tetano
Editor, Senior Moderator
Nat Commun
. 2021 Feb 8;12(1):866.
doi: 10.1038/s41467-021-21171-x.
Distinct mechanisms for TMPRSS2 expression explain organ-specific inhibition of SARS-CoV-2 infection by enzalutamide
Fei Li[SUP] #[/SUP][SUP] 1 2 [/SUP], Ming Han[SUP] #[/SUP][SUP] 1 2 [/SUP], Pengfei Dai[SUP] #[/SUP][SUP] 1 2 [/SUP], Wei Xu[SUP] #[/SUP][SUP] 3 [/SUP], Juan He[SUP] #[/SUP][SUP] 1 2 [/SUP], Xiaoting Tao[SUP] #[/SUP][SUP] 4 5 [/SUP], Yang Wu[SUP] #[/SUP][SUP] 3 [/SUP], Xinyuan Tong[SUP] 1 2 [/SUP], Xinyi Xia[SUP] 1 2 [/SUP], Wangxin Guo[SUP] 1 2 [/SUP], Yunjiao Zhou[SUP] 3 [/SUP], Yunguang Li[SUP] 1 [/SUP], Yiqin Zhu[SUP] 1 [/SUP], Xiaoyu Zhang[SUP] 1 [/SUP], Zhuang Liu[SUP] 1 [/SUP], Rebiguli Aji[SUP] 1 2 [/SUP], Xia Cai[SUP] 3 [/SUP], Yutang Li[SUP] 3 [/SUP], Di Qu[SUP] 3 [/SUP], Yu Chen[SUP] 6 [/SUP], Shibo Jiang[SUP] 3 [/SUP], Qiao Wang[SUP] 3 [/SUP], Hongbin Ji[SUP] 1 [/SUP], Youhua Xie[SUP] 7 [/SUP], Yihua Sun[SUP] 8 9 [/SUP], Lu Lu[SUP] 10 [/SUP], Dong Gao[SUP] 11 12 13 [/SUP]
Affiliations
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.
. 2021 Feb 8;12(1):866.
doi: 10.1038/s41467-021-21171-x.
Distinct mechanisms for TMPRSS2 expression explain organ-specific inhibition of SARS-CoV-2 infection by enzalutamide
Fei Li[SUP] #[/SUP][SUP] 1 2 [/SUP], Ming Han[SUP] #[/SUP][SUP] 1 2 [/SUP], Pengfei Dai[SUP] #[/SUP][SUP] 1 2 [/SUP], Wei Xu[SUP] #[/SUP][SUP] 3 [/SUP], Juan He[SUP] #[/SUP][SUP] 1 2 [/SUP], Xiaoting Tao[SUP] #[/SUP][SUP] 4 5 [/SUP], Yang Wu[SUP] #[/SUP][SUP] 3 [/SUP], Xinyuan Tong[SUP] 1 2 [/SUP], Xinyi Xia[SUP] 1 2 [/SUP], Wangxin Guo[SUP] 1 2 [/SUP], Yunjiao Zhou[SUP] 3 [/SUP], Yunguang Li[SUP] 1 [/SUP], Yiqin Zhu[SUP] 1 [/SUP], Xiaoyu Zhang[SUP] 1 [/SUP], Zhuang Liu[SUP] 1 [/SUP], Rebiguli Aji[SUP] 1 2 [/SUP], Xia Cai[SUP] 3 [/SUP], Yutang Li[SUP] 3 [/SUP], Di Qu[SUP] 3 [/SUP], Yu Chen[SUP] 6 [/SUP], Shibo Jiang[SUP] 3 [/SUP], Qiao Wang[SUP] 3 [/SUP], Hongbin Ji[SUP] 1 [/SUP], Youhua Xie[SUP] 7 [/SUP], Yihua Sun[SUP] 8 9 [/SUP], Lu Lu[SUP] 10 [/SUP], Dong Gao[SUP] 11 12 13 [/SUP]
Affiliations
- PMID: 33558541
- DOI: 10.1038/s41467-021-21171-x
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.