About: TMPRSS2 and furin are both essential for proteolytic activation and spread of SARS-CoV-2 in human airway epithelial cells and provide promising drug targets

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About: TMPRSS2 and furin are both essential for proteolytic activation and spread of SARS-CoV-2 in human airway epithelial cells and provide promising drug targets Goto Sponge NotDistinct Permalink

An Entity of Type : schema:ScholarlyArticle, within Data Space : wasabi.inria.fr associated with source document(s)

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type	Academic Article research paper schema:ScholarlyArticle
isDefinedBy	Covid-on-the-Web dataset
title	TMPRSS2 and furin are both essential for proteolytic activation and spread of SARS-CoV-2 in human airway epithelial cells and provide promising drug targets
Creator	Eickmann, Markus Becker, Stephan Böttcher-Friebertshäuser, Eva Klenk, Hans-Dieter Garten, Wolfgang Rohde, Cornelius Moulton, Hong Stein, David Hardes, Kornelia Steinmetzer, Torsten Bestle, Dorothea Limburg, Hannah Dolnik, Lam Van, Thuy Pilgram, Ruth, Miriam
source	BioRxiv
abstract	In December 2019, a novel coronavirus named SARS-CoV-2 first reported in Wuhan, China, emerged and rapidly spread to numerous other countries globally, causing the current pandemic. SARS-CoV-2 causes acute infection of the respiratory tract (COVID-19) that can result in severe disease and lethality. Currently, there is no approved antiviral drug for treating COVID-19 patients and there is an urgent need for specific antiviral therapies and vaccines. In order for SARS-CoV-2 to enter cells, its surface glycoprotein spike (S) must be cleaved at two different sites by host cell proteases, which therefore represent potential drug targets. In the present study we investigated which host cell proteases activate the SARS-CoV-2 S protein in Calu-3 human airway epithelial cells. We show that S can be cleaved by both the proprotein convertase furin at the S1/S2 site and the transmembrane serine protease 2 (TMPRSS2) at the S2’ site. We demonstrate that TMPRSS2 is essential for activation of SARS-CoV-2 S in Calu-3 cells through antisense-mediated knockdown of TMPRSS2 expression. Further, we show that SARS-CoV-2 replication can be efficiently inhibited by two synthetic inhibitors of TMPRSS2 and also by the broad range serine protease inhibitor aprotinin. Additionally, SARS-CoV-2 replication was also strongly inhibited by the synthetic furin inhibitor MI-1851. Combining various TMPRSS2 inhibitors with MI-1851 produced more potent antiviral activity against SARS-CoV-2 than an equimolar amount of any single serine protease inhibitor. In contrast, inhibition of endosomal cathepsins by E64d did not affect virus replication. Our data demonstrate that both TMPRSS2 and furin are essential for SARS-CoV-2 activation in human airway cells and are promising drug targets for the treatment of COVID-19 either by targeting one of these proteases alone or by a combination of furin and TMPRSS2 inhibitors. Therefore, this approach has a high therapeutic potential for treatment of COVID-19.
has issue date	2020-04-15(xsd:dateTime)
bibo:doi	10.1101/2020.04.15.042085
has license	biorxiv
sha1sum (hex)	c7a3ade5d2994efd9b2b29e94e874b822d560144
schema:url	https://doi.org/10.1101/2020.04.15.042085
resource representing a document's title	TMPRSS2 and furin are both essential for proteolytic activation and spread of SARS-CoV-2 in human airway epithelial cells and provide promising drug targets
schema:publication	bioRxiv
resource representing a document's body	covid:c7a3ade5d2994efd9b2b29e94e874b822d560144#body_text
is schema:about of	named entity 'China' named entity 'specific' named entity 'current' named entity 'respiratory tract' named entity 'COVID-19' named entity 'acute infection' named entity 'antiviral drug' named entity 'Wuhan' named entity 'SARS-CoV-2' named entity 'respiratory tract' named entity 'airway' named entity 'furin' named entity 'proteolytic' named entity 'pandemic' named entity 'protease inhibitors' named entity 'recombinant' named entity 'antivirals' named entity 'protein' named entity 'COVID-19' named entity 'TMPRSS2' named entity 'SDS-PAGE' named entity 'SARS-CoV-2' named entity 'SARS' named entity 'substrates' named entity 'Calu-3' named entity 'HCoV-OC43' named entity 'cell cultures' named entity 'furin' named entity 'PCR' named entity 'furin' named entity 'mRNA' named entity 'virus replication' named entity 'mRNA' named entity 'FRET' named entity 'FRET' named entity 'furin' named entity 'proteases' named entity 'Calu-3' named entity 'SARS-CoV' named entity 'furin' named entity 'TMPRSS2' named entity 'Myc' named entity 'inoculated' named entity 'R-X' named entity 'SARS-CoV-2' named entity 'TMPRSS2' named entity 'FRET' named entity 'antibody' named entity 'TMPRSS2' named entity 'HCoV-NL63' named entity 'furin' named entity 'TMPRSS2' named entity 'cleavage site' named entity 'epithelial cells' named entity 'primers' named entity 'Myc' named entity 'protein' named entity 'cellular membranes' named entity 'Proteolytic processing' named entity 'TMPRSS2' named entity 'IBV' named entity 'TMPRSS2' named entity 'plasmid' named entity 'furin' named entity 'TMPRSS2' named entity 'HCoV-HKU1' named entity 'viruses' named entity 'proteases' named entity 'furin'

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