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The time\u2010of\u2010addition and virus step\u2010specific assays indicated that hesperetin reduces the levels of viral DNA, mRNA, and proteins in the target cells. Further, by immunoprecipitation (IP) of the viral RNA from BPXV\u2010infected Vero cells and a cell\u2010free RNA\u2010IP assay, we demonstrated that hesperetin\u2010induced reduction in BPXV protein synthesis is also consistent with diminished interaction between eukaryotic translation initiation factor eIF4E and the 5\u2032 cap of viral mRNA. Molecular docking and MD simulation studies were also consistent with the binding of hesperetin to the cap\u2010binding pocket of eIF4E, adopting a conformation similar to m7GTP binding. Furthermore, in a BPXV egg infection model, hesperetin was shown to suppress the development of pock lesions on the chorioallantoic membrane and associated mortality in the chicken embryos. Most importantly, long\u2010term culture of BPXV in the presence of hesperetin did not induce the generation of drug\u2010resistant viral mutants. In conclusion, we, for the first time, demonstrated the antiviral activity of hesperetin against multiple poxviruses, besides providing some insights into its potential mechanisms of action.<\/jats:p>","DOI":"10.1002\/jmv.29555","type":"journal-article","created":{"date-parts":[[2024,3,28]],"date-time":"2024-03-28T11:40:41Z","timestamp":1711626041000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["Hesperetin blocks poxvirus replication with a low tendency to select for drug\u2010resistant viral variants"],"prefix":"10.1002","volume":"96","author":[{"given":"Assim","family":"Verma","sequence":"first","affiliation":[{"name":"National Centre for Veterinary Type Cultures ICAR\u2010National Research Centre on Equines Hisar India"},{"name":"Department of Bio and Nano Technology Guru Jambheshwar University of Science and Technology Hisar Haryana India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ramesh Kumar","family":"Dedar","sequence":"additional","affiliation":[{"name":"National Centre for Veterinary Type Cultures ICAR\u2010National Research Centre on Equines Hisar India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ram","family":"Kumar","sequence":"additional","affiliation":[{"name":"National Centre for Veterinary Type Cultures ICAR\u2010National Research Centre on Equines Hisar India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yogesh","family":"Chander","sequence":"additional","affiliation":[{"name":"National Centre for Veterinary Type Cultures ICAR\u2010National Research Centre on Equines Hisar India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Himanshu","family":"Kamboj","sequence":"additional","affiliation":[{"name":"National Centre for Veterinary Type Cultures ICAR\u2010National Research Centre on Equines Hisar India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Garvit","family":"Kumar","sequence":"additional","affiliation":[{"name":"National Centre for Veterinary Type Cultures ICAR\u2010National Research Centre on Equines Hisar India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rekha","family":"Verma","sequence":"additional","affiliation":[{"name":"Pt. 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