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Review
. 2021 May;48(5):4667-4675.
doi: 10.1007/s11033-021-06390-1. Epub 2021 May 22.

Targeting the intestinal TMPRSS2 protease to prevent SARS-CoV-2 entry into enterocytes-prospects and challenges

Ismail Sami Mahmoud  1 , Yazun Bashir Jarrar  2
Affiliations
Review

Targeting the intestinal TMPRSS2 protease to prevent SARS-CoV-2 entry into enterocytes-prospects and challenges

Ismail Sami Mahmoud et al. Mol Biol Rep. 2021 May.

Abstract

The transmembrane protease serine 2 (TMPRSS2) is a membrane anchored protease that primarily expressed by epithelial cells of respiratory and gastrointestinal systems and has been linked to multiple pathological processes in humans including tumor growth, metastasis and viral infections. Recent studies have shown that TMPRSS2 expressed on cell surface of host cells could play a crucial role in activation of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein which facilitates the rapid early entry of the virus into host cells. In addition, direct suppression of TMPRSS2 using small drug inhibitors has been demonstrated to be effective in decreasing SARS-CoV-2 infection in vitro, which presents TMPRSS2 protease as a potential therapeutic strategy for SARS-CoV-2 infection. Recently, SARS-CoV-2 has been shown to be capable of infecting gastrointestinal enterocytes and to provoke gastrointestinal disorders in patients with COVID-19 disease, which is considered as a new transmission route and target organ of SARS-CoV-2. In this review, we highlight the biochemical properties of TMPRSS2 protease and discuss the potential targeting of TMPRSS2 by inhibitors to prevent the SARS-CoV-2 spreading through gastro-intestinal tract system as well as the hurdles that need to be overcome.

Keywords: Drug inhibitor; Enterocytes; SARS-CoV-2; Serine protease; TMPRSS2.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Fig. 1
Fig. 1
Structural domains of TMPRSS2 protein. A linear map of structural domains of TMPRSS2 protein. The C-terminus (COOH end) contains the key domains; serine protease domain, required for cleavage of the virus (S) protein, and the scavenger receptor cysteine rich domain and LDL class A like receptor which are required for binding to extracellular molecules and calcium binding, subsequently. It also contains a transmembrane domain (TM) for membrane anchoring and an intracellular N-terminus (NH2 end) cytoplasmic tail for appropriate intracellular trafficking. The figure was created using BioRender.com
Fig. 2
Fig. 2
TMPRSS2 mediated entry of SARS-CoV-2 into host cells. Upon SARS-CoV-2 binding to the cell surface, TMPRSS2 could potentially activate the virus entry into host cells by at least two main pathways. (Left) TMPRSS2 on the host cell surface mediates the proteolytic cleavage of the viral (S) protein which induces direct fusion of the viral and plasma membrane leading to release of the viral ssRNA into the cytoplasm. (Right) Alternatively, TMPRSS2 may cooperate with host cell receptor ACE2 in activation of SARS-CoV-2 (S) protein which then stimulates receptor mediated endocytosis, subsequently SARS-CoV-2 ends in endosomal compartments, where a decrease in endosomal pH stimulates cathepsin L enzymes which further cleave and activate viral (S) glycoprotein and facilitate the release of the viral ssRNA into the cytosol. The figure was created using BioRender.com
See this image and copyright information in PMC

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