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

dc.citation.firstpage55en_US
dc.citation.issueNumber1en_US
dc.citation.journalTitlePathogens and Immunityen_US
dc.citation.lastpage74en_US
dc.citation.volumeNumber6en_US
dc.contributor.authorAzouz, Nurit P.en_US
dc.contributor.authorKlingler, Andrea M.en_US
dc.contributor.authorCallahan, Victoriaen_US
dc.contributor.authorAkhrymuk, Ivan V.en_US
dc.contributor.authorElez, Katarinaen_US
dc.contributor.authorRaich, Lluísen_US
dc.contributor.authorHenry, Brandon M.en_US
dc.contributor.authorBenoit, Justin L.en_US
dc.contributor.authorBenoit, Stefanie W.en_US
dc.contributor.authorNoé, Franken_US
dc.contributor.authorKehn-Hall, Kyleneen_US
dc.contributor.authorRothenberg, Marc E.en_US
dc.date.accessioned2021-05-27T18:13:33Zen_US
dc.date.available2021-05-27T18:13:33Zen_US
dc.date.issued2021en_US
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.en_US
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.en_US
dc.identifier.doihttps://doi.org/10.20411/pai.v6i1.408en_US
dc.identifier.urihttps://hdl.handle.net/1911/110649en_US
dc.language.isoengen_US
dc.publisherCase Western Reserve Universityen_US
dc.rightsThis is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International License.en_US
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/en_US
dc.subject.keywordCOVIDen_US
dc.subject.keywordcoronavirusen_US
dc.subject.keywordTMPRSS2en_US
dc.subject.keywordproteaseen_US
dc.subject.keywordalpha 1 antitrypsinen_US
dc.subject.keywordcamostat mesylateen_US
dc.titleAlpha 1 Antitrypsin is an Inhibitor of the SARS-CoV-2–Priming Protease TMPRSS2en_US
dc.typeJournal articleen_US
dc.type.dcmiTexten_US
dc.type.publicationpublisher versionen_US
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