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Alpha 1 Antitrypsin is an Inhibitor of the SARS-CoV-2-Priming Protease TMPRSS2.
Azouz, Nurit P; Klingler, Andrea M; Callahan, Victoria; Akhrymuk, Ivan V; Elez, Katarina; Raich, Lluís; Henry, Brandon M; Benoit, Justin L; Benoit, Stefanie W; Noé, Frank; Kehn-Hall, Kylene; Rothenberg, Marc E.
  • Azouz NP; Division of Allergy and Immunology, Cincinnati Children's Hospital Medical Center, Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH.
  • Klingler AM; Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH.
  • Callahan V; Division of Allergy and Immunology, Cincinnati Children's Hospital Medical Center, Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH.
  • Akhrymuk IV; National Center for Biodefense and Infectious Diseases, School of Systems Biology, George Mason University, Manassas, VA.
  • Elez K; National Center for Biodefense and Infectious Diseases, School of Systems Biology, George Mason University, Manassas, VA.
  • Raich L; Department of Biomedical Sciences and Pathobiology, Virginia Polytechnic Institute and State University, Blacksburg, VA.
  • Henry BM; Freie Universität Berlin, Department of Mathematics and Computer Science, Berlin, Germany.
  • Benoit JL; Freie Universität Berlin, Department of Mathematics and Computer Science, Berlin, Germany.
  • Benoit SW; Cardiac Intensive Care Unit, The Heart Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, OH.
  • Noé F; Department of Emergency Medicine, University of Cincinnati, Cincinnati, OH.
  • Kehn-Hall K; Division of Nephrology and Hypertension, Cincinnati Children's Hospital Medical Center, Cincinnati, OH.
  • Rothenberg ME; Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH.
Pathog Immun ; 6(1): 55-74, 2021.
Article in English | MEDLINE | ID: covidwho-1222332
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.
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Full text: Available Collection: International databases Database: MEDLINE Type of study: Prognostic study Language: English Journal: Pathog Immun Year: 2021 Document Type: Article

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Full text: Available Collection: International databases Database: MEDLINE Type of study: Prognostic study Language: English Journal: Pathog Immun Year: 2021 Document Type: Article