tetano
Editor, Senior Moderator
Nat Commun
. 2021 Mar 19;12(1):1726.
doi: 10.1038/s41467-021-21972-0.
Alpha-1 antitrypsin inhibits TMPRSS2 protease activity and SARS-CoV-2 infection
Lukas Wettstein[SUP] #[/SUP][SUP] 1 [/SUP], Tatjana Weil[SUP] #[/SUP][SUP] 1 [/SUP], Carina Conzelmann[SUP] #[/SUP][SUP] 1 [/SUP], Janis A M?ller[SUP] 1 [/SUP], R?diger Gro?[SUP] 1 [/SUP], Maximilian Hirschenberger[SUP] 1 [/SUP], Alina Seidel[SUP] 1 [/SUP], Susanne Klute[SUP] 1 [/SUP], Fabian Zech[SUP] 1 [/SUP], Caterina Prelli Bozzo[SUP] 1 [/SUP], Nico Preising[SUP] 2 [/SUP], Giorgio Fois[SUP] 3 [/SUP], Robin Lochbaum[SUP] 3 [/SUP], Philip Maximilian Knaff[SUP] 4 5 [/SUP], Volker Mail?nder[SUP] 4 5 [/SUP], Ludger St?ndker[SUP] 2 [/SUP], Dietmar Rudolf Thal[SUP] 6 7 [/SUP], Christian Schumann[SUP] 8 [/SUP], Steffen Stenger[SUP] 9 [/SUP], Alexander Kleger[SUP] 10 [/SUP], G?nter Lochnit[SUP] 11 [/SUP], Benjamin Mayer[SUP] 12 [/SUP], Yasser B Ruiz-Blanco[SUP] 13 [/SUP], Markus Hoffmann[SUP] 14 15 [/SUP], Konstantin M J Sparrer[SUP] 1 [/SUP], Stefan P?hlmann[SUP] 14 [/SUP], Elsa Sanchez-Garcia[SUP] 13 [/SUP], Frank Kirchhoff[SUP] 1 [/SUP], Manfred Frick[SUP] 3 [/SUP], Jan M?nch[SUP] 16 17 [/SUP]
Affiliations
Abstract
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 ?[SUB]1[/SUB]-antitrypsin (?[SUB]1[/SUB]AT), a highly abundant circulating serine protease inhibitor. Here, we report that ?[SUB]1[/SUB]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 ?[SUB]1[/SUB]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 ?[SUB]1[/SUB]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 ?[SUB]1[/SUB]AT-containing drugs has prospects for the therapy of COVID-19.
. 2021 Mar 19;12(1):1726.
doi: 10.1038/s41467-021-21972-0.
Alpha-1 antitrypsin inhibits TMPRSS2 protease activity and SARS-CoV-2 infection
Lukas Wettstein[SUP] #[/SUP][SUP] 1 [/SUP], Tatjana Weil[SUP] #[/SUP][SUP] 1 [/SUP], Carina Conzelmann[SUP] #[/SUP][SUP] 1 [/SUP], Janis A M?ller[SUP] 1 [/SUP], R?diger Gro?[SUP] 1 [/SUP], Maximilian Hirschenberger[SUP] 1 [/SUP], Alina Seidel[SUP] 1 [/SUP], Susanne Klute[SUP] 1 [/SUP], Fabian Zech[SUP] 1 [/SUP], Caterina Prelli Bozzo[SUP] 1 [/SUP], Nico Preising[SUP] 2 [/SUP], Giorgio Fois[SUP] 3 [/SUP], Robin Lochbaum[SUP] 3 [/SUP], Philip Maximilian Knaff[SUP] 4 5 [/SUP], Volker Mail?nder[SUP] 4 5 [/SUP], Ludger St?ndker[SUP] 2 [/SUP], Dietmar Rudolf Thal[SUP] 6 7 [/SUP], Christian Schumann[SUP] 8 [/SUP], Steffen Stenger[SUP] 9 [/SUP], Alexander Kleger[SUP] 10 [/SUP], G?nter Lochnit[SUP] 11 [/SUP], Benjamin Mayer[SUP] 12 [/SUP], Yasser B Ruiz-Blanco[SUP] 13 [/SUP], Markus Hoffmann[SUP] 14 15 [/SUP], Konstantin M J Sparrer[SUP] 1 [/SUP], Stefan P?hlmann[SUP] 14 [/SUP], Elsa Sanchez-Garcia[SUP] 13 [/SUP], Frank Kirchhoff[SUP] 1 [/SUP], Manfred Frick[SUP] 3 [/SUP], Jan M?nch[SUP] 16 17 [/SUP]
Affiliations
- PMID: 33741941
- DOI: 10.1038/s41467-021-21972-0
Abstract
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 ?[SUB]1[/SUB]-antitrypsin (?[SUB]1[/SUB]AT), a highly abundant circulating serine protease inhibitor. Here, we report that ?[SUB]1[/SUB]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 ?[SUB]1[/SUB]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 ?[SUB]1[/SUB]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 ?[SUB]1[/SUB]AT-containing drugs has prospects for the therapy of COVID-19.