The discovery and development of transmembrane serine protease 2 (TMPRSS2) inhibitors as candidate drugs for the treatment of COVID-19

ABSTRACT

Introduction

Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has caused the devastating pandemic named coronavirus disease 2019 (COVID-19). Unfortunately, the discovery of antiviral agents to combat COVID-19 is still an unmet need. Transmembrane serine protease 2 (TMPRSS2) is an important mediator in viral infection and thus, TMPRRS2 inhibitors may be attractive agents for COVID-19 treatment.

Areas covered

This review article discusses the role of TMPRSS2 in SARS-CoV-2 cell entry and summarizes the inhibitors of TMPRSS2 and their potential anti-SARS activity. Two known TMPRSS2 inhibitors, namely camostat and nafamostat, approved drugs for the treatment of pancreatitis, are under clinical trials as potential drugs against COVID-19.

Expert opinion

Due to the lack of the crystal structure of TMPRSS2, homology models have been developed to study the interactions of known inhibitors, including repurposed drugs, with the enzyme. However, novel TMPRSS2 inhibitors have been identified through high-throughput screening, and appropriate assays studying their in vitro activity have been set up. The discovery of TMPRSS2ʹs crystal structure will facilitate the rational design of novel inhibitors and in vivo studies and clinical trials will give a clear answer if TMPRSS2 inhibitors could be a new weapon against COVID-19.

KEYWORDS:

• Clinical trials
• COVID-19
• inhibitors
• SARS-CoV-2
• transmembrane serine protease 2 (TMPRSS2)

Article highlights

• Transmembrane serine protease 2 (TMPRSS2) is an enzyme that plays an important role in cell entry and viral infection by SARS-CoV-2, and thus, it is an attractive target for the development of inhibitors as new antiviral agents.

• Adopting high-throughput strategies and homology model studies, novel agents able to inhibit TMPRRS2 have been already identified.

• Camostat and nafamostat, known TMPRRS2 inhibitors and approved drugs for the treatment of pancreatitis, are under clinical trials against COVID-19.

• The determination of TMPRSS2 crystal structure may facilitate the rational design of novel inhibitors.

• Inhibitors of TMPRRS2 may be new therapeutic agents for the treatment of COVID-19.

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Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.