Alpha 1 Antitrypsin is an Inhibitor of the SARS-CoV-2–Priming Protease TMPRSS2

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dc.citation.firstpage55
dc.citation.issueNumber1
dc.citation.journalTitlePathogens and Immunity
dc.citation.lastpage74
dc.citation.volumeNumber6
dc.contributor.authorAzouz, Nurit P.
dc.contributor.authorKlingler, Andrea M.
dc.contributor.authorCallahan, Victoria
dc.contributor.authorAkhrymuk, Ivan V.
dc.contributor.authorElez, Katarina
dc.contributor.authorRaich, Lluís
dc.contributor.authorHenry, Brandon M.
dc.contributor.authorBenoit, Justin L.
dc.contributor.authorBenoit, Stefanie W.
dc.contributor.authorNoé, Frank
dc.contributor.authorKehn-Hall, Kylene
dc.contributor.authorRothenberg, Marc E.
dc.date.accessioned2021-05-27T18:13:33Z
dc.date.available2021-05-27T18:13:33Z
dc.date.issued2021
dc.description.abstractBackground: 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.
dc.identifier.citationAzouz, 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.
dc.identifier.doihttps://doi.org/10.20411/pai.v6i1.408
dc.identifier.urihttps://hdl.handle.net/1911/110649
dc.language.isoeng
dc.publisherCase Western Reserve University
dc.rightsThis is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International License.
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/
dc.subject.keywordCOVID
dc.subject.keywordcoronavirus
dc.subject.keywordTMPRSS2
dc.subject.keywordprotease
dc.subject.keywordalpha 1 antitrypsin
dc.subject.keywordcamostat mesylate
dc.titleAlpha 1 Antitrypsin is an Inhibitor of the SARS-CoV-2–Priming Protease TMPRSS2
dc.typeJournal article
dc.type.dcmiText
dc.type.publicationpublisher version
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