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The frequent epidemics of CHIKV across the world pose a significant public health burden necessitating the development of effective antiviral therapeutics. A cellular imaging-based high-content screening of natural compounds identified withaferin A (WFA), a steroidal lactone isolated from the plant <jats:italic>Withania somnifera<\/jats:italic>, as a potent antiviral against CHIKV. In the ERMS cells, WFA inhibited CHIKV replication early during the life cycle by binding the CHIKV non-structural protein nsP2 and inhibiting its protease activity. This inhibited the viral polyprotein processing and the minus-sense viral RNA synthesis. WFA mounted the nsP2 protease inhibitory activity through its oxidising property as the reducing agents N-acetylcysteine and Glutathione-monoethyl ester effectively reversed the WFA-mediated protease inhibition <jats:italic>in vitro<\/jats:italic> and abolished the WFA-mediated antiviral activity in cultured cells. WFA inhibited CHIKV replication in the C57BL\/6 mouse model of chikungunya disease, resulting in significantly lower viremia. Importantly, CHIKV-infected mice showed significant joint swelling which was not seen in WFA-treated mice. These data demonstrate the potential of WFA as a novel CHIKV antiviral.<\/jats:p>","DOI":"10.1371\/journal.ppat.1012816","type":"journal-article","created":{"date-parts":[[2024,12,30]],"date-time":"2024-12-30T18:50:01Z","timestamp":1735584601000},"page":"e1012816","update-policy":"https:\/\/doi.org\/10.1371\/journal.ppat.corrections_policy","source":"Crossref","is-referenced-by-count":22,"title":["Withaferin A inhibits Chikungunya virus nsP2 protease and shows antiviral activity in the cell culture and mouse model of virus infection"],"prefix":"10.1371","volume":"20","author":[{"given":"Kiran Bala","family":"Sharma","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chandru","family":"Subramani","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Khashpatika","family":"Ganesh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anshula","family":"Sharma","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brohmomoy","family":"Basu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shivani","family":"Balyan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ghanshyam","family":"Sharma","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shouri","family":"KA","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arundhati","family":"Deb","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mitul","family":"Srivastava","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Saurabh","family":"Chugh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sapna","family":"Sehrawat","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kanchan","family":"Bharadwaj","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Archana","family":"Rout","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pankaj Kumar","family":"Sahoo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Suman","family":"Saurav","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rajender K.","family":"Motiani","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ramandeep","family":"Singh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Deepti","family":"Jain","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shailendra","family":"Asthana","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Renu","family":"Wadhwa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9984-3897","authenticated-orcid":true,"given":"Sudhanshu","family":"Vrati","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2024,12,30]]},"reference":[{"key":"ppat.1012816.ref001","doi-asserted-by":"crossref","first-page":"313","DOI":"10.1146\/annurev-ento-011019-025207","article-title":"Chikungunya Virus: Role of Vectors in Emergence from Enzootic Cycles","volume":"65","author":"SC Weaver","year":"2020","journal-title":"Annu Rev Entomol"},{"key":"ppat.1012816.ref002","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1038\/s41572-023-00429-2","article-title":"Chikungunya fever.","volume":"9","author":"K Bartholomeeusen","year":"2023","journal-title":"Nat Rev Dis Primers"},{"key":"ppat.1012816.ref003","article-title":"Epidemic Alphaviruses: Ecology, Emergence and Outbreaks.","volume":"8","author":"SR Azar","year":"2020","journal-title":"Microorganisms"},{"key":"ppat.1012816.ref004","doi-asserted-by":"crossref","DOI":"10.3390\/v14050969","article-title":"A Review on Chikungunya Virus Epidemiology, Pathogenesis and Current Vaccine Development.","volume":"14","author":"TYV de Lima Cavalcanti","year":"2022","journal-title":"Viruses"},{"key":"ppat.1012816.ref005","unstructured":"ECDC. 2023. 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