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CoVs are also known for their importance in veterinary medicine and are responsible for severe pathologies in pets and livestock. These include feline infectious peritonitis virus (FIPV), which causes fatal disease in cats. In livestock, porcine CoVs such as transmissible gastroenteritis virus (TGEV) and porcine epidemic diarrhoea virus (PEDV) are the causative agents of acute enteric disease in piglets, which has a high mortality rate and a significant impact on the pork industry. In addition, animal CoVs may represent zoonotic reservoirs. Therefore, efficient antiviral strategies are needed to inhibit the replication of CoVs that infect various animal species. Here, we synthesized twenty small-molecule ligands that target cyclophilins, a family of cellular chaperones hijacked by several viruses, including CoVs. We screened their antiviral activity against feline and porcine \u03b1-CoVs and identified F83233 as a potent inhibitor of FIPV, TGEV and PEDV replication at micromolar concentrations that was effective in feline, porcine, and simian cells. As cyclophilins are highly conserved among mammals, F83233 could be a promising antiviral to treat different animal and zoonotic CoVs.<\/jats:p>","DOI":"10.1186\/s13567-025-01654-1","type":"journal-article","created":{"date-parts":[[2025,11,5]],"date-time":"2025-11-05T12:22:11Z","timestamp":1762345331000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Identification and characterization of a nonpeptidic cyclophilin ligand with antiviral activity against feline and porcine \u03b1-coronaviruses"],"prefix":"10.1186","volume":"56","author":[{"given":"Manon","family":"Delaplace","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mantasha","family":"Khan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"H\u00e9l\u00e8ne","family":"Huet","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Laurent","family":"Softic","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nazim","family":"Ahnou","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lionel","family":"Bigault","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jean-Fran\u00e7ois","family":"Guichou","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Abdelhakim","family":"Ahmed-Belkacem","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6135-7781","authenticated-orcid":false,"given":"Quentin","family":"Nevers","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sophie","family":"Le Poder","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2025,11,5]]},"reference":[{"key":"1654_CR1","doi-asserted-by":"publisher","DOI":"10.1093\/femsre\/fuaa057","volume":"45","author":"JK Millet","year":"2021","unstructured":"Millet JK, Jaimes JA, Whittaker GR (2021) Molecular diversity of coronavirus host cell entry receptors. 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