Background: Host proteases have been suggested to be crucial for dissemination of MERS, SARS-CoV, and SARS-CoV-2 coronaviruses, but the relative contribution of membrane versus intracellular proteases remains controversial. Transmembrane serine protease 2 (TMPRSS2) is regarded as one of the main proteases implicated in the coronavirus S protein priming, an important step for binding of the S protein to the angiotensin-converting enzyme 2 (ACE2) receptor before cell entry. Methods: We developed a cell-based assay to identify TMPRSS2 inhibitors. Inhibitory activity was established in SARS-CoV-2 viral load systems. Results: We identified the human extracellular serine protease inhibitor (serpin) alpha 1 anti-trypsin (A1AT) as a novel TMPRSS2 inhibitor. Structural modeling revealed that A1AT docked to an extracellular domain of TMPRSS2 in a conformation that is suitable for catalysis, resembling similar serine protease inhibitor complexes. Inhibitory activity of A1AT was established in a SARS-CoV-2 viral load system. Notably, plasma A1AT levels were associated with COVID-19 disease severity. Conclusions: Our data support the key role of extracellular serine proteases in SARS CoV-2 infections and indicate that treatment with serpins, particularly the FDA-approved drug A1AT, may be effective in limiting SARS-CoV-2 dissemination by affecting the surface of the host cells.
【저자키워드】 coronavirus, Camostat mesylate, protease, COVID, Alpha 1 antitrypsin, TMPRSS2, 【초록키워드】 SARS CoV-2, Treatment, SARS-CoV-2, ACE2, Coronaviruses, SARS-CoV, disease severity, Infection, MERS, angiotensin-converting enzyme 2, membrane, Alpha, plasma, receptor, dissemination, binding, host cells, Support, TMPRSS2 inhibitors, FDA-approved drug, SARS-CoV-2 viral load, domain, cell entry, priming, serine protease, TMPRSS2 inhibitor, serine protease inhibitor, coronavirus S protein, effective, Extracellular, identify, suggested, complexes, the S protein, implicated, affecting, docked, with COVID-19, 【제목키워드】 antitrypsin,