Nurit P Azouz, Andrea M Klingler, Victoria Callahan, Ivan V Akhrymuk, Katarina Elez, Lluís Raich, Brandon M Henry, Justin L Benoit, Stefanie W Benoit, Frank Noé, Kylene Kehn-Hall, Marc E Rothenberg
{"title":"α 1抗胰蛋白酶是sars - cov -2启动蛋白酶TMPRSS2的抑制剂。","authors":"Nurit P Azouz, Andrea M Klingler, Victoria Callahan, Ivan V Akhrymuk, Katarina Elez, Lluís Raich, Brandon M Henry, Justin L Benoit, Stefanie W Benoit, Frank Noé, Kylene Kehn-Hall, Marc E Rothenberg","doi":"10.20411/pai.v6i1.408","DOIUrl":null,"url":null,"abstract":"<p><strong>Background: </strong>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.</p><p><strong>Methods: </strong>We developed a cell-based assay to identify TMPRSS2 inhibitors. Inhibitory activity was established in SARS-CoV-2 viral load systems.</p><p><strong>Results: </strong>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.</p><p><strong>Conclusions: </strong>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.</p>","PeriodicalId":36419,"journal":{"name":"Pathogens and Immunity","volume":"6 1","pages":"55-74"},"PeriodicalIF":0.0000,"publicationDate":"2021-04-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8097828/pdf/","citationCount":"30","resultStr":"{\"title\":\"Alpha 1 Antitrypsin is an Inhibitor of the SARS-CoV-2-Priming Protease TMPRSS2.\",\"authors\":\"Nurit P Azouz, Andrea M Klingler, Victoria Callahan, Ivan V Akhrymuk, Katarina Elez, Lluís Raich, Brandon M Henry, Justin L Benoit, Stefanie W Benoit, Frank Noé, Kylene Kehn-Hall, Marc E Rothenberg\",\"doi\":\"10.20411/pai.v6i1.408\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Background: </strong>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.</p><p><strong>Methods: </strong>We developed a cell-based assay to identify TMPRSS2 inhibitors. Inhibitory activity was established in SARS-CoV-2 viral load systems.</p><p><strong>Results: </strong>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.</p><p><strong>Conclusions: </strong>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.</p>\",\"PeriodicalId\":36419,\"journal\":{\"name\":\"Pathogens and Immunity\",\"volume\":\"6 1\",\"pages\":\"55-74\"},\"PeriodicalIF\":0.0000,\"publicationDate\":\"2021-04-26\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8097828/pdf/\",\"citationCount\":\"30\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Pathogens and Immunity\",\"FirstCategoryId\":\"1085\",\"ListUrlMain\":\"https://doi.org/10.20411/pai.v6i1.408\",\"RegionNum\":0,\"RegionCategory\":null,\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"2021/1/1 0:00:00\",\"PubModel\":\"eCollection\",\"JCR\":\"Q1\",\"JCRName\":\"Medicine\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Pathogens and Immunity","FirstCategoryId":"1085","ListUrlMain":"https://doi.org/10.20411/pai.v6i1.408","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2021/1/1 0:00:00","PubModel":"eCollection","JCR":"Q1","JCRName":"Medicine","Score":null,"Total":0}
Alpha 1 Antitrypsin is an Inhibitor of the SARS-CoV-2-Priming Protease TMPRSS2.
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.