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J Med Virol . Native and activated antithrombin inhibits TMPRSS2 activity and SARS-CoV-2 infection

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  • J Med Virol . Native and activated antithrombin inhibits TMPRSS2 activity and SARS-CoV-2 infection


    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 1 , Patrick Immenschuh 1 , Tatjana Weil 1 , Carina Conzelmann 1 , Yasser Almeida-Hernández 2 , Markus Hoffmann 3 4 , Amy Kempf 3 4 , Inga Nehlmeier 3 , Rishikesh Lotke 5 , Moritz Petersen 5 , Steffen Stenger 6 , Frank Kirchhoff 1 , Daniel Sauter 5 , Stefan Pöhlmann 3 4 , Elsa Sanchez-Garcia 2 , Jan Münch 1



    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.

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