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.
【저자키워드】 SARS-CoV-2, Translational research, TMPRSS2, 【초록키워드】 COVID-19, therapy, Antiviral, knowledge, drug, inhibitors, Spike protein, Novel coronavirus, Protein, Viral, viral replication, SARS-CoV-2 spike protein, membrane fusion, respiratory tract, respiratory, inhibitor, innate immune, Bronchoalveolar lavage, Concentration, airway epithelium, cell lines, physiological, primary cells, primary cell, Factor, Serine, inhibitors of SARS-CoV-2, acute phase, respiratory pathogen, SARS-CoV-2 entry, fraction, serine protease, serine protease TMPRSS2, circulating, cultures, cell line, serine protease inhibitor, Defense, infect, bind, identify, inhibit, screened, suppresse, human airway epithelial, the SARS-CoV-2, 【제목키워드】 SARS-COV-2 infection, TMPRSS2 protease, inhibit,