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

Qiao et al., PNAS, doi:10.1073/pnas.222180912
Jul 2023  
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In Vitro study showing dose-dependent inhibition of multiple SARS-CoV-2 variants with proxalutamide. Authors find that proxalutamide increased levels of NRF2 and decreased lung inflammation. Authors conclude that there is compelling evidence that proxalutamide can prevent SARS-CoV-2 infection and cytokine-induced lung damage.
2 preclinical studies support the efficacy of proxalutamide for COVID-19:
Qiao et al., 17 Jul 2023, peer-reviewed, 22 authors.
In Vitro studies are an important part of preclinical research, however results may be very different in vivo.
This PaperProxalutamideAll
Proxalutamide reduces SARS-CoV-2 infection and associated inflammatory response
Yuanyuan Qiao, Jesse W Wotring, Yang Zheng, Charles J Zhang, Yuping Zhang, Xia Jiang, Carla D Pretto, Sanjana Eyunni, Abhijit Parolia, Tongchen He, Caleb Cheng, Xuhong Cao, Rui Wang, Fengyun Su, Stephanie J Ellison, Yini Wang, Jun Qin, Honghua Yan, Qianxiang Zhou, Liandong Ma, Jonathan Z Sexton, Arul M Chinnaiyan
Proceedings of the National Academy of Sciences, doi:10.1073/pnas.2221809120
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was shown in initial clinical studies to benefit COVID-19 patients; however, further validation is needed as one study was retracted.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 IC 50 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.
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