Androgen Receptors for COVID-19

There’s a report of an interesting small-molecule drug effort against the coronavirus that seems to have produced rather significant results. The idea goes back to effects that were noticed last year – for example, in this population-based study from Italy. It’s been known since the early days of the pandemic that males were overall more susceptible to severe disease than females, and there have been a number of hypotheses put forward to try to explain this. But an answer might lie back in the virus’s mechanism of infection. As the world knows, the current coronavirus uses the ACE2 protein as a cellular entry point, followed by a key protein cleavage effected by the nearby TMPRSS2 transmembrane serine protease. That one’s involved in more than one viral infection route, and the idea of using serine protease inhibitors as antivirals had already been tried against type A influenza  – but, it has to be said, without any dramatic success. Favipiravir is one such molecule, but it hasn’t made much of a dent in the pandemic, either.

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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