tetano
Editor, Senior Moderator
Pathog Immun
. 2021 Apr 26;6(1):55-74.
doi: 10.20411/pai.v6i1.408. eCollection 2021.
Alpha 1 Antitrypsin is an Inhibitor of the SARS-CoV-2-Priming Protease TMPRSS2
Nurit P Azouz[SUP] 1 2 [/SUP], Andrea M Klingler[SUP] 1 [/SUP], Victoria Callahan[SUP] 3 [/SUP], Ivan V Akhrymuk[SUP] 3 4 [/SUP], Katarina Elez[SUP] 5 [/SUP], Llu?s Raich[SUP] 5 [/SUP], Brandon M Henry[SUP] 6 [/SUP], Justin L Benoit[SUP] 7 [/SUP], Stefanie W Benoit[SUP] 8 2 [/SUP], Frank No?[SUP] 5 9 10 [/SUP], Kylene Kehn-Hall[SUP] 3 4 [/SUP], Marc E Rothenberg[SUP] 1 2 [/SUP]
Affiliations
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.
. 2021 Apr 26;6(1):55-74.
doi: 10.20411/pai.v6i1.408. eCollection 2021.
Alpha 1 Antitrypsin is an Inhibitor of the SARS-CoV-2-Priming Protease TMPRSS2
Nurit P Azouz[SUP] 1 2 [/SUP], Andrea M Klingler[SUP] 1 [/SUP], Victoria Callahan[SUP] 3 [/SUP], Ivan V Akhrymuk[SUP] 3 4 [/SUP], Katarina Elez[SUP] 5 [/SUP], Llu?s Raich[SUP] 5 [/SUP], Brandon M Henry[SUP] 6 [/SUP], Justin L Benoit[SUP] 7 [/SUP], Stefanie W Benoit[SUP] 8 2 [/SUP], Frank No?[SUP] 5 9 10 [/SUP], Kylene Kehn-Hall[SUP] 3 4 [/SUP], Marc E Rothenberg[SUP] 1 2 [/SUP]
Affiliations
- PMID: 33969249
- PMCID: PMC8097828
- DOI: 10.20411/pai.v6i1.408
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.