{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,25]],"date-time":"2026-08-25T11:24:10Z","timestamp":1787657050023,"version":"build-2736575974"},"reference-count":39,"publisher":"Wiley","issue":"8","license":[{"start":{"date-parts":[[2026,8,6]],"date-time":"2026-08-06T00:00:00Z","timestamp":1785974400000},"content-version":"vor","delay-in-days":5,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2026,8,1]],"date-time":"2026-08-01T00:00:00Z","timestamp":1785542400000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100007300","name":"China Medical University","doi-asserted-by":"publisher","award":["CMU113\u2010ASIA\u201011"],"award-info":[{"award-number":["CMU113\u2010ASIA\u201011"]}],"id":[{"id":"10.13039\/501100007300","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100007300","name":"China Medical University","doi-asserted-by":"publisher","award":["CMU114\u2010ASIA\u201004"],"award-info":[{"award-number":["CMU114\u2010ASIA\u201004"]}],"id":[{"id":"10.13039\/501100007300","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100007300","name":"China Medical University","doi-asserted-by":"publisher","award":["CMU115\u2010ASIA\u201009"],"award-info":[{"award-number":["CMU115\u2010ASIA\u201009"]}],"id":[{"id":"10.13039\/501100007300","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Journal of Medical Virology"],"published-print":{"date-parts":[[2026,8]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    Zika virus (ZIKV) remains a significant global health concern, underscoring the need for effective antiviral agents. In this study, we evaluated the antiviral activity and mechanisms of the HIV protease inhibitors darunavir (DRV), fosamprenavir (FPV), and amprenavir (APV) against ZIKV. DRV and FPV, but not APV, exhibited potent antiviral activity in BHK\u201021 and TE\u2010671 cells, as demonstrated by reduced cytopathic effects and decreased viral protein expression. Both compounds inhibited ZIKV infectivity and viral yield with submicromolar EC\n                    <jats:sub>50<\/jats:sub>\n                    values. Mechanistic analyses using time\u2010of\u2010addition and temperature\u2010shift assays revealed that DRV and FPV act at multiple stages of the viral life cycle, including attachment, entry, and post\u2010entry processes. Molecular docking and mutagenesis studies identified the \u03b2\u2010octyl glucoside (\u03b2\u2010OG) binding pocket within domain II of the ZIKV envelope (E) protein as a critical target, with Lys209 and Asp278 serving as key interaction residues. Disruption of these residues significantly reduced compound efficacy, confirming their functional importance in viral attachment inhibition. In addition, both DRV and FPV directly inhibited ZIKV NS2B\u2013NS3 protease activity, with NS2B Asp83 identified as a key determinant for drug binding. In contrast, neither compound significantly affected NS5 RNA\u2010dependent RNA polymerase activity. In a suckling mouse model, both DRV and FPV reduced viral loads in brain tissues in a dose\u2010dependent manner, with DRV showing superior efficacy at lower doses. Collectively, these findings demonstrate that DRV and FPV exert potent anti\u2010ZIKV activity through dual targeting of viral entry and protease function, highlighting their potential as repurposed therapeutics for ZIKV infection.\n                  <\/jats:p>","DOI":"10.1002\/jmv.71092","type":"journal-article","created":{"date-parts":[[2026,8,6]],"date-time":"2026-08-06T08:02:42Z","timestamp":1786003362000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Darunavir and Fosamprenavir Inhibit Zika Virus Replication via Dual Targeting of the Envelope Protein and NS2B\u2013NS3 Protease"],"prefix":"10.1002","volume":"98","author":[{"given":"Ju\u2010Ying","family":"Kan","sequence":"first","affiliation":[{"name":"The Ph.D. Program of Biotechnology and Biomedical Industry, China Medical University  Taichung Taiwan"},{"name":"Department of Medical Laboratory Science and Biotechnology China Medical University  Taichung 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Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shih\u2010Wen","family":"Chiu","sequence":"additional","affiliation":[{"name":"Institute of Bioinformatics and Systems Biology, National Yang Ming Chiao Tung University Hsinchu City Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Po\u2010Chen","family":"Wu","sequence":"additional","affiliation":[{"name":"Institute of Bioinformatics and Systems Biology, National Yang Ming Chiao Tung University Hsinchu City Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Po\u2010Ren","family":"Hsueh","sequence":"additional","affiliation":[{"name":"Division of Infectious Diseases, Department of Internal Medicine China Medical University Hospital, China Medical University  Taichung Taiwan"},{"name":"Department of Laboratory Medicine China Medical University Hospital, China Medical University  Taichung Taiwan"},{"name":"School of Medicine, China Medical University  Taichung 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