Journal Article

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

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

2021

Overview

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 α 1 -antitrypsin (α 1 AT), a highly abundant circulating serine protease inhibitor. Here, we report that α 1 AT 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 α 1 AT binds and inactivates the serine protease TMPRSS2, which enzymatically primes the SARS-CoV-2 spike protein for membrane fusion. Thus, the acute phase protein α 1 AT 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 α 1 AT-containing drugs has prospects for the therapy of COVID-19. Here, via screening of a polypeptide library from bronchoalveolar lavage, the authors identify and characterize α 1 -antitrypsin (α 1 AT) as SARS-CoV-2 inhibitor and show that α 1 AT binds and inactivates the serine protease TMPRSS2, which enzymatically primes the SARS-CoV-2 spike protein for membrane fusion.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 13 / 13/1 / 13/51 / 14 / 631/326/596/4130 / 692/308/575 / 82/58 / A1-antitrypsin / Acute phase proteins / alpha 1-Antitrypsin - pharmacology / Alveoli / Antibodies, Viral - blood / Antiviral agents / Antiviral Agents - pharmacology / Antiviral drugs / Bronchus / Caco-2 Cells / Cell lines / Coronaviruses / COVID-19 / COVID-19 - blood / COVID-19 - drug therapy / Epithelium / Fusion protein / Humanities and Social Sciences / Humans / Immune system / Immunoglobulin G - blood / Immunosuppressive agents / Lavage / Libraries / Membrane fusion / Membrane proteins / Membranes / Molecular Docking Simulation / multidisciplinary / Polypeptides / Protease / Protease inhibitors / Proteinase inhibitors / Proteins / Respiratory tract / SARS-CoV-2 - drug effects / Science / Science (multidisciplinary) / Serine / Serine Endopeptidases - metabolism / Serine proteinase / Serine Proteinase Inhibitors - pharmacology / Severe acute respiratory syndrome coronavirus 2 / Spike Glycoprotein, Coronavirus - metabolism / Spike protein / Viral diseases / Virus Internalization - drug effects / Virus Replication - drug effects