TMPRSS2 Inhibitor Discovery Facilitated through an In Silico and Biochemical Screening Platform

Area of Science:

• Biochemistry
• Virology
• Drug Discovery

Background:

• The COVID-19 pandemic necessitates novel antiviral therapies due to the ineffectiveness of current drugs against SARS-CoV-2.
• The host transmembrane serine protease, TMPRSS2, is a key target for antiviral development as it facilitates viral entry by priming the spike protein.

Purpose of the Study:

• To identify novel noncovalent inhibitors of TMPRSS2 using virtual screening and biochemical assays.
• To evaluate the efficacy of identified inhibitors in blocking SARS-CoV-2 infectivity in a cellular model.

Main Methods:

• Virtual screening of compound libraries to identify potential TMPRSS2 inhibitors.
• Optimization of recombinant TMPRSS2 peptidase domain expression and purification.
• Biochemical kinetic assays for inhibitor characterization.
• Cellular assays to assess SARS-CoV-2 infectivity inhibition.

Main Results:

• Identification of a focused collection of potential TMPRSS2 inhibitors.
• Discovery of new noncovalent TMPRSS2 inhibitors demonstrating efficacy in blocking SARS-CoV-2 infectivity.
• Debrisoquine identified as a potent inhibitor with high ligand efficiency and tractability for further development.

Conclusions:

• Noncovalent TMPRSS2 inhibitors represent a viable therapeutic strategy against SARS-CoV-2.
• Debrisoquine is a promising hit compound for developing new antiviral agents targeting TMPRSS2.