Distinct mechanisms for TMPRSS2 expression explain organ-specific inhibition of SARS-CoV-2 infection by enzalutamide.
Distinct mechanisms for TMPRSS2 expression explain organ-specific inhibition of SARS-CoV-2 infection by enzalutamide.
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DOI：
10.1038/s41467-021-21171-x
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发表时间：
2021-02-08
影响因子：
16.6
通讯作者：
Gao D
中科院分区：
文献类型：
--
作者：
Li F;Han M;Dai P;Xu W;He J;Tao X;Wu Y;Tong X;Xia X;Guo W;Zhou Y;Li Y;Zhu Y;Zhang X;Liu Z;Aji R;Cai X;Li Y;Qu D;Chen Y;Jiang S;Wang Q;Ji H;Xie Y;Sun Y;Lu L;Gao D
由严重急性呼吸综合征冠状病毒2型（SARS-CoV-2）引起的2019冠状病毒病（COVID-19）大流行已迅速成为全球公共卫生威胁。在临床试验中已经对几种改型药物的疗效进行了评价。在这些药物中，第二代抗雄激素药物enzalutamide被提出，因为它可以降低跨膜丝氨酸蛋白酶2 （TMPRSS2）的表达，TMPRSS2是介导sars - cov -2驱动进入前列腺癌细胞的关键成分。然而，缺乏关于恩杂鲁胺对COVID-19治疗效果的明确证据。在这里，我们评估了恩杂鲁胺对前列腺癌细胞、肺癌细胞、人肺类器官和ad - ace2转导小鼠的抗病毒效果。敲除Tmprss2可显著抑制体内SARS-CoV-2感染。恩杂鲁胺能有效抑制人前列腺细胞中的SARS-CoV-2感染，但在人肺细胞和类器官中缺乏这种抗病毒效果。因此，enzalutamide在小鼠和人肺上皮细胞中表达与ar无关的TMPRSS2，因此没有抗病毒活性。此外，我们观察到前列腺细胞和肺细胞之间存在不同的AR结合模式，并且在人肺细胞中AR缺乏与TMPRSS2调控位点的直接结合。因此，我们的研究结果不支持恩杂鲁胺通过降低肺细胞中TMPRSS2的表达来治疗COVID-19的保护作用。恩杂鲁胺（Enzalutamide）是一种获批的前列腺癌药物，其作用于TMPRSS2的表达，而TMPRSS2是SARS-CoV-2感染的关键媒介。在这里，作者描述了Enzalutamide在前列腺癌细胞、肺癌细胞、人肺类器官和hace2转导的Tmprss2敲除小鼠中的抗sars - cov -2作用，并显示在人肺细胞和人肺类器官中缺乏抗病毒作用，可能是由于小鼠和人肺上皮细胞中ar独立的Tmprss2表达。
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. Enzalutamide, an approved drug for prostate cancer, acts on TMPRSS2 expression, a key mediator for SARS-CoV-2 infection. Here, the authors characterize the anti-SARS-CoV-2 effects of Enzalutamide in prostate cancer cells, lung cancer cells, human lung organoids and in hACE2-transduced Tmprss2 knockout mice and show lack antiviral action in human lung cells and human lung organoids, likely due to the AR-independent TMPRSS2 expression in mouse and human lung epithelial cells.
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影响因子：
7.3
作者：
Gao J;Aksoy BA;Dogrusoz U;Dresdner G;Gross B;Sumer SO;Sun Y;Jacobsen A;Sinha R;Larsson E;Cerami E;Sander C;Schultz N
通讯作者：
Schultz N
影响因子：
6.7
作者：
Hatesuer B;Bertram S;Mehnert N;Bahgat MM;Nelson PS;Pöhlmann S;Schughart K
通讯作者：
Schughart K
影响因子：
48
作者：
Langmead, Ben;Salzberg, Steven L.
通讯作者：
Salzberg, Steven L.
DOI：
10.1126/science.abc4730
发表时间：
2020-09-25
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Gu H;Chen Q;Yang G;He L;Fan H;Deng YQ;Wang Y;Teng Y;Zhao Z;Cui Y;Li Y;Li XF;Li J;Zhang NN;Yang X;Chen S;Guo Y;Zhao G;Wang X;Luo DY;Wang H;Yang X;Li Y;Han G;He Y;Zhou X;Geng S;Sheng X;Jiang S;Sun S;Qin CF;Zhou Y
通讯作者：
Zhou Y
影响因子：
--
作者：
Kregel S;Chen JL;Tom W;Krishnan V;Kach J;Brechka H;Fessenden TB;Isikbay M;Paner GP;Szmulewitz RZ;Vander Griend DJ
通讯作者：
Vander Griend DJ