Camostat mesylate inhibits SARS-CoV-2 activation by TMPRSS2-related proteases and its metabolite GBPA exerts antiviral activity

Hoffmann, Markus, Hofmann-Winkler, Heike, Smith, Joan C, Krüger, Nadine, Arora, Prerna, Sørensen, Lambert K, Søgaard, Ole S, Hasselstrøm, Jørgen Bo, Winkler, Michael, Hempel, Tim, Raich, Lluís, Olsson, Simon, Danov, Olga, Jonigk, Danny, Yamazoe, Takashi, Yamatsuta, Katsura, Mizuno, Hirotaka, Ludwig, Stephan, Noé, Frank, Kjolby, Mads, Braun, Armin, Sheltzer, Jason M, Pöhlmann, Stefan (March 2021) Camostat mesylate inhibits SARS-CoV-2 activation by TMPRSS2-related proteases and its metabolite GBPA exerts antiviral activity. EBioMedicine, 65. p. 103255. ISSN 2352-3964

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Abstract

BACKGROUND: Antivirals are needed to combat the COVID-19 pandemic, which is caused by SARS-CoV-2. The clinically-proven protease inhibitor Camostat mesylate inhibits SARS-CoV-2 infection by blocking the virus-activating host cell protease TMPRSS2. However, antiviral activity of Camostat mesylate metabolites and potential viral resistance have not been analyzed. Moreover, antiviral activity of Camostat mesylate in human lung tissue remains to be demonstrated. METHODS: We used recombinant TMPRSS2, reporter particles bearing the spike protein of SARS-CoV-2 or authentic SARS-CoV-2 to assess inhibition of TMPRSS2 and viral entry, respectively, by Camostat mesylate and its metabolite GBPA. FINDINGS: We show that several TMPRSS2-related proteases activate SARS-CoV-2 and that two, TMPRSS11D and TMPRSS13, are robustly expressed in the upper respiratory tract. However, entry mediated by these proteases was blocked by Camostat mesylate. The Camostat metabolite GBPA inhibited recombinant TMPRSS2 with reduced efficiency as compared to Camostat mesylate. In contrast, both inhibitors exhibited similar antiviral activity and this correlated with the rapid conversion of Camostat mesylate into GBPA in the presence of serum. Finally, Camostat mesylate and GBPA blocked SARS-CoV-2 spread in human lung tissue ex vivo and the related protease inhibitor Nafamostat mesylate exerted augmented antiviral activity. INTERPRETATION: Our results suggest that SARS-CoV-2 can use TMPRSS2 and closely related proteases for spread in the upper respiratory tract and that spread in the human lung can be blocked by Camostat mesylate and its metabolite GBPA. FUNDING: NIH, Damon Runyon Foundation, ACS, NYCT, DFG, EU, Berlin Mathematics center MATH+, BMBF, Lower Saxony, Lundbeck Foundation, Novo Nordisk Foundation.

Item Type:	Paper
Subjects:	bioinformatics diseases & disorders bioinformatics > genomics and proteomics > genetics & nucleic acid processing bioinformatics > genomics and proteomics bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification diseases & disorders > viral diseases organs, tissues, organelles, cell types and functions > cell types and functions > cell types > cell line organs, tissues, organelles, cell types and functions > cell types and functions > cell types > cell line organs, tissues, organelles, cell types and functions > cell types and functions > cell types > cell line organs, tissues, organelles, cell types and functions > cell types and functions > cell types organs, tissues, organelles, cell types and functions > cell types and functions > cell types organs, tissues, organelles, cell types and functions > cell types and functions > cell types organs, tissues, organelles, cell types and functions > cell types and functions diseases & disorders > viral diseases > coronavirus diseases & disorders > viral diseases > coronavirus > covid 19 bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > enzymes organs, tissues, organelles, cell types and functions > organs types and functions > lung organs, tissues, organelles, cell types and functions > tissues types and functions > transport > membrane transport organs, tissues, organelles, cell types and functions > tissues types and functions > membranes organs, tissues, organelles, cell types and functions bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > enzymes > Protease bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types organs, tissues, organelles, cell types and functions > tissues types and functions organs, tissues, organelles, cell types and functions > tissues types and functions > transport
CSHL Authors:	Sheltzer, Jason Smith, Joan C.
Communities:	CSHL labs > Sheltzer lab CSHL Cancer Center Program CSHL Cancer Center Program > Cellular Communication in Cancer Program
SWORD Depositor:	CSHL Elements
Depositing User:	CSHL Elements
Date:	March 2021
Date Deposited:	11 May 2021 18:55
Last Modified:	13 Feb 2024 17:00
PMCID:	PMC7930809
URI:	https://repository.cshl.edu/id/eprint/40085

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