Distinct mechanisms for TMPRSS2 expression explain organ-specific inhibition of SARS-CoV-2 infection by enzalutamide.

Abstract

The coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has rapidly become a global public health threat. The efficacy of several repurposed drugs has been evaluated in clinical trials. Among these drugs, a second-generation antiandrogen agent, enzalutamide, was proposed because it reduces the expression of transmembrane serine protease 2 (TMPRSS2), a key component mediating SARS-CoV-2-driven entry, in prostate cancer cells. However, definitive evidence for the therapeutic efficacy of enzalutamide in COVID-19 is lacking. Here, we evaluated the antiviral efficacy of enzalutamide in prostate cancer cells, lung cancer cells, human lung organoids and Ad-ACE2-transduced mice. Tmprss2 knockout significantly inhibited SARS-CoV-2 infection in vivo. Enzalutamide effectively inhibited SARS-CoV-2 infection in human prostate cells, however, such antiviral efficacy was lacking in human lung cells and organoids. Accordingly, enzalutamide showed no antiviral activity due to the AR-independent TMPRSS2 expression in mouse and human lung epithelial cells. Moreover, we observed distinct AR binding patterns between prostate cells and lung cells and a lack of direct binding of AR to TMPRSS2 regulatory locus in human lung cells. Thus, our findings do not support the postulated protective role of enzalutamide in treating COVID-19 through reducing TMPRSS2 expression in lung cells.

• Authors: Fei Li, Ming Han, Pengfei Dai, Wei Xu, Juan He, Xiaoting Tao, Yang Wu, Xinyuan Tong, Xinyi Xia, Wangxin Guo, Yunjiao Zhou, Yunguang Li, Yiqin Zhu, Xiaoyu Zhang, Zhuang Liu, Rebiguli Aji, Xia Cai, Yutang Li, Di Qu, Yu Chen, Shibo Jiang, Qiao Wang, Hongbin Ji, Youhua Xie, Yihua Sun, Lu Lu, Dong Gao
• Journal: Nature communications (Nat Commun) Vol. 12 Issue 1 Pg. 866 (02 08 2021) ISSN: 2041-1723 [Electronic] England
• PMID: 33558541 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Benzamides
• Nitriles
• Phenylthiohydantoin
• enzalutamide
• Angiotensin-Converting Enzyme 2
• Serine Endopeptidases
• TMPRSS2 protein, human
• TMPRSS2 protein, mouse

Topics

• Angiotensin-Converting Enzyme 2 (genetics, metabolism)
• Animals
• Benzamides
• COVID-19 (epidemiology, prevention & control, virology)
• Cell Line, Tumor
• Cells, Cultured
• Gene Expression (drug effects)
• Host-Pathogen Interactions (drug effects)
• Humans
• Male
• Mice, Knockout
• Nitriles
• Organ Specificity (genetics)
• Pandemics
• Phenylthiohydantoin (analogs & derivatives, pharmacology)
• Prostatic Neoplasms (metabolism, pathology, virology)
• Protein Binding (drug effects)
• SARS-CoV-2 (drug effects, physiology)
• Serine Endopeptidases (genetics, metabolism)
• Mice