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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.
Highlights
The COVID-19 pandemic is caused by the severe acute respiratory syndrome (SARS)-coronavirus (CoV)-2
Using serial dilutions of recombinant TMPRSS2, we estimated that the amount of TMPRSS2 that is expressed by TMPRSS2-overexpressing cells is about 100 ng/well (Supplementary Figure 1)
Our results suggest that TMPRSS2 interacts with alpha 1 antitrypsin (A1AT) through its reactive center loop (RCL), driven by complementary electrostatic interactions at their surfaces (Figure 3B)
Summary
The COVID-19 pandemic is caused by the severe acute respiratory syndrome (SARS)-coronavirus (CoV)-2. SARS-CoV-2 entry into host cells relies on the proteolytic processing of spike (S) protein by host proteases and engagement of the angiotensin-converting enzyme 2 (ACE2) receptor [1]. The S protein cleavage may occur extracellularly near the plasma membrane by cell surface proteases or intracellularly by lysosomal endopeptidase enzymes, such as cathepsin L, which facilitate viral entry by activating membrane fusion and subsequent cell entry through endocytosis, as in the case of MERS-CoV [2]. Host proteases have been suggested to be crucial for dissemination of MERS, SARSCoV, 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
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