TMPRSS2: A Key Host Factor in SARS-CoV-2 Infection and Potential Therapeutic Target

Abstract

The transmembrane serine protease 2 (TMPRSS2) gene plays a crucial role in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection by priming the viral spike protein for membrane fusion and facilitating viral entry into host cells. This review aims to explore the molecular function of TMPRSS2, its genetic variations, and its potential as a therapeutic target in corona virus disease 2019 (COVID-19) and other respiratory viral infections. TMPRSS2 is highly expressed in lung and prostate tissues and is regulated by androgens, which may contribute to sex-based differences in COVID-19 severity. Genetic polymorphisms in TMPRSS2 have been been associated with variability in disease susceptibility and severity across populations. Several TMPRSS2 inhibitors, including serine protease inhibitors, such as camostat mesylate and nafamostat, have demonstarted promise in blocking viral entry. In addition, RNA based strategies such as siRNA and clustered regularly interspaced short palindromic repeats offer potential approaches for downregulating TMPRSS2 expression. However, the development of selective inhibitors that avoid off target effects remains a challenge. The presence of TMPRSS2-ERG gene fusion, commonly found in prostate cancer, has also been linked to altered COVID-19 susceptibility, suggesting a complex interplay between viral infection and cancer biology. This review also discusses future perspectives, including large-scale genomic studies to identify high-risk individuals, the development of next-generation TMPRSS2 inhibitors, and potential broad-spectrum antiviral therapies targeting TMPRSS2.

Keywords: Severe acute respiratory syndrome coronavirus 2; Transmembrane serine protease 2; corona virus disease-2019; therapeutic target; viral entry.

Figure 1

Illustration of TMPRSS2 protein structure from the PDB database. TMPRSS2: Transmembrane protease serine 2, PDB: Protein Data Bank

Figure 2

TMPRSS2 structural domains. TMPRSS2: Transmembrane protease serine 2, LDLRA: Low-density lipoprotein receptor class A, SRCR: Scavenger Receptor Cysteine-Rich

Figure 3

Illustration of TMPRSS2 protein structure from the PDB database. TMPRSS2: Transmembrane protease serine 2, PDB: Protein Data Bank, ACE2: Angiotensin-converting enzyme 2, SARS-CoV-2: Severe acute respiratory syndrome coronavirus 2