TMPRSS2 and furin are both essential for proteolytic activation of SARS-CoV-2 in human airway cells

The novel emerged SARS-CoV-2 has rapidly spread around the world causing acute infection of the respiratory tract (COVID-19) that can result in severe disease and lethality. For SARS-CoV-2 to enter cells, its surface glycoprotein spike (S) must be cleaved at two different sites by host cell protease...

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Vydané v:	Life science alliance Ročník 3; číslo 9; s. e202000786
Hlavní autori:	Bestle, Dorothea, Heindl, Miriam Ruth, Limburg, Hannah, Van Lam van, Thuy, Pilgram, Oliver, Moulton, Hong, Stein, David A, Hardes, Kornelia, Eickmann, Markus, Dolnik, Olga, Rohde, Cornelius, Klenk, Hans-Dieter, Garten, Wolfgang, Steinmetzer, Torsten, Böttcher-Friebertshäuser, Eva
Médium:	Journal Article
Jazyk:	English
Vydavateľské údaje:	United States Life Science Alliance 01.09.2020 Life Science Alliance LLC
Predmet:	Alveolar Epithelial Cells - cytology Alveolar Epithelial Cells - virology Amino acids Animals Antisense therapy Antiviral activity Betacoronavirus - physiology Binding Sites Bronchitis Cathepsins Cell Line Chlorocebus aethiops COVID-19 Energy transfer Enzyme kinetics Epithelial cells Furin Furin - genetics Glycoproteins HEK293 Cells Humans Infections Influenza Lethality Middle East respiratory syndrome Peptides Proprotein convertases Proteases Proteinase inhibitors Proteins Proteolysis Replication Respiratory diseases SARS-CoV-2 Serine Endopeptidases - genetics Serine proteinase Severe acute respiratory syndrome coronavirus 2 Spike Glycoprotein, Coronavirus - chemistry Spike Glycoprotein, Coronavirus - metabolism Therapeutic targets Toxins Vero Cells Virus Internalization Virus Replication Viruses
ISSN:	2575-1077, 2575-1077
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Shrnutí:	The novel emerged SARS-CoV-2 has rapidly spread around the world causing acute infection of the respiratory tract (COVID-19) that can result in severe disease and lethality. 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 show that S can be cleaved by 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 human airway epithelial cells through antisense-mediated knockdown of TMPRSS2 expression. Furthermore, SARS-CoV-2 replication was also strongly inhibited by the synthetic furin inhibitor MI-1851 in human airway cells. In contrast, inhibition of endosomal cathepsins by E64d did not affect virus replication. Combining various TMPRSS2 inhibitors with furin inhibitor MI-1851 produced more potent antiviral activity against SARS-CoV-2 than an equimolar amount of any single serine protease inhibitor. Therefore, this approach has considerable therapeutic potential for treatment of COVID-19.
Bibliografia:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23 Dorothea Bestle, Miriam Ruth Heindl, and Hannah Limburg contributed equally to this work
ISSN:	2575-1077 2575-1077
DOI:	10.26508/lsa.202000786