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With no specific antiviral therapies available, these outbreaks pose a major public health challenge, particularly in tropical regions. There is thus urgent need to develop novel antivirals. Drug repurposing is an attractive strategy to identify potential antivirals targeting CHIKV replication.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>The Spectrum collection of approved drugs was screened using high-content cell imaging to identify potential CHIKV replication inhibitors. Efficacy of these CHIKV inhibitors was evaluated in a C57BL\/6 mouse model of chikungunya disease, monitoring viremia and clinical symptoms like joint swelling. The CHIKV inhibitor's effect on virus uptake, replication, RNA synthesis, and protein production was studied in ERMS cells. In silico molecular docking was used to study the inhibitor\u2019s binding to the CHIKV proteins. Binding was validated in vitro using microscale thermophoresis and isothermal titration calorimetry. CHIKV helicase, protease, and ATPase activities were measured in the presence of emetine dihydrochloride (ED) to determine its mechanism of action.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Out of the four CHIKV inhibitors identified by high content screening, ED potently inhibited CHIKV replication in the mouse model, yielding significantly lower viremia levels. Notably, CHIKV-infected mice treated with ED showed no clinical symptoms of joint swelling. In ERMS cells, ED blocked CHIKV uptake and early replication by suppressing viral RNA synthesis, which in turn prevented viral protein production. Computational modelling predicted ED\u2019s binding around the RNA-binding site of the CHIKV nsP2 helicase domain. In vitro validation confirmed dose-dependent ED binding with CHIKV nsP2. ED specifically inhibited helicase unwinding in a concentration-dependent manner without affecting ATPase or protease activity.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>This study demonstrates that ED inhibits CHIKV replication in cultured cells and a mouse model of infection through binding to CHIKV nsP2 and inhibition of its helicase activity. While this is a promising virus-targeted mechanism of ED\u2019s antiviral action, additional host-directed mechanisms warrant further investigation.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1186\/s12929-026-01280-9","type":"journal-article","created":{"date-parts":[[2026,7,20]],"date-time":"2026-07-20T15:05:22Z","timestamp":1784559922000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Emetine dihydrochloride inhibits Chikungunya virus nsP2 helicase and shows robust antiviral activity in cells and mice"],"prefix":"10.1186","volume":"33","author":[{"given":"Anshula","family":"Sharma","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chandru","family":"Subramani","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"K. 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