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.

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 103255

Subject Categories

Pharmacology and Toxicology

Medicinal Chemistry

Microbiology in the medical area

DOI

10.1016/j.ebiom.2021.103255

PubMed

33676899

More information

Latest update

4/5/2022 5