- Arg and Lys residues within ACE2 amino acids 697-716 are required for cleavage
- Cleavage of ACE2 receptor might promote spike protein driven entry of the virus

State University of New York at Stony Brook

TMPRSS2 is a human serine protease, an enzyme that cleaves a peptide chain via hydrolysis.  This enzyme has been shown to activate SARS-Cov-2 S protein by cleaving the S1 and S2 subunits of the S protein in order to expose the S2 subunit.  This allows the viral membrane to fuse with the cellular membrane.  Consequently, this process helps facilitate infection.  TMPRSS2 is also responsible for cleaving ACE2 receptors to further enhance SARS-CoV-2 entry.  This serine protease does not have a known, relevant function in human physiology and therefore could be a promising therapeutic target.  

TMPRSS2 in the Pathogenesis of COVID-19

Heurich, A., Hofmann-Winkler, H., Gierer, S., Liepold, T., Jahn, O., & Pöhlmann, S. (2014). TMPRSS2 and ADAM17 cleave ACE2 differentially and only proteolysis by TMPRSS2 augments entry driven by the severe acute respiratory syndrome coronavirus spike protein. Journal of virology, 88(2), 1293-1307.
doi: 10.1128/JVI.02202-13

TMPRSS2 and ADAM17 Cleave ACE2 Differentially and Only Proteolysis by TMPRSS2 Augments Entry Driven by the Severe Acute Respiratory Syndrome Coronavirus Spike Protein

Four potential TMPRSS2 protease inhibitors were tested:

- Chemostat

- Upamostat

- Nafmostat

- Bromhexine hydrochloride

Each of these existing, clinically proven drugs were found to bind to the catalytic pocket of TMPRSS2 with high precision and specificity.  Theoretically, these drugs could impede SARS-CoV-2 S proteins from interacting with TMPRSS2 which would consequently influence infectivity.  This could be a hopeful target for antiviral drugs or a future vaccine.  

Using Serine Protease Inhibitors to Treat or Prevent COVID-19

Two potential TMPRSS2 binding sites on the SARS-CoV-2 spike protein have deep identified:

- Site 1: aa837 to aa 845

- Site 2: aa 976 to aa986

Both of these sites are located in the S2 subunit of the S protein.  As shown in this figure, these binding sites are largely homologous to those of SARS-CoV-1.

TMPRSS2 Binding Sites in SARS-CoV-2 S Protein

Because the incidence and mortality rates of COVID-19 are significantly different in different regions of the world, it is thought that human variation may play a greater role than viral variation in determining these outcomes.  Significant variation in the gene TMPRSS2, which codes for the protease TMPRSS2, has been observed in different ethnic groups.  This may contribute to the different rates of infectivity seen in different populations.  

Genetic variation within the TMPRSS2 protease may play a role in COVID-19 infection

This graph displays the variance in the amount of TMPRSS2 expression there is in different types of tissues within the human body.

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