volume":"12","author":"Kokic","year":"2021","journal-title":"Nat. Commun."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"109882","DOI":"10.1016\/j.celrep.2021.109882","article-title":"Remdesivir overcomes the S861 roadblock in SARS-CoV-2 polymerase elongation complex","volume":"37","author":"Wu","year":"2021","journal-title":"Cell Rep."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"101529","DOI":"10.1016\/j.jbc.2021.101529","article-title":"Efficient incorporation and template-dependent polymerase inhibition are major determinants for the broad-spectrum antiviral activity of remdesivir","volume":"298","author":"Gordon","year":"2022","journal-title":"J. Biol. Chem."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"104899","DOI":"10.1016\/j.antiviral.2020.104899","article-title":"Remdesivir triphosphate can efficiently inhibit the RNA-dependent RNA polymerase from various flaviviruses","volume":"182","author":"Konkolova","year":"2020","journal-title":"Antivir. Res."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1442","DOI":"10.1093\/infdis\/jis470","article-title":"A randomized, double-blind placebo controlled trial of balapiravir, a polymerase inhibitor, in adult dengue patients","volume":"207","author":"Nguyen","year":"2013","journal-title":"J. Infect. Dis."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"12945","DOI":"10.1021\/acs.jmedchem.4c00899","article-title":"Discovery of GS-7682, a Novel 4\u2032-Cyano-Modified C-Nucleoside Prodrug with Broad Activity against Pneumo- and Picornaviruses and Efficacy in RSV-Infected African Green Monkeys","volume":"67","author":"Siegel","year":"2024","journal-title":"J. Med. Chem."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"107514","DOI":"10.1016\/j.jbc.2024.107514","article-title":"Mechanism and spectrum of inhibition of a 4 -cyano modified nucleotide analog against diverse RNA polymerases of prototypic respiratory RNA viruses","volume":"300","author":"Gordon","year":"2024","journal-title":"J. Biol. Chem."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"2256","DOI":"10.1080\/22221751.2020.1829994","article-title":"Identifying optimal capsid duplication length for the stability of reporter flaviviruses","volume":"9","author":"Baker","year":"2020","journal-title":"Emerg. Microbes Infect."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1528","DOI":"10.1021\/acsinfecdis.5c00086","article-title":"Mechanism of Inhibition of the Active Triphosphate Form of 2\u2032-alpha-Fluoro,2\u2032-beta-bromouridine against Yellow Fever Virus RNA-Dependent RNA Polymerase","volume":"11","author":"Gordon","year":"2025","journal-title":"ACS Infect. Dis."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1583","DOI":"10.1038\/nbt1036","article-title":"Baculovirus expression system for heterologous multiprotein complexes","volume":"22","author":"Berger","year":"2004","journal-title":"Nat. Biotechnol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"5.20.1","DOI":"10.1002\/0471140864.ps0520s51","article-title":"MultiBac: Multigene baculovirus-based eukaryotic protein complex production","volume":"51","author":"Bieniossek","year":"2008","journal-title":"Curr. Protoc. Protein Sci."},{"key":"ref_41","doi-asserted-by":"crossref","unstructured":"Tchesnokov, E.P., Feng, J.Y., Porter, D.P., and Gotte, M. (2019). Mechanism of Inhibition of Ebola Virus RNA-Dependent RNA Polymerase by Remdesivir. Viruses, 11.","DOI":"10.3390\/v11040326"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"3636","DOI":"10.1128\/AAC.02666-14","article-title":"Efficiency of incorporation and chain termination determines the inhibition potency of 2\u2032-modified nucleotide analogs against hepatitis C virus polymerase","volume":"58","author":"Fung","year":"2014","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_43","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":"Gordon","year":"2020","journal-title":"J. Biol. Chem."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"5397","DOI":"10.1038\/s41598-019-41998-1","article-title":"Development of a fluorescence-based method for the rapid determination of Zika virus polymerase activity and the screening of antiviral drugs","volume":"9","author":"Arias","year":"2019","journal-title":"Sci. Rep."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"1127","DOI":"10.1007\/s40265-014-0247-z","article-title":"Sofosbuvir: A review of its use in patients with chronic hepatitis C","volume":"74","author":"Keating","year":"2014","journal-title":"Drugs"},{"key":"ref_46","unstructured":"Gilead Sciences Inc (2025, December 04). Sovaldi\u2122 (Sofosbuvir) Tablets, for Oral Use: US Prescribing Information. Available online: https:\/\/www.gilead.com\/-\/media\/files\/pdfs\/medicines\/liver-disease\/sovaldi\/sovaldi_patient_pi.pdf."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"2920","DOI":"10.1128\/AAC.00186-07","article-title":"Pyrophosphorolytic excision of nonobligate chain terminators by hepatitis C virus NS5B polymerase","volume":"51","author":"Deval","year":"2007","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"E348","DOI":"10.1073\/pnas.1214924110","article-title":"NTP-mediated nucleotide excision activity of hepatitis C virus RNA-dependent RNA polymerase","volume":"110","author":"Jin","year":"2013","journal-title":"Proc. Natl. Acad. Sci. USA"}],"container-title":["Viruses"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1999-4915\/18\/2\/257\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,2,20]],"date-time":"2026-02-20T05:12:39Z","timestamp":1771564359000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1999-4915\/18\/2\/257"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,2,18]]},"references-count":48,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2026,2]]}},"alternative-id":["v18020257"],"URL":"https:\/\/doi.org\/10.3390\/v18020257","relation":{},"ISSN":["1999-4915"],"issn-type":[{"value":"1999-4915","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,2,18]]}}}