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

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 () and Dong Gao ()
Additional contact information
Fei Li: Chinese Academy of Sciences
Ming Han: Chinese Academy of Sciences
Pengfei Dai: Chinese Academy of Sciences
Wei Xu: Fudan University
Juan He: Chinese Academy of Sciences
Xiaoting Tao: Fudan University Shanghai Cancer Center
Yang Wu: Fudan University
Xinyuan Tong: Chinese Academy of Sciences
Xinyi Xia: Chinese Academy of Sciences
Wangxin Guo: Chinese Academy of Sciences
Yunjiao Zhou: Fudan University
Yunguang Li: Chinese Academy of Sciences
Yiqin Zhu: Chinese Academy of Sciences
Xiaoyu Zhang: Chinese Academy of Sciences
Zhuang Liu: Chinese Academy of Sciences
Rebiguli Aji: Chinese Academy of Sciences
Xia Cai: Fudan University
Yutang Li: Fudan University
Di Qu: Fudan University
Yu Chen: Memorial Sloan-Kettering Cancer Center
Shibo Jiang: Fudan University
Qiao Wang: Fudan University
Hongbin Ji: Chinese Academy of Sciences
Youhua Xie: Fudan University
Yihua Sun: Fudan University Shanghai Cancer Center
Lu Lu: Fudan University
Dong Gao: Chinese Academy of Sciences

Nature Communications, 2021, vol. 12, issue 1, 1-14

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41467-021-21171-x

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