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To rapidly identify potential treatments, we aimed to screen an FDA\u2010approved drug library for inhibitors of CHIKV infection. Tirbanibulin, a dual\u2010microtubule polymerization and Src kinase inhibitor, was assessed for its potential anti\u2010CHIKV activity.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      We performed a high\u2010throughput screen of an FDA\u2010approved drug library. Mechanism\u2010of\u2010action studies included entry\u2010step analysis, surface plasmon resonance (SPR) binding assays and molecular docking.\n                      <jats:italic>In vivo<\/jats:italic>\n                      efficacy was evaluated in lethal murine neuroinfection and CHIKV\u2010induced arthritis models following oral administration of the candidate compound.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Experimental approach<\/jats:title>\n                    <jats:p>\n                      Tirbanibulin exhibited nanomolar to low\u2010micromolar antiviral activity (EC\n                      <jats:sub>50<\/jats:sub>\n                      range: 0.035\u201375.64\u2009\u03bcM) across multiple cell lines, with high selective indices in key target HT22 and Huh7 cells. It acted at a post\u2010attachment entry step, inhibiting clathrin\u2010mediated endocytosis and potentially viral fusion. Surface plasmon resonance confirmed direct, high\u2010affinity binding to the CHIKV E1 and E2 glycoprotein complex (K_D\u2009=\u200973\u2009nM). In the lethal neuroinfection model, oral tirbanibulin significantly improved survival and reduced brain viral loads; in the arthritis model, it markedly attenuated footpad swelling and inflammatory pathology.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion and implications<\/jats:title>\n                    <jats:p>Tirbanibulin is a novel, orally bioavailable entry\u2010stage inhibitor that directly targets the E2 glycoprotein. Multiple preclinical and clinical studies have confirmed its favourable oral bioavailability and safety. Given its established clinical safety profile, it represents a promising repurposing candidate for clinical evaluation against Chikungunya fever.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1111\/bph.70642","type":"journal-article","created":{"date-parts":[[2026,8,10]],"date-time":"2026-08-10T00:00:52Z","timestamp":1786320052000},"page":"6519-6533","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Repurposing tirbanibulin as an orally active E2\u2010targeting entry inhibitor against Chikungunya virus"],"prefix":"10.1111","volume":"183","author":[{"ORCID":"https:\/\/orcid.org\/0009-0000-5998-3329","authenticated-orcid":false,"given":"Jing\u2010wen","family":"Gu","sequence":"first","affiliation":[{"name":"Department of Radiation Medicine, Faculty of Naval Medicine Naval Medical University  Shanghai 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