Targeting androgen regulation of TMPRSS2 and ACE2 as a therapeutic strategy to combat COVID-19

Abstract

The COVID-19 pandemic is expected to have an adverse effect on the progression of multiple cancers, including prostate cancer, due to the ensuing cytokine storm and associated oncogenic signaling. Epidemiological data showing increased severity and mortality of COVID-19 in men suggests a potential role for androgen in SARS-CoV-2 infection. Here, we present evidence for the transcriptional regulation of SARS-CoV-2 host cell receptor ACE2 and co-receptor TMPRSS2 by androgen in mouse tissues and human prostate and lung cell lines. Additionally, we demonstrate the endogenous interaction between TMPRSS2 and ACE2 in human cells and validate ACE2 as a TMPRSS2 substrate. In an overexpression model, and the prostate and lung cells, Camostat – a TMPRSS2 inhibitor, blocked the cleavage of pseudotype SARS-CoV-2 surface Spike without disrupting TMPRSS2-ACE2 interaction. Thus providing evidence for the first time a direct role of TMPRSS2 in priming the SARS-CoV-2 Spike protein, required for viral fusion to the host cell. Importantly, androgen-deprivation, anti-androgens such as enzalutamide/AR-PROTAC, or Camostat treatment attenuated the SARS-CoV-2 S-mediated entry in lung and prostate cells. Together, our preclinical data provide a strong rationale for clinical evaluations of the TMPRSS2 inhibitors, androgen-deprivation therapy and androgen receptor antagonists alone or in combination with anti-viral drugs as early as clinically possible to prevent inflammation driven COVID-19 progression.

Evolutionary Inference Predicts Novel ACE2 Protein Interactions Relevant to COVID-19 Pathologies

“…Androgen-AR signaling induces ACE2 (Wu et al, 2020), while knockdowns of AR result in downregulation of ACE2 (Samuel et al, 2020). AR agonists also reduce SARS-CoV-2 spike protein-mediated cellular entry (Deng, Rasool, Russell, Natesan, & Asangani, 2021). Additionally, AR is associated with COVID comorbidities (Dolan et al, 2020), and recently implicated in the severity of COVID-19 in women with polycystic ovarian syndrome, a disorder associate with high androgen levels and androgen sensitivity (Gotluru, Roach, Cherry, & Runowicz, 2021).…”

Increased Hospitalization and Mortality from COVID-19 in Prostate Cancer Patients

“…Camostat mesylate, a serine protease inhibitor, was found to block SARS-CoV-2 infection in the lungs by interfering with the activity of TMPRSS2 [ 23 ]. The regulation of TMPRSS2 by AR is also seen in the lungs [ 24 ] and has significant implications for COVID-19. A recent study demonstrated that blocking androgen receptors using AR antagonists, e.g., enzalutamide, apalutamide or AR degrader ARD-61, Bromodomain and extra-terminal domain (BET) agonist, or BET degrader, has a potential to block against SARS-Co-V2 infection [ 25 ].…”

“…A recent study demonstrated that blocking androgen receptors using AR antagonists, e.g., enzalutamide, apalutamide or AR degrader ARD-61, Bromodomain and extra-terminal domain (BET) agonist, or BET degrader, has a potential to block against SARS-Co-V2 infection [ 25 ]. Another study showed that a combination of antiviral drugs with TMPRSS2 or AR inhibitors could prevent SARS-Co-V2 infection [ 24 ].…”

A novel glucocorticoid and androgen receptor modulator reduces viral entry and innate immune inflammatory responses in the Syrian Hamster model of SARS-CoV-2

“…However, the low-dose PT150 treatment decreased TMPRSS2 expression at 5 and 7DPI, whereas high-dose PT150 treatment decreased TMPRSS2 expression at all timepoints, demonstrating a dose-response effect in modulating expression of TMPRSS2 in lung. Decreased production of both TMPRSS2 and ACE2 suggests that PT150 is a transcriptional inhibitor of these genes that likely prevents binding of co-activator proteins to the enhancer regions of TMPRSS2 [51] as well as ACE2 [50]. These data suggest that the anti-viral activity of PT150 is due to direct modulation of host defense that decreases viral entry points.…”

“…The copyright holder for this preprint this version posted February 22, 2021. ; https://doi.org/10.1101/2021.02.20.432110 doi: bioRxiv preprint inhibition of androgen receptor binding to the promoter of Ace2, thereby decreasing transcriptional activation, as reported for other anti-androgens [50]. Expression of TMPRSS2 was also investigated due to the requirement of this cell surface serine protease for processing of the viral S1 spike protein that is necessary for viral entry in complex with ACE2 (Fig 6).…”