Camostat mesylate inhibits SARS-CoV-2 activation by TMPRSS2-related proteases and its metabolite GBPA exerts antiviral activity
Journal article, 2021
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.
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.
SARS-CoV-2
GBPA
FOY-251
Camostat
TMPRSS2
Author
Markus Hoffmann
German Primate Center
University of Göttingen
Heike Hofmann-Winkler
German Primate Center
Joan C. Smith
Google Inc.
Cold Spring Harbor Laboratory
Nadine Krüger
German Primate Center
Prerna Arora
German Primate Center
University of Göttingen
Lambert K. Sørensen
Aarhus University
Ole S. Søgaard
Aarhus University
Arhus Universitetshospital
Jørgen Bo Hasselstrøm
Aarhus University
Michael Winkler
German Primate Center
Tim Hempel
Freie Universität Berlin
Lluís Raich
Freie Universität Berlin
Simon Olsson
Chalmers, Computer Science and Engineering (Chalmers), Data Science
Freie Universität Berlin
Olga Danov
Fraunhofer Institut fur Toxikologie und Experimentelle Medizin - ITEM
Danny Jonigk
Fraunhofer Institut fur Toxikologie und Experimentelle Medizin - ITEM
Hannover Medical School (MHH)
Takashi Yamazoe
Ono Pharmaceutical Co., Ltd.
Katsura Yamatsuta
Ono Pharmaceutical Co., Ltd.
Hirotaka Mizuno
Ono Pharmaceutical Co., Ltd.
Stephan Ludwig
University of Münster
Frank Noé
Freie Universität Berlin
Rice University
Mads Kjolby
Aarhus University
Arhus Universitetshospital
Armin Braun
Fraunhofer Institut fur Toxikologie und Experimentelle Medizin - ITEM
Jason M. Sheltzer
Cold Spring Harbor Laboratory
Stefan Pohlmann
German Primate Center
University of Göttingen
EBioMedicine
2352-3964 (eISSN)
Vol. 65 103255Subject Categories
Pharmacology and Toxicology
Medicinal Chemistry
Microbiology in the medical area
DOI
10.1016/j.ebiom.2021.103255
PubMed
33676899