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

BioRxiv : the Preprint Server for Biology
Markus HoffmannStefan Pöhlmann

Abstract

Antiviral therapy is urgently needed to combat the coronavirus disease 2019 (COVID-19) pandemic, which is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The protease inhibitor camostat mesylate inhibits SARS-CoV-2 infection of lung cells by blocking the virus-activating host cell protease TMPRSS2. Camostat mesylate has been approved for treatment of pancreatitis in Japan and is currently being repurposed for COVID-19 treatment. However, potential mechanisms of viral resistance as well as camostat mesylate metabolization and antiviral activity of metabolites are unclear. Here, we show that SARS-CoV-2 can employ TMPRSS2-related host cell proteases for activation and that several of them are expressed in viral target cells. However, entry mediated by these proteases was blocked by camostat mesylate. The camostat metabolite GBPA inhibited the activity of recombinant TMPRSS2 with reduced efficiency as compared to camostat mesylate and was rapidly generated in the presence of serum. Importantly, the infection experiments in which camostat mesylate was identified as a SARS-CoV-2 inhibitor involved preincubation of target cells with camostat mesylate in the presence of serum for 2 h and thus allowed conversion ...Continue Reading

Citations

Nov 23, 2020·International Immunopharmacology·Mohadeseh Haji AbdolvahabLeila Farahmand
Apr 27, 2021·Frontiers in Molecular Biosciences·Muthu Kumaradoss KathiravanSenthilkumar Palaniappan
Apr 19, 2021·Frontiers in Endocrinology·David J EastyBryan T Hennessy
Apr 28, 2021·Hematology, Transfusion and Cell Therapy·Sumit Saha, Sachin Kadam

Datasets Mentioned

BETA
GSE1229603

Methods Mentioned

BETA
RNA-Seq
FCS
transfection
Assay

Clinical Trials Mentioned

NCT04321096
NCT04353284
NCT04355052
NCT04374019

Related Concepts

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