But there are other ways to target this mechanism. It turns out that TMPRSS2 expression is linked to the transcriptional-activating activity of the androgen receptor. The Italian work linked above found that men who were taking androgen receptor antagonists (generally as a treatment for prostate cancer) seemed to be at significantly lower COVID-19 risk, which result is especially striking considering that pre-existing cancer in general is a risk factor for severe coronavirus outcomes. Instead of trying to inhibit TMPRSS2 activity at its active site, AR antagonists keep it from being expressed in the cell membrane in the first place.
This line of thought has led to several followups. Here’s a proposal from last June that androgen antagonists be tried out in this fashion, and here’s a later study from Michigan that established that specific cell types in the airway do indeed co-express androgen receptors and TMPRSS2, which is then regulated in the lung by AR activity. In July, a Chinese company (Kintor Pharmaceutical) announced that it was providing an investigational androgen receptor antagonist (proxalutamide) for a clinical trial to be run in Brazil. And that trial has now read out. The press release says that there were very significant reductions in disease severity, in overall mortality, and in the length of hospitalization.
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