{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,4]],"date-time":"2026-08-04T13:46:42Z","timestamp":1785851202476,"version":"3.56.0"},"reference-count":32,"publisher":"American Society for Microbiology","issue":"8","license":[{"start":{"date-parts":[[2026,8,5]],"date-time":"2026-08-05T00:00:00Z","timestamp":1785888000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,8,5]],"date-time":"2026-08-05T00:00:00Z","timestamp":1785888000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.asm.org\/non-commercial-tdm-license"}],"funder":[{"DOI":"10.13039\/501100002915","name":"Fondation pour la Recherche M\u00e9dicale","doi-asserted-by":"publisher","award":["EQU202003010618"],"award-info":[{"award-number":["EQU202003010618"]}],"id":[{"id":"10.13039\/501100002915","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003323","name":"Agence Nationale de Recherches sur le Sida et les H\u00e9patites Virales","doi-asserted-by":"publisher","award":["ANRS-MIE EMERGEN"],"award-info":[{"award-number":["ANRS-MIE EMERGEN"]}],"id":[{"id":"10.13039\/501100003323","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["journals.asm.org"],"crossmark-restriction":true},"short-container-title":["Antimicrob Agents Chemother"],"published-print":{"date-parts":[[2026,8,5]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:sec>\n                    <jats:title\/>\n                    <jats:p>\n                      We evaluated the antiviral activity of a library of 36 urea-based small-molecule cyclophilin inhibitors (SMCypIs) against human respiratory syncytial virus (hRSV) and human metapneumovirus (hMPV). Structure\u2013spectrum analysis revealed virus-specific structural requirements for antiviral efficacy. By combining the key determinants identified for each virus, we rationally designed optimized dual-acting derivatives. Among these, the optimized compound F832\/33 emerged as a potent, broad-spectrum antiviral agent with nanomolar activity against both hRSV and hMPV, submicromolar inhibition of cyclophilin (Cyp) peptidyl-prolyl isomerase (PPIase) activity, and no detectable cytotoxicity. Interestingly, no direct correlation was observed between Cyp PPIase inhibition and antiviral potency, suggesting that Cyp engagement rather than enzymatic inhibition\n                      <jats:italic toggle=\"yes\">per se<\/jats:italic>\n                      is required for antiviral activity. Competition assays with alisporivir confirmed that the antiviral effects of SMCypIs depend on their specific interaction with Cyp. Beyond its dual efficacy, F832\/33 displayed strong antiviral activity against additional clinically relevant respiratory pathogens, including parainfluenza virus type 3, enterovirus D68, and both ancestral and Omicron severe acute respiratory syndrome coronavirus 2 strains, in immortalized cell lines and fully differentiated human nasal epithelial cells, a physiologically relevant model of respiratory infection. Collectively, our results demonstrate that structure\u2013activity relationship-guided optimization can be successfully applied to expand the antiviral spectrum of SMCypIs, positioning F832\/33 as a promising host-targeted broad-spectrum antiviral candidate. Further\n                      <jats:italic toggle=\"yes\">in vivo<\/jats:italic>\n                      studies are warranted to evaluate its therapeutic potential and clarify its precise mechanism of action.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1128\/aac.01721-25","type":"journal-article","created":{"date-parts":[[2026,7,17]],"date-time":"2026-07-17T14:27:07Z","timestamp":1784298427000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":0,"title":["Optimization of the antiviral spectrum of cyclophilin inhibitors targeting respiratory viruses"],"prefix":"10.1128","volume":"70","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6040-5040","authenticated-orcid":true,"given":"Laurent","family":"Softic","sequence":"first","affiliation":[{"name":"Team \"Viruses, Hepatology, Cancer\", Institut Mondor, INSERM U955, Universit\u00e9 Paris-Est","place":["Cr\u00e9teil, France"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-1962-0666","authenticated-orcid":true,"given":"Bryan","family":"Jimenez-Araya","sequence":"additional","affiliation":[{"name":"Team \"Viruses, Hepatology, Cancer\", Institut Mondor, INSERM U955, Universit\u00e9 Paris-Est","place":["Cr\u00e9teil, France"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nazim","family":"Ahnou","sequence":"additional","affiliation":[{"name":"Team \"Viruses, Hepatology, Cancer\", Institut Mondor, INSERM U955, Universit\u00e9 Paris-Est","place":["Cr\u00e9teil, France"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maxime","family":"Duval","sequence":"additional","affiliation":[{"name":"Team \"Viruses, Hepatology, Cancer\", Institut Mondor, INSERM U955, Universit\u00e9 Paris-Est","place":["Cr\u00e9teil, France"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Quentin","family":"Nevers","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/01jvz7e61","id-type":"ROR","asserted-by":"publisher"}],"name":"Unit\u00e9 de Virologie et Immunologie Mol\u00e9culaires (VIM), INRAE, Universit\u00e9 Paris-Saclay","place":["Jouy-en-Josas, France"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rozenn","family":"Brillet","sequence":"additional","affiliation":[{"name":"Team \"Viruses, Hepatology, Cancer\", Institut Mondor, INSERM U955, Universit\u00e9 Paris-Est","place":["Cr\u00e9teil, France"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jean-Francois","family":"Guichou","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/051escj72","id-type":"ROR","asserted-by":"publisher"}],"name":"Centre de Biologie Structurale (CBS), CNRS UMR 5048, INSERM U 1054, Universit\u00e9 de Montpellier","place":["Montpellier, 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Hepatology, Cancer\", Institut Mondor, INSERM U955, Universit\u00e9 Paris-Est","place":["Cr\u00e9teil, France"]},{"name":"Department of Virology, H\u00f4pital Henri Mondor, AP-HP, Universit\u00e9 Paris-Est","place":["Cr\u00e9teil, France"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1236-5467","authenticated-orcid":true,"given":"Slim","family":"Fourati","sequence":"additional","affiliation":[{"name":"Team \"Viruses, Hepatology, Cancer\", Institut Mondor, INSERM U955, Universit\u00e9 Paris-Est","place":["Cr\u00e9teil, France"]},{"name":"Department of Virology, H\u00f4pital Henri Mondor, AP-HP, Universit\u00e9 Paris-Est","place":["Cr\u00e9teil, France"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6489-5091","authenticated-orcid":true,"given":"Abdelhakim","family":"Ahmed-Belkacem","sequence":"additional","affiliation":[{"name":"Team \"Viruses, Hepatology, Cancer\", Institut Mondor, INSERM 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M Khan M Huet H Softic L Bigault L Guichou J-F Ahmed-Belkacem A Nevers Q Le Poder S. 2025. Identification and characterization of a non-peptidic cyclophilin ligand with antiviral activity against feline and porcine \u03b1-coronaviruses. bioRxiv. doi:10.1101\/2025.05.24.655938","DOI":"10.1101\/2025.05.24.655938"}],"container-title":["Antimicrobial Agents and Chemotherapy"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/journals.asm.org\/doi\/pdf\/10.1128\/aac.01721-25","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/journals.asm.org\/doi\/pdf\/10.1128\/aac.01721-25","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,4]],"date-time":"2026-08-04T13:02:47Z","timestamp":1785848567000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.asm.org\/doi\/10.1128\/aac.01721-25"}},"subtitle":[],"editor":[{"given":"Zhaohui","family":"Qian","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2026,8,5]]},"references-count":32,"journal-issue":{"issue":"8","published-print":{"date-parts":[[2026,8,5]]}},"alternative-id":["10.1128\/aac.01721-25"],"URL":"https:\/\/doi.org\/10.1128\/aac.01721-25","relation":{},"ISSN":["0066-4804","1098-6596"],"issn-type":[{"value":"0066-4804","type":"print"},{"value":"1098-6596","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,8,5]]},"assertion":[{"value":"2025-11-12","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-06-05","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-07-17","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e01721-25"}}