Alpha 1 Antitrypsin is an Inhibitor of the SARS-CoV-2–Priming Protease TMPRSS2
dc.citation.firstpage | 55 | en_US |
dc.citation.issueNumber | 1 | en_US |
dc.citation.journalTitle | Pathogens and Immunity | en_US |
dc.citation.lastpage | 74 | en_US |
dc.citation.volumeNumber | 6 | en_US |
dc.contributor.author | Azouz, Nurit P. | en_US |
dc.contributor.author | Klingler, Andrea M. | en_US |
dc.contributor.author | Callahan, Victoria | en_US |
dc.contributor.author | Akhrymuk, Ivan V. | en_US |
dc.contributor.author | Elez, Katarina | en_US |
dc.contributor.author | Raich, Lluís | en_US |
dc.contributor.author | Henry, Brandon M. | en_US |
dc.contributor.author | Benoit, Justin L. | en_US |
dc.contributor.author | Benoit, Stefanie W. | en_US |
dc.contributor.author | Noé, Frank | en_US |
dc.contributor.author | Kehn-Hall, Kylene | en_US |
dc.contributor.author | Rothenberg, Marc E. | en_US |
dc.date.accessioned | 2021-05-27T18:13:33Z | en_US |
dc.date.available | 2021-05-27T18:13:33Z | en_US |
dc.date.issued | 2021 | en_US |
dc.description.abstract | 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. | en_US |
dc.identifier.citation | Azouz, 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. | en_US |
dc.identifier.doi | https://doi.org/10.20411/pai.v6i1.408 | en_US |
dc.identifier.uri | https://hdl.handle.net/1911/110649 | en_US |
dc.language.iso | eng | en_US |
dc.publisher | Case Western Reserve University | en_US |
dc.rights | This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International License. | en_US |
dc.rights.uri | https://creativecommons.org/licenses/by/4.0/ | en_US |
dc.subject.keyword | COVID | en_US |
dc.subject.keyword | coronavirus | en_US |
dc.subject.keyword | TMPRSS2 | en_US |
dc.subject.keyword | protease | en_US |
dc.subject.keyword | alpha 1 antitrypsin | en_US |
dc.subject.keyword | camostat mesylate | en_US |
dc.title | Alpha 1 Antitrypsin is an Inhibitor of the SARS-CoV-2–Priming Protease TMPRSS2 | en_US |
dc.type | Journal article | en_US |
dc.type.dcmi | Text | en_US |
dc.type.publication | publisher version | en_US |
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