Identification of Z-Tyr-Ala-CHN 2 , a Cathepsin L Inhibitor with Broad-Spectrum Cell-Specific Activity against Coronaviruses, including SARS-CoV-2.

Autor: Doijen J; Janssen Pharmaceutica NV, Turnhoutseweg 30, 2340 Beerse, Belgium., Temmerman K; Janssen Pharmaceutica NV, Turnhoutseweg 30, 2340 Beerse, Belgium., Van den Eynde C; Janssen Pharmaceutica NV, Turnhoutseweg 30, 2340 Beerse, Belgium., Diels A; Janssen Pharmaceutica NV, Turnhoutseweg 30, 2340 Beerse, Belgium., Van den Broeck N; Charles River Laboratories, Turnhoutseweg 30, 2340 Beerse, Belgium., Van Gool M; Janssen Cilag S.A., C/Jarama 75A, 45007 Toledo, Spain., Heo I; Janssen Pharmaceutica NV, Turnhoutseweg 30, 2340 Beerse, Belgium., Jaensch S; Janssen Pharmaceutica NV, Turnhoutseweg 30, 2340 Beerse, Belgium., Zwaagstra M; Faculty of Veterinary Medicine, Yalelaan 1, Virology Division, Department of Biomolecular Health Sciences, Infectious Diseases and Immunology, Utrecht University, 3584 Utrecht, The Netherlands., Diosa Toro M; Faculty of Veterinary Medicine, Yalelaan 1, Virology Division, Department of Biomolecular Health Sciences, Infectious Diseases and Immunology, Utrecht University, 3584 Utrecht, The Netherlands., Chiu W; Laboratory of Virology and Chemotherapy, Herestraat 49, Rega Institute for Medical Research, Department of Microbiology, Immunology and Transplantation, KU Leuven, 3000 Leuven, Belgium., De Jonghe S; Laboratory of Virology and Chemotherapy, Herestraat 49, Rega Institute for Medical Research, Department of Microbiology, Immunology and Transplantation, KU Leuven, 3000 Leuven, Belgium., Leyssen P; Laboratory of Virology and Chemotherapy, Herestraat 49, Rega Institute for Medical Research, Department of Microbiology, Immunology and Transplantation, KU Leuven, 3000 Leuven, Belgium., Bojkova D; Institute for Medical Virology, University Hospital, Paul-Ehrlich-Str. 40, Frankfurt University, 60596 Frankfurt am Main, Germany., Ciesek S; Institute for Medical Virology, University Hospital, Paul-Ehrlich-Str. 40, Frankfurt University, 60596 Frankfurt am Main, Germany., Cinatl J; Institute for Medical Virology, University Hospital, Paul-Ehrlich-Str. 40, Frankfurt University, 60596 Frankfurt am Main, Germany., Verschueren L; Janssen Pharmaceutica NV, Turnhoutseweg 30, 2340 Beerse, Belgium., Buyck C; Janssen Pharmaceutica NV, Turnhoutseweg 30, 2340 Beerse, Belgium., Van Kuppeveld F; Faculty of Veterinary Medicine, Yalelaan 1, Virology Division, Department of Biomolecular Health Sciences, Infectious Diseases and Immunology, Utrecht University, 3584 Utrecht, The Netherlands., Neyts J; Laboratory of Virology and Chemotherapy, Herestraat 49, Rega Institute for Medical Research, Department of Microbiology, Immunology and Transplantation, KU Leuven, 3000 Leuven, Belgium., Van Loock M; Janssen Pharmaceutica NV, Turnhoutseweg 30, 2340 Beerse, Belgium., Van Damme E; Janssen Pharmaceutica NV, Turnhoutseweg 30, 2340 Beerse, Belgium.
Jazyk: angličtina
Zdroj: Microorganisms [Microorganisms] 2023 Mar 10; Vol. 11 (3). Date of Electronic Publication: 2023 Mar 10.
DOI: 10.3390/microorganisms11030717
Abstrakt: 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-CHN 2 , 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-CHN 2 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-CHN 2 makes it an interesting tool compound for studying the biology of coronavirus entry and replication.
Databáze: MEDLINE
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