{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,16]],"date-time":"2026-10-16T15:27:15Z","timestamp":1792164435922,"version":"4.4.0"},"reference-count":86,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2023,3,10]],"date-time":"2023-03-10T00:00:00Z","timestamp":1678406400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Janssen Research &amp; Development, LLC","award":["101005077"],"award-info":[{"award-number":["101005077"]}]},{"name":"Janssen Research &amp; Development, LLC","award":["HHSO100201700018C"],"award-info":[{"award-number":["HHSO100201700018C"]}]},{"name":"Janssen Research &amp; Development, LLC","award":["HHSO100201800012C"],"award-info":[{"award-number":["HHSO100201800012C"]}]},{"name":"European Union\u2019s Horizon 2020 research and innovation program, EFPIA, Bill &amp; Melinda Gates Foundation, Global Health Drug Discovery Institute, and the University of Dundee","award":["101005077"],"award-info":[{"award-number":["101005077"]}]},{"name":"European Union\u2019s Horizon 2020 research and innovation program, EFPIA, Bill &amp; Melinda Gates Foundation, Global Health Drug Discovery Institute, and the University of Dundee","award":["HHSO100201700018C"],"award-info":[{"award-number":["HHSO100201700018C"]}]},{"name":"European Union\u2019s Horizon 2020 research and innovation program, EFPIA, Bill &amp; Melinda Gates Foundation, Global Health Drug Discovery Institute, and the University of Dundee","award":["HHSO100201800012C"],"award-info":[{"award-number":["HHSO100201800012C"]}]},{"name":"Office of the Assistant Secretary for Preparedness and Response, Biomedical Advanced Research and Development Authority (BARDA)","award":["101005077"],"award-info":[{"award-number":["101005077"]}]},{"name":"Office of the Assistant Secretary for Preparedness and Response, Biomedical Advanced Research and Development Authority (BARDA)","award":["HHSO100201700018C"],"award-info":[{"award-number":["HHSO100201700018C"]}]},{"name":"Office of the Assistant Secretary for Preparedness and Response, Biomedical Advanced Research and Development Authority (BARDA)","award":["HHSO100201800012C"],"award-info":[{"award-number":["HHSO100201800012C"]}]},{"name":"Hercules Foundation (Research Foundation Flanders) and Rega Foundation, KU Leuven","award":["101005077"],"award-info":[{"award-number":["101005077"]}]},{"name":"Hercules Foundation (Research Foundation Flanders) and Rega Foundation, KU Leuven","award":["HHSO100201700018C"],"award-info":[{"award-number":["HHSO100201700018C"]}]},{"name":"Hercules Foundation (Research Foundation Flanders) and Rega Foundation, KU Leuven","award":["HHSO100201800012C"],"award-info":[{"award-number":["HHSO100201800012C"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Microorganisms"],"abstract":"<jats:p>The ongoing COVID-19 pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is partly under control by vaccination. However, highly potent and safe antiviral drugs for SARS-CoV-2 are still needed to avoid development of severe COVID-19. We report the discovery of a small molecule, Z-Tyr-Ala-CHN2, which was identified in a cell-based antiviral screen. The molecule exerts sub-micromolar antiviral activity against SARS-CoV-2, SARS-CoV-1, and human coronavirus 229E. Time-of-addition studies reveal that Z-Tyr-Ala-CHN2 acts at the early phase of the infection cycle, which is in line with the observation that the molecule inhibits cathepsin L. This results in antiviral activity against SARS-CoV-2 in VeroE6, A549-hACE2, and HeLa-hACE2 cells, but not in Caco-2 cells or primary human nasal epithelial cells since the latter two cell types also permit entry via transmembrane protease serine subtype 2 (TMPRSS2). Given their cell-specific activity, cathepsin L inhibitors still need to prove their value in the clinic; nevertheless, the activity profile of Z-Tyr-Ala-CHN2 makes it an interesting tool compound for studying the biology of coronavirus entry and replication.<\/jats:p>","DOI":"10.3390\/microorganisms11030717","type":"journal-article","created":{"date-parts":[[2023,3,10]],"date-time":"2023-03-10T03:02:08Z","timestamp":1678417328000},"page":"717","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Identification of Z-Tyr-Ala-CHN2, a Cathepsin L Inhibitor with Broad-Spectrum Cell-Specific Activity against Coronaviruses, including SARS-CoV-2"],"prefix":"10.3390","volume":"11","author":[{"given":"Jordi","family":"Doijen","sequence":"first","affiliation":[{"name":"Janssen Pharmaceutica NV, Turnhoutseweg 30, 2340 Beerse, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Koen","family":"Temmerman","sequence":"additional","affiliation":[{"name":"Janssen Pharmaceutica NV, Turnhoutseweg 30, 2340 Beerse, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christel","family":"Van den Eynde","sequence":"additional","affiliation":[{"name":"Janssen Pharmaceutica NV, Turnhoutseweg 30, 2340 Beerse, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Annick","family":"Diels","sequence":"additional","affiliation":[{"name":"Janssen Pharmaceutica NV, Turnhoutseweg 30, 2340 Beerse, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5900-4813","authenticated-orcid":false,"given":"Nick","family":"Van den Broeck","sequence":"additional","affiliation":[{"name":"Charles River Laboratories, Turnhoutseweg 30, 2340 Beerse, 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Utrecht, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mayra","family":"Diosa Toro","sequence":"additional","affiliation":[{"name":"Faculty of Veterinary Medicine, Yalelaan 1, Virology Division, Department of Biomolecular Health Sciences, Infectious Diseases and Immunology, Utrecht University, 3584 Utrecht, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5236-623X","authenticated-orcid":false,"given":"Winston","family":"Chiu","sequence":"additional","affiliation":[{"name":"Laboratory of Virology and Chemotherapy, Herestraat 49, Rega Institute for Medical Research, Department of Microbiology, Immunology and Transplantation, KU Leuven, 3000 Leuven, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3872-6558","authenticated-orcid":false,"given":"Steven","family":"De Jonghe","sequence":"additional","affiliation":[{"name":"Laboratory of Virology and Chemotherapy, Herestraat 49, Rega Institute for Medical Research, Department of Microbiology, Immunology and Transplantation, KU Leuven, 3000 Leuven, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pieter","family":"Leyssen","sequence":"additional","affiliation":[{"name":"Laboratory of Virology and Chemotherapy, Herestraat 49, Rega Institute for Medical Research, Department of Microbiology, Immunology and Transplantation, KU Leuven, 3000 Leuven, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Denisa","family":"Bojkova","sequence":"additional","affiliation":[{"name":"Institute for Medical Virology, University Hospital, Paul-Ehrlich-Str. 40, Frankfurt University, 60596 Frankfurt am Main, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1802-7565","authenticated-orcid":false,"given":"Sandra","family":"Ciesek","sequence":"additional","affiliation":[{"name":"Institute for 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Damme","sequence":"additional","affiliation":[{"name":"Janssen Pharmaceutica NV, Turnhoutseweg 30, 2340 Beerse, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,3,10]]},"reference":[{"key":"ref_1","unstructured":"Centers for Disease Control and Prevention (2022, February 28). 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