Distinct mechanisms for TMPRSS2 expression explain organ-specific inhibition of SARS-CoV-2 infection by enzalutamide

Area of Science:

• Virology and Molecular Biology
• Drug Repurposing for Infectious Diseases

Background:

• The COVID-19 pandemic, caused by SARS-CoV-2, necessitates exploring effective therapeutic agents.
• Enzalutamide, an antiandrogen, was proposed to inhibit SARS-CoV-2 entry by reducing TMPRSS2 expression in prostate cancer cells.

Purpose of the Study:

• To evaluate the antiviral efficacy of enzalutamide against SARS-CoV-2 in various cell types and in vivo models.
• To investigate the mechanism behind enzalutamide's potential antiviral activity, focusing on TMPRSS2 expression and androgen receptor (AR) binding.

Main Methods:

• Assessment of enzalutamide's antiviral efficacy in prostate cancer cells, lung cancer cells, and human lung organoids.
• In vivo studies using Ad-ACE2-transduced mice with and without Tmprss2 knockout.
• Analysis of AR binding patterns and AR's regulatory role on TMPRSS2 expression in different cell types.

Main Results:

• Enzalutamide effectively inhibited SARS-CoV-2 infection in human prostate cells but showed no antiviral efficacy in human lung cells and organoids.
• Tmprss2 knockout significantly inhibited SARS-CoV-2 infection in vivo.
• AR-independent TMPRSS2 expression in lung epithelial cells and distinct AR binding patterns explain the lack of enzalutamide's antiviral activity in lung tissues.

Conclusions:

• Enzalutamide does not exhibit antiviral activity against SARS-CoV-2 in lung cells or organoids.
• The proposed therapeutic role of enzalutamide for COVID-19 via TMPRSS2 reduction in the lungs is not supported by these findings.
• Distinct AR regulation of TMPRSS2 in prostate versus lung cells underlies the differential efficacy of enzalutamide.