Azouz, Nurit P.Klingler, Andrea M.Callahan, VictoriaAkhrymuk, Ivan V.Elez, KatarinaRaich, LluísHenry, Brandon M.Benoit, Justin L.Benoit, Stefanie W.Noé, FrankKehn-Hall, KyleneRothenberg, Marc E.2021-05-272021-05-272021Azouz, Nurit P., Klingler, Andrea M., Callahan, Victoria, et al.. "Alpha 1 Antitrypsin is an Inhibitor of the SARS-CoV-2–Priming Protease TMPRSS2." <i>Pathogens and Immunity,</i> 6, no. 1 (2021) Case Western Reserve University: 55-74. https://doi.org/10.20411/pai.v6i1.408.https://hdl.handle.net/1911/110649Background: 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.engThis is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International License.Journal articleCOVIDcoronavirusTMPRSS2proteasealpha 1 antitrypsincamostat mesylatehttps://doi.org/10.20411/pai.v6i1.408