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

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

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

Pathog Immun. 2021 Apr 26;6(1):55-74. doi: 10.20411/pai.v6i1.408. eCollection 2021.

Authors

Nurit P Azouz^{1

2}, Andrea M Klingler¹, Victoria Callahan³, Ivan V Akhrymuk^{3

4}, Katarina Elez⁵, Lluís Raich⁵, Brandon M Henry⁶, Justin L Benoit⁷, Stefanie W Benoit^{8

2}, Frank Noé^{5

9

10}, Kylene Kehn-Hall^{3

4}, Marc E Rothenberg^{1

2}

Affiliations

¹ Division of Allergy and Immunology, Cincinnati Children's Hospital Medical Center, Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH.
² Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH.
³ National Center for Biodefense and Infectious Diseases, School of Systems Biology, George Mason University, Manassas, VA.
⁴ Department of Biomedical Sciences and Pathobiology, Virginia Polytechnic Institute and State University, Blacksburg, VA.
⁵ Freie Universität Berlin, Department of Mathematics and Computer Science, Berlin, Germany.
⁶ Cardiac Intensive Care Unit, The Heart Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, OH.
⁷ Department of Emergency Medicine, University of Cincinnati, Cincinnati, OH.
⁸ Division of Nephrology and Hypertension, Cincinnati Children's Hospital Medical Center, Cincinnati, OH.
⁹ Freie Universität Berlin, Department of Physics, Berlin, Germany.
¹⁰ Rice University, Department of Chemistry, Houston, TX.

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.

Keywords: COVID; TMPRSS2; alpha 1 antitrypsin; camostat mesylate; coronavirus; protease.