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Alpha-1 antitrypsin inhibits TMPRSS2 protease activity and SARS-CoV-2 infection

2021; Nature Portfolio; Volume: 12; Issue: 1 Linguagem: Inglês

10.1038/s41467-021-21972-0

2041-1723

Lukas Wettstein, Tatjana Weil, Carina Conzelmann, Janis A. Müller, Rüdiger Groß, Maximilian Hirschenberger, Alina Seidel, Susanne Klute, Fabian Zech, Caterina Prelli Bozzo, Nico Preising, Giorgio Fois, Robin Lochbaum, Philip Maximilian Knaff, Volker Mailänder, Ludger Ständker, Dietmar Rudolf Thal, Christian Schumann, Steffen Stenger, Alexander Kleger, Günter Lochnit, Benjamin Mayer, Yasser B. Ruiz‐Blanco, Markus Hoffmann, Konstantin M. J. Sparrer, Stefan Pöhlmann, Elsa Sánchez‐García, Frank Kirchhoff, Manfred Frick, Jan Münch,

COVID-19 Clinical Research Studies

SARS-CoV-2 is a respiratory pathogen and primarily infects the airway epithelium. As our knowledge about innate immune factors of the respiratory tract against SARS-CoV-2 is limited, we generated and screened a peptide/protein library derived from bronchoalveolar lavage for inhibitors of SARS-CoV-2 spike-driven entry. Analysis of antiviral fractions revealed the presence of α1-antitrypsin (α1AT), a highly abundant circulating serine protease inhibitor. Here, we report that α1AT inhibits SARS-CoV-2 entry at physiological concentrations and suppresses viral replication in cell lines and primary cells including human airway epithelial cultures. We further demonstrate that α1AT binds and inactivates the serine protease TMPRSS2, which enzymatically primes the SARS-CoV-2 spike protein for membrane fusion. Thus, the acute phase protein α1AT is an inhibitor of TMPRSS2 and SARS-CoV-2 entry, and may play an important role in the innate immune defense against the novel coronavirus. Our findings suggest that repurposing of α1AT-containing drugs has prospects for the therapy of COVID-19.