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

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 alpha (1)-antitrypsin (alpha (1)AT), a highly abundant circulating serine protease inhibitor. Here, we report that alpha (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 alpha (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 alpha (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 alpha (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 alpha (1)-antitrypsin (alpha (1)AT) as SARS-CoV-2 inhibitor and show that alpha (1)AT binds and inactivates the serine protease TMPRSS2, which enzymatically primes the SARS-CoV-2 spike protein for membrane fusion.

Automated summary

This study identifies alpha (1)-antitrypsin (alpha (1)AT) as an inhibitor of SARS-CoV-2 entry by binding and inactivating the serine protease TMPRSS2, which primes the virus spike protein for membrane fusion. Alpha (1)AT suppresses viral replication and may have therapeutic potential for COVID-19 treatment.