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

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dc.contributor.authorAzouz, N. P.en
dc.contributor.authorKlingler, A. M.en
dc.contributor.authorCallahan, Victoriaen
dc.contributor.authorAkhrymuk, Ivan V.en
dc.contributor.authorElez, K.en
dc.contributor.authorRaich, L.en
dc.contributor.authorHenry, B. M.en
dc.contributor.authorBenoit, J. L.en
dc.contributor.authorBenoit, S. W.en
dc.contributor.authorNoé, F.en
dc.contributor.authorKehn-Hall, Kyleneen
dc.contributor.authorRothenberg, M. E.en
dc.contributor.departmentBiomedical Sciences and Pathobiologyen
dc.date.accessioned2021-08-25T16:15:55Zen
dc.date.available2021-08-25T16:15:55Zen
dc.date.issued2021-01-01en
dc.date.updated2021-08-25T16:15:51Zen
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
dc.description.versionPublished versionen
dc.format.extentPages 55-74en
dc.format.mimetypeapplication/pdfen
dc.identifier.doihttps://doi.org/10.20411/pai.v6i1.408en
dc.identifier.eissn2469-2964en
dc.identifier.issn2469-2964en
dc.identifier.issue1en
dc.identifier.orcidKehn-Hall, Kylene [0000-0001-8036-7213]en
dc.identifier.otherPMC8097828en
dc.identifier.otherpai.v6i1.408 (PII)en
dc.identifier.pmid33969249en
dc.identifier.urihttp://hdl.handle.net/10919/104707en
dc.identifier.volume6en
dc.language.isoenen
dc.relation.urihttps://www.ncbi.nlm.nih.gov/pubmed/33969249en
dc.rightsCreative Commons Attribution 4.0 Internationalen
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/en
dc.subjectCOVIDen
dc.subjectTMPRSS2en
dc.subjectalpha 1 antitrypsinen
dc.subjectcamostat mesylateen
dc.subjectcoronavirusen
dc.subjectproteaseen
dc.titleAlpha 1 Antitrypsin is an Inhibitor of the SARS-CoV-2–Priming Protease TMPRSS2en
dc.title.serialPathogens and Immunityen
dc.typeArticle - Refereeden
dc.type.dcmitypeTexten
dc.type.otherJournal Articleen
dcterms.dateAccepted2021-03-12en
pubs.organisational-group/Virginia Techen
pubs.organisational-group/Virginia Tech/Veterinary Medicineen
pubs.organisational-group/Virginia Tech/Veterinary Medicine/Biomedical Sciences and Pathobiologyen
pubs.organisational-group/Virginia Tech/All T&R Facultyen
pubs.organisational-group/Virginia Tech/Veterinary Medicine/CVM T&R Facultyen

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