Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2022 Jan 25;23(3):1351.
doi: 10.3390/ijms23031351.

The Transmembrane Protease TMPRSS2 as a Therapeutic Target for COVID-19 Treatment

Lukas Wettstein  1 , Frank Kirchhoff  1 , Jan Münch  1
Affiliations
Review

The Transmembrane Protease TMPRSS2 as a Therapeutic Target for COVID-19 Treatment

Lukas Wettstein et al. Int J Mol Sci. .

Abstract

TMPRSS2 is a type II transmembrane protease with broad expression in epithelial cells of the respiratory and gastrointestinal tract, the prostate, and other organs. Although the physiological role of TMPRSS2 remains largely elusive, several endogenous substrates have been identified. TMPRSS2 serves as a major cofactor in SARS-CoV-2 entry, and primes glycoproteins of other respiratory viruses as well. Consequently, inhibiting TMPRSS2 activity is a promising strategy to block viral infection. In this review, we provide an overview of the role of TMPRSS2 in the entry processes of different respiratory viruses. We then review the different classes of TMPRSS2 inhibitors and their clinical development, with a focus on COVID-19 treatment.

Keywords: SARS-CoV-2; TMPRSS2; coronavirus; influenza; protease inhibitor.

PubMed Disclaimer

Conflict of interest statement

L.W. and J.M. are inventors on patent applications claiming to use TMPRSS2-inhibitory peptidomimetics, peptides and proteins as antivirals.

Figures

Figure 1
Figure 1
(Patho)-physiological role of TMPRSS2. Left panel: the protease activity of TMPRSS2 contributes to the activation of viral glycoproteins, the progression of prostate cancer, and the cleavage of endogenous substrates such as the epithelial sodium channel, TTSP zymogens, and protease activated receptors. Inhibition of TMPRSS2 expression or protease activity (red arrows, right panel) results in reduced prostate cancer growth and viral entry, although it may also lead to reduced cleavage of endogenous substrates. Figure created with BioRender.com (accessed on 13 December 2021).
Figure 2
Figure 2
Architecture of TMPRSS2. CP: cytoplasmatic domain; TM: transmembrane domain; EC: extracellular domain; LDLRA: low density lipoprotein receptor class A domain; SRCR: scavenger receptor cysteine-rich domain; H, D, S: catalytic triad (histidine, aspartate, serine); N and C: N- and C-terminus, respectively. S-S indicates disulfide bridge (note that only the disulfide bridge between the catalytic and SRCR domains is shown, with the remaining disulfide bridges omitted for clarity). Numbers indicate amino acid position according to UniProt O15393. Figure created with BioRender.com (accessed on 13 December 2021).
Figure 3
Figure 3
Schematic representation of (a) influenza virus hemagglutinin (HA) and (b) coronavirus spike (S) glycoproteins. FP: fusion peptide, TM: transmembrane domain. Downward arrows indicate TMPRSS2 cleavage sites. Sequences derived from Uniprot Q9WFX3 (H1N1); P59594 (SARS-CoV); A0A023SFE5 (MERS-CoV); P0DTC2 (SARS-CoV-2). (c) Schematic representation of SARS-CoV-2 entry mediated by TMPRSS2. Figure created with BioRender (accessed on 13 December 2021).
Figure 4
Figure 4
Overview of inhibitors of TMPRSS2 protease activity.
See this image and copyright information in PMC

References

    1. Turk B. Targeting proteases: Successes, failures and future prospects. Nat. Rev. Drug Discov. 2006;5:785–799. doi: 10.1038/nrd2092. - DOI - PubMed
    1. López-Otín C., Bond J.S. Proteases: Multifunctional enzymes in life and disease. J. Biol. Chem. 2008;283:30433–30437. doi: 10.1074/jbc.R800035200. - DOI - PMC - PubMed
    1. Hedstrom L. Serine protease mechanism and specificity. Chem. Rev. 2002;102:4501–4523. doi: 10.1021/cr000033x. - DOI - PubMed
    1. Bugge T.H., Antalis T.M., Wu Q. Type II transmembrane serine proteases. J. Biol. Chem. 2009;284:23177–23181. doi: 10.1074/jbc.R109.021006. - DOI - PMC - PubMed
    1. Barré O., Dufour A., Eckhard U., Kappelhoff R., Béliveau F., Leduc R., Overall C.M. Cleavage specificity analysis of six type II transmembrane serine proteases (TTSPs) using PICS with proteome-derived peptide libraries. PLoS ONE. 2014;9:e105984. doi: 10.1371/journal.pone.0105984. - DOI - PMC - PubMed

MeSH terms

Substances

LinkOut - more resources