Camostat mesylate inhibits SARS-CoV-2 activation by TMPRSS2-related proteases and its metabolite GBPA exerts antiviral activity
Artikel i vetenskaplig tidskrift, 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

Författare

Markus Hoffmann

Deutsches Primatenzentrum

Georg-August-Universität Göttingen

Heike Hofmann-Winkler

Deutsches Primatenzentrum

Joan C. Smith

Google Inc.

Cold Spring Harbor Laboratory

Nadine Krüger

Deutsches Primatenzentrum

Prerna Arora

Deutsches Primatenzentrum

Georg-August-Universität Göttingen

Lambert K. Sørensen

Aarhus Universitet

Ole S. Søgaard

Aarhus Universitet

Arhus Universitetshospital

Jørgen Bo Hasselstrøm

Aarhus Universitet

Michael Winkler

Deutsches Primatenzentrum

Tim Hempel

Freie Universität Berlin

Lluís Raich

Freie Universität Berlin

Simon Olsson

Chalmers, Data- och informationsteknik, 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

Medizinische Hochschule Hannover (MHH)

Takashi Yamazoe

Ono Pharmaceutical Co., Ltd.

Katsura Yamatsuta

Ono Pharmaceutical Co., Ltd.

Hirotaka Mizuno

Ono Pharmaceutical Co., Ltd.

Stephan Ludwig

Universität Münster

Frank Noé

Freie Universität Berlin

Rice University

Mads Kjolby

Aarhus Universitet

Arhus Universitetshospital

Armin Braun

Fraunhofer Institut fur Toxikologie und Experimentelle Medizin - ITEM

Jason M. Sheltzer

Cold Spring Harbor Laboratory

Stefan Pohlmann

Deutsches Primatenzentrum

Georg-August-Universität Göttingen

EBioMedicine

2352-3964 (eISSN)

Vol. In press 103255

Ämneskategorier

Farmakologi och toxikologi

Läkemedelskemi

Mikrobiologi inom det medicinska området

DOI

10.1016/j.ebiom.2021.103255

Mer information

Senast uppdaterat

2021-03-18