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


Authors: 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.
Article Title: 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. © 2021, The Author(s).
Keywords: controlled study; human tissue; human cell; genetics; drug efficacy; nonhuman; mouse; animal; metabolism; animals; mice, knockout; animal tissue; cells, cultured; gene expression; animal experiment; animal model; protein binding; in vivo study; in vitro study; drug effect; pathology; cell line, tumor; physiology; genetic transduction; virology; prostatic neoplasms; serine proteinase; serine endopeptidases; cell culture; public health; prostate tumor; tumor cell line; lung; organ specificity; antibody specificity; androgen receptor; adenovirus vector; epidemiology; data analysis software; knockout mouse; host pathogen interaction; antiviral activity; prevention and control; phenylthiohydantoin; inhibition; infectious disease; virus entry; virus inhibition; host-pathogen interactions; pandemic; lung alveolus cell; coronavirus; sars coronavirus; transmembrane protease serine 2; enzalutamide; viral disease; cancer; humans; human; male; article; lung cancer cell line; drug repositioning; prostate cancer cell line; organoid; gene knockout; mrna expression level; pandemics; severe acute respiratory syndrome coronavirus 2; coronavirus disease 2019; covid-19; angiotensin converting enzyme 2; sars-cov-2; tmprss2 protein, human; bromethol; tmprss2 protein, mouse; prostate cell; angiotensin-converting enzyme 2
Journal Title: Nature Communications
Volume: 12
ISSN: 2041-1723
Publisher: Nature Publishing Group  
Date Published: 2021-02-08
Start Page: 866
Language: English
DOI: 10.1038/s41467-021-21171-x
PUBMED: 33558541
PROVIDER: scopus
PMCID: PMC7870838
DOI/URL:
Notes: Article -- Export Date: 1 April 2021 -- Source: Scopus
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  1. Yu Chen
    96 Chen