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

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 TMPRSS2 by androgen in mouse and human cells. Additionally, we demonstrate the endogenous interaction between TMPRSS2 and ACE2 in human cells and validate ACE2 as a TMPRSS2 substrate. Furthermore, 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 of a direct role of TMPRSS2 in priming the SARS-CoV-2 Spike, required for viral fusion to the host cell. Importantly, androgen-deprivation, anti-androgens, or camostat attenuated the SARS-CoV-2 S-mediated cellular entry. Together, our data provide a strong rationale for clinical evaluations of TMPRSS2 inhibitors and androgen-deprivation therapy/androgen receptor antagonists alone or in combination with antiviral drugs as early as clinically possible to prevent COVID-19 progression.

Automated summary

The study suggests a potential role of androgen in SARS-CoV-2 infection by regulating ACE2 and TMPRSS2 transcription. Camostat, a TMPRSS2 inhibitor, blocks the cleavage of SARS-CoV-2 Spike protein, providing evidence of TMPRSS2's direct role in viral fusion to host cells. Androgen-deprivation, anti-androgens, or camostat attenuate SARS-CoV-2 cellular entry, highlighting the importance of TMPRSS2 inhibitors and androgen-deprivation therapy in preventing COVID-19 progression.