tetano
Editor, Senior Moderator
J Med Virol
. 2022 Sep 3.
doi: 10.1002/jmv.28124. Online ahead of print.
Native and activated antithrombin inhibits TMPRSS2 activity and SARS-CoV-2 infection
Lukas Wettstein[SUP] 1 [/SUP], Patrick Immenschuh[SUP] 1 [/SUP], Tatjana Weil[SUP] 1 [/SUP], Carina Conzelmann[SUP] 1 [/SUP], Yasser Almeida-Hernández[SUP] 2 [/SUP], Markus Hoffmann[SUP] 3 4 [/SUP], Amy Kempf[SUP] 3 4 [/SUP], Inga Nehlmeier[SUP] 3 [/SUP], Rishikesh Lotke[SUP] 5 [/SUP], Moritz Petersen[SUP] 5 [/SUP], Steffen Stenger[SUP] 6 [/SUP], Frank Kirchhoff[SUP] 1 [/SUP], Daniel Sauter[SUP] 5 [/SUP], Stefan Pöhlmann[SUP] 3 4 [/SUP], Elsa Sanchez-Garcia[SUP] 2 [/SUP], Jan Münch[SUP] 1 [/SUP]
Affiliations
Abstract
Host cell proteases such as TMPRSS2 are critical determinants of SARS-CoV-2 tropism and pathogenesis. Here, we show that antithrombin (AT), an endogenous serine protease inhibitor regulating coagulation, is a broad-spectrum inhibitor of coronavirus infection. Molecular docking and enzyme activity assays demonstrate that AT binds and inhibits TMPRSS2, a serine protease that primes the Spike proteins of coronaviruses for subsequent fusion. Consequently, AT blocks entry driven by the Spikes of SARS-CoV, MERS-CoV, hCoV-229E, SARS-CoV-2 and its variants of concern including Omicron, and suppresses lung cell infection with genuine SARS-CoV-2. Thus, AT is an endogenous inhibitor of SARS-CoV-2 that may be involved in COVID-19 pathogenesis. We further demonstrate that activation of AT by anticoagulants, such as heparin or fondaparinux, increases the anti-TMPRSS2 and anti-SARS-CoV-2 activity of AT, suggesting that repurposing of native and activated AT for COVID-19 treatment should be explored. This article is protected by copyright. All rights reserved.
Keywords: Antithrombin; Protease inhibitor; SARS-CoV-2; SERPINC1; TMPRSS2.
. 2022 Sep 3.
doi: 10.1002/jmv.28124. Online ahead of print.
Native and activated antithrombin inhibits TMPRSS2 activity and SARS-CoV-2 infection
Lukas Wettstein[SUP] 1 [/SUP], Patrick Immenschuh[SUP] 1 [/SUP], Tatjana Weil[SUP] 1 [/SUP], Carina Conzelmann[SUP] 1 [/SUP], Yasser Almeida-Hernández[SUP] 2 [/SUP], Markus Hoffmann[SUP] 3 4 [/SUP], Amy Kempf[SUP] 3 4 [/SUP], Inga Nehlmeier[SUP] 3 [/SUP], Rishikesh Lotke[SUP] 5 [/SUP], Moritz Petersen[SUP] 5 [/SUP], Steffen Stenger[SUP] 6 [/SUP], Frank Kirchhoff[SUP] 1 [/SUP], Daniel Sauter[SUP] 5 [/SUP], Stefan Pöhlmann[SUP] 3 4 [/SUP], Elsa Sanchez-Garcia[SUP] 2 [/SUP], Jan Münch[SUP] 1 [/SUP]
Affiliations
- PMID: 36056630
- DOI: 10.1002/jmv.28124
Abstract
Host cell proteases such as TMPRSS2 are critical determinants of SARS-CoV-2 tropism and pathogenesis. Here, we show that antithrombin (AT), an endogenous serine protease inhibitor regulating coagulation, is a broad-spectrum inhibitor of coronavirus infection. Molecular docking and enzyme activity assays demonstrate that AT binds and inhibits TMPRSS2, a serine protease that primes the Spike proteins of coronaviruses for subsequent fusion. Consequently, AT blocks entry driven by the Spikes of SARS-CoV, MERS-CoV, hCoV-229E, SARS-CoV-2 and its variants of concern including Omicron, and suppresses lung cell infection with genuine SARS-CoV-2. Thus, AT is an endogenous inhibitor of SARS-CoV-2 that may be involved in COVID-19 pathogenesis. We further demonstrate that activation of AT by anticoagulants, such as heparin or fondaparinux, increases the anti-TMPRSS2 and anti-SARS-CoV-2 activity of AT, suggesting that repurposing of native and activated AT for COVID-19 treatment should be explored. This article is protected by copyright. All rights reserved.
Keywords: Antithrombin; Protease inhibitor; SARS-CoV-2; SERPINC1; TMPRSS2.