文章基本信息

标题：Targeting androgen regulation of TMPRSS2 and ACE2 as a therapeutic strategy to combat COVID-19
本地全文：下载
作者：Qu Deng ; Reyaz ur Rasool ; Ronnie M. Russell 等
期刊名称：iScience
印刷版ISSN：2589-0042
出版年度：2021
卷号：24
期号：3
页码：1-39
DOI：10.1016/j.isci.2021.102254
语种：English
出版社：Elsevier
摘要：SummaryEpidemiological data showing increased severity and mortality of COVID-19 in men suggests a potential role for androgen in SARS-CoV-2 infection. Here, we present evidence for the transcriptional regulation of SARS-CoV-2 host cell receptor ACE2 and TMPRSS2 by androgen in mouse and human cells. Additionally, we demonstrate the endogenous interaction between TMPRSS2 and ACE2 in human cells and validate ACE2 as a TMPRSS2 substrate. Furthermore, camostat—a TMPRSS2 inhibitor—blocked the cleavage of pseudotype SARS-CoV-2 surface Spike without disrupting TMPRSS2-ACE2 interaction, thus providing evidence for the first time of a direct role of TMPRSS2 in priming the SARS-CoV-2 Spike, required for viral fusion to the host cell. Importantly, androgen-deprivation, anti-androgens, or camostat attenuated the SARS-CoV-2 S-mediated cellular entry. Together, our data provide a strong rationale for clinical evaluations of TMPRSS2 inhibitors and androgen-deprivation therapy/androgen receptor antagonists alone or in combination with antiviral drugs as early as clinically possible to prevent COVID-19 progression.Graphical abstractDisplay OmittedHighlights•Androgen regulates the expression of SARS-Cov-2 receptor ACE2 and TMPRSS2•TMPRSS2 interacts with ACE2 in prostate and lung cells•Camostat blocks TMPRSS2-mediated cleavage of SARS-Cov-2 Spike•Androgen deprivation or AR antagonists attenuate SARS-CoV-2 Spike-mediated cell entryBiological Sciences; Molecular Biology; Virology