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

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.

Human Cell Organelles in SARS-CoV-2 Infection: An Up-to-Date Overview

“…Furthermore, transmembrane protease serine 4 (TMPRSS4) is reported to activate SARS-CoV-2 S proteins along with TMPRSS2, and enable viral infection of the human small intestine [ 85 ]. TTSP enzymes are constructed of an N-terminal intracellular domain, a transmembrane domain, an extracellular variable stem region, and a C-terminal serine protease domain [ 86 ]. Although the physiological aspect of TMPRSS2 remains incomprehensible, it certainly plays an essential role in viral infection by priming and activating SARS-CoV-2 S proteins [ 48 ].…”

“…A large spectrum of TMPRSS2 inhibitors has already been reported, including small molecule compounds, peptides/proteins, and peptidomimetics ( Figure 2 ). The drugs usually inhibit proteolytic activity; however, reducing expression or synthesis of TMPRSS2 is being considered as a therapeutic target [ 86 ]. Camostat mesylate (CM) and nafamostat mesylate (NM) are identified as serine protease inhibitors belonging to the group of small molecule compounds that demonstrate activity against TMPRSS2.…”

“…Bestle et al reported strong inhibition of SARS-CoV-2 replication by treatment of Calu-3 cells with MI-432 and MI-1900 [ 87 ]. Consequently, the physiological tolerability of these compounds should be considered during the future development of antiviral therapeutics [ 86 , 124 ].…”

Will Peptides Help to Stop COVID-19?

“…The protease activity of TMPRSS2 facilitates activation of viral glycoproteins, prostate cancer progression, and cleavage of endogenous substrates, including PAR2 receptor, which modulates infl ammatory reactions, obesity, metabolism, and cancer. Inhibition of TMPRSS2 expression decreases the effi ciency of virus entry into the cell, although it can also reduce the cleavage of endogenous substrates [94]. In order to block the virus entry into the cell, TMPRSS2 could be inhibited with peptides containing arginine [95] or hydrophobic amino acids (e.g., isoleucine) used to block the hydrophobic pocket at the S1 subunit of the S protein that binds the protease [96].…”

Peptidomimetic inhibitors of TMPRSS2 block SARS-CoV-2 infection in cell culture

“…Subsequently, the transmembrane protease serine subtype 2 (TMPRSS2) primes the S protein which triggers conformational changes in S2 leading to fusion of the viral with the cellular membrane and delivery of the nucleocapsid into the cytoplasm 19 . Of note, TMPRSS2 not only cleaves and primes SARS-CoV-2 spike, but also surface proteins of several other viruses, including the hemagglutinin (HA) of certain influenza A virus strains, the fusion protein (F) of human metapneumovirus, and the spike proteins of human coronavirus 229E (HCoV-229E), Middle East respiratory syndrome coronavirus (MERS-CoV), and SARS-CoV 19 – 25 . TMPRSS2 priming is essential for triggering fusion of these virions with target cells and disruption of TMPRSS2 expression was found to markedly reduce influenza A virus, SARS-CoV and MERS-CoV infection and pathogenesis in mice.…”