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Clinical treatment of RSV or influenza A virus (IAV) is limited and may be postponed because of misdiagnosis or coinfection with multiple pathogens. Here, we described VV251, the prodrug of 4\u2032-fluorouridine, a novel oral nucleoside analog that exhibits potent inhibitory activity against RSV laboratory strains and clinical isolates, as well as IAV,\n                      <jats:italic toggle=\"yes\">in vitro<\/jats:italic>\n                      . The EC\n                      <jats:sub>50<\/jats:sub>\n                      values of VV251 against these viruses ranged from nanomolar to low micromolar. Moreover, VV251 significantly reduced the viral titer of RSV A2 or IAV PR8 in a BALB\/c infection model. Importantly, we further established a simultaneous RSV\/IAV coinfection model to investigate the antiviral activity of VV251. Oral administration of VV251 once daily significantly inhibited viral replication and decreased the mortality of RSV\/IAV-coinfected mice. Our findings establish VV251 as a broad-spectrum drug candidate for the treatment of RSV, IAV, and RSV\/IAV coinfection.\n                    <\/jats:p>\n                    <jats:sec>\n                      <jats:title>IMPORTANCE<\/jats:title>\n                      <jats:p>Respiratory syncytial virus (RSV) and influenza virus are the two predominant causative agents of acute respiratory tract infections, leading to a substantial number of hospitalizations and thousands of deaths annually. The cost of treating disease caused by infection with RSV and influenza viruses is a huge financial burden on the world. We have identified a nucleotide analog with favorable pharmacokinetic properties and antiviral activity against RSV and influenza A virus (IAV) during mono- or coinfection in a mouse model. This compound has the potential to be used for the treatment of RSV, IAV, and RAV\/IAV coinfection.<\/jats:p>\n                    <\/jats:sec>\n                  <\/jats:sec>","DOI":"10.1128\/jvi.00006-26","type":"journal-article","created":{"date-parts":[[2026,4,21]],"date-time":"2026-04-21T13:00:39Z","timestamp":1776776439000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":0,"title":["The oral nucleoside analogue inhibitor VV251 effectively inhibits coinfection by respiratory syncytial virus and influenza A virus"],"prefix":"10.1128","volume":"100","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2518-6185","authenticated-orcid":false,"given":"Ruxue","family":"Zhang","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/01jxjav08","id-type":"ROR","asserted-by":"publisher"}],"name":"State Key Laboratory of Virology, Wuhan Institute of Virology, Chinese Academy of Sciences, Center for Biosafety 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