Suppression of Androgen Receptor (AR)-ACE2/TMPRSS2 Axis by AR Antagonists May Be Therapeutically Beneficial for Male COVID-19 Patients

Abstract

Background: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes a worldwide pandemic named coronavirus disease 2019 (COVID-19). The disease progression and mortality rates of patients with COVID-19 are higher in males than in females. Hence, we explored the potential mechanism of the COVID-19 gender disparity and searched for potential alternative therapeutic agents as unmet medical needs for male patients with COVID-19. Methods: We collected clinical data from 1339 COVID-19 patients and analyzed androgen receptor (AR) chromatin binding and expression patterns by ChIP-seq and scRNA-seq data. Moreover, we studied the androgen-induced expression of ACE-2 and TMPRSS2, two key proteins for SARS-CoV-2 cellular entry and infection and the blockage of these two key proteins with our AR antagonist Proxalutamide (GT0918) in normal lung cells, cancer cells derived from prostate and lung cancers. Furthermore, we examined the effect of GT0918 on inducible nitric oxide synthase (iNOS) and Tumor necrosis factor-alpha (TNF-α), the macrophage-activation markers, in mouse macrophage cells. Results: We demonstrated higher rates of disease progression and mortality of male COVID-19 patients. The mechanism of the gender disparity may result from the androgen-AR activation in male patients with COVID-19. We revealed that androgen-AR activation induced the expression of ACE2 and TMPRSS2 under the androgen-dependent condition in cells derived from prostate and lung cancer, which was inhibited by the blockage of AR signaling with AR antagonist GT0918. Importantly, GT0918 also inhibited the expression of macrophage activation markers iNOS and TNF-α, the biomarkers for macrophage polarization. These results support the role of androgen-AR signaling in the disease progression and mortality in male patients with COVID-19.