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Currently, no effective drugs or multivalent vaccines are available. Pterostilbene (Pte), a naturally occurring compound found in blueberries and other plants, is a type of stilbene with a similar structure to resveratrol. Pterostilbene exerts antioxidant, anti\u2010inflammatory, and anticancer properties. However, few studies have explored its antiviral activity. This study aimed to investigate the anti\u2010enteroviral effect and mechanisms of Pte against EV\u2010A71 and EV\u2010D68. Cytotoxicity and antiviral assays were performed to assess the safety of Pte to cells and its antiviral effects against enteroviruses. Viral attachment, inactivation assays, cellular receptor binding, western blotting, time\u2010of\u2010addition and time\u2010of\u2010removal assays, particle stability thermal release assay, and molecular docking were performed to elucidate the antiviral mechanisms of Pte. Additionally, we validated the antiviral effects of Pte using in\u00a0vivo experiments. Among the stilbenes examined, Pte exerted a broad\u2010spectrum inhibitory effect on various enteroviruses, including EV\u2010A71, EV\u2010D68, and coxsackieviruses at 40\u2009\u03bcM, without cytotoxicity. Mechanistically, Pte significantly inhibited enteroviral attachment, inactivated viral particles, blocked viral binding to its receptors, and increased virion stability. Molecular docking analysis revealed that Pte occupied a hydrophobic pocket in viral protein 1, indicating a strong binding affinity and acting as an efficient inhibitor. Notably, sequence alignment of multiple enteroviruses indicated that the Pte\u2010interacting residues in VP1 were highly conserved. In\u00a0vivo studies demonstrated that oral administration of Pte significantly alleviated infection symptoms and reduced mortality in hSCARB2 transgenic mice. Pte possesses potential application as a broad\u2010efficacy antiviral drug against enteroviral infections.<\/jats:p>","DOI":"10.1002\/ptr.8496","type":"journal-article","created":{"date-parts":[[2025,4,16]],"date-time":"2025-04-16T04:54:58Z","timestamp":1744779298000},"page":"2672-2688","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Pterostilbene Exhibits Broad\u2010Spectrum Antiviral Activity by Targeting the Enterovirus Capsid, Inactivating Viral Particles, Blocking Viral Binding, and Protecting Mice From Lethal <scp>EV<\/scp>\u2010<scp>A71<\/scp> Challenge"],"prefix":"10.1002","volume":"39","author":[{"given":"Kuan\u2010Ting","family":"Chuang","sequence":"first","affiliation":[{"name":"Department of Medical Research National Taiwan University Hospital  Taipei Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Siao\u2010Cian","family":"Pan","sequence":"additional","affiliation":[{"name":"Department of Medical Research National Taiwan University Hospital  Taipei Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bor\u2010Luen","family":"Chiang","sequence":"additional","affiliation":[{"name":"Department of Medical Research National Taiwan University Hospital  Taipei Taiwan"},{"name":"Department of Pediatrics National Taiwan University Hospital  Taipei Taiwan"},{"name":"Graduate Institute of Immunology College of Medicine  Taipei Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shih\u2010Hsun","family":"Chen","sequence":"additional","affiliation":[{"name":"Institute of Biochemical Sciences National Taiwan University  Taipei 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Taipei Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing\u2010Yi","family":"Lin","sequence":"additional","affiliation":[{"name":"Department of Clinical Laboratory Sciences and Medical Biotechnology College of Medicine, National Taiwan University  Taipei Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6287-3646","authenticated-orcid":false,"given":"Yu\u2010Li","family":"Lin","sequence":"additional","affiliation":[{"name":"Department of Medical Research National Taiwan University Hospital  Taipei 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