Proxalutamide reduces SARS-CoV-2 infection and associated inflammatory response

by Selleckchem | Nov 25 2023

Early in the COVID-19 pandemic, data suggested that males had a higher risk of developing severe disease and that androgen deprivation therapy might be associated with protection. Combined with the fact that TMPRSS2 (transmembrane serine protease 2), a host entry factor for the SARS-CoV-2 virus, was a well-known androgen-regulated gene, this led to an upsurge of research investigating androgen receptor (AR)-targeting drugs. Proxalutamide, an AR antagonist, was shown in initial clinical studies to benefit COVID-19 patients; however, further validation is needed as one study was retracted. Due to continued interest in proxalutamide, which is in phase 3 trials, we examined its ability to impact SARS-CoV-2 infection and downstream inflammatory responses. Proxalutamide exerted similar effects as enzalutamide, an AR antagonist prescribed for advanced prostate cancer, in decreasing AR signaling and expression of TMPRSS2 and angiotensin-converting enzyme 2 (ACE2), the SARS-CoV-2 receptor. However, proxalutamide led to degradation of AR protein, which was not observed with enzalutamide. Proxalutamide inhibited SARS-CoV-2 infection with an IC50 value of 97 nM, compared to 281 nM for enzalutamide. Importantly, proxalutamide inhibited infection by multiple SARS-CoV-2 variants and synergized with remdesivir. Proxalutamide protected against cell death in response to tumor necrosis factor alpha and interferon gamma, and overall survival of mice was increased with proxalutamide treatment prior to cytokine exposure. Mechanistically, we found that proxalutamide increased levels of NRF2, an essential transcription factor that mediates antioxidant responses, and decreased lung inflammation. These data provide compelling evidence that proxalutamide can prevent SARS-CoV-2 infection and cytokine-induced lung damage, suggesting that promising clinical data may emerge from ongoing phase 3 trials.

Comments:

The information you provided describes a study or research findings related to the potential use of proxalutamide, an androgen receptor (AR) antagonist, in the treatment of COVID-19. Based on the information provided:

1. **Background:** Early in the pandemic, it was observed that males had a higher risk of severe disease, and androgen deprivation therapy seemed to offer some protection. This led to research on AR-targeting drugs due to the association between androgens and COVID-19 severity.

2. **Proxalutamide and AR Signaling:** Proxalutamide, similar to enzalutamide, decreased AR signaling and the expression of TMPRSS2 and ACE2, which are essential for SARS-CoV-2 entry into cells. Proxalutamide also degraded AR protein, a feature not shared with enzalutamide.

3. **Inhibition of SARS-CoV-2:** Proxalutamide demonstrated a stronger inhibition of SARS-CoV-2 infection compared to enzalutamide, as indicated by its lower IC50 value. It was effective against multiple SARS-CoV-2 variants and worked synergistically with remdesivir, a known antiviral medication for COVID-19.

4. **Protection Against Inflammation:** Proxalutamide protected cells from death caused by inflammatory cytokines. In mice, treatment with proxalutamide before cytokine exposure increased overall survival. The mechanism behind this protection involved increased levels of NRF2, a transcription factor that mediates antioxidant responses, and reduced lung inflammation.

5. **Implications and Ongoing Trials:** The findings suggest that proxalutamide has the potential to prevent SARS-CoV-2 infection and cytokine-induced lung damage. The data are promising, indicating that ongoing phase 3 trials might yield positive clinical results.

It's important to note that while these findings are encouraging, they are part of a specific study and should be considered in the context of broader scientific research. As of my last update in September 2021, I do not have access to real-time data or developments after that date. For the most recent and accurate information on this topic, I recommend consulting peer-reviewed scientific journals, medical databases, or trusted health organizations.