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

Authors :
Yuanyuan Qiao
Wotring, Jesse W.
Yang Zheng
Zhang, Charles J.
Yuping Zhang
Xia Jiang
Pretto, Carla D.
Eyunni, Sanjana
Parolia, Abhijit
Tongchen He
Caleb Cheng
Xuhong Cao
Rui Wang
Fengyun Su
Ellison, Stephanie J.
Yini Wang
Jun Qin
Honghua Yan
Qianxiang Zhou
Liandong Ma
Source :
Proceedings of the National Academy of Sciences of the United States of America; 7/25/2023, Vol. 120 Issue 30, Following p1-10, 13p
Publication Year :
2023

Abstract

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was shown in initial clinical studies to benefit COVID-19 patients; however, further validation is needed as one study was retracted.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<subscript>50</subscript> 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. [ABSTRACT FROM AUTHOR]

Details

Language :
English
ISSN :
00278424
Volume :
120
Issue :
30
Database :
Complementary Index
Journal :
Proceedings of the National Academy of Sciences of the United States of America
Publication Type :
Academic Journal
Accession number :
165561941
Full Text :
https://doi.org/10.1073/pnas.2221809120