2021
DOI: 10.1038/s41467-021-21171-x
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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 … Show more

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Cited by 87 publications
(92 citation statements)
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“…SARS-CoV-2 cell entry into type II pneumocytes is blocked by TMPRSS2 inhibitors ( 22 , 23 ) and TMPRSS2 transcription inhibitors (antiandrogens) ( 1 , 3 ). We expect an antiandrogen-class effect on protection from COVID-19, which may be explained by mechanisms distinct from the androgen-mediated SARS-COV-2 cell entry mechanism ( 24 ). A non-immunosuppressive anti-inflammatory effect may occur, as the activation of the androgen receptor by dihydrotestosterone leads to increased IL-6 production in macrophages, delaying repair of injury ( 25 ).…”
Section: Discussionmentioning
confidence: 96%
“…SARS-CoV-2 cell entry into type II pneumocytes is blocked by TMPRSS2 inhibitors ( 22 , 23 ) and TMPRSS2 transcription inhibitors (antiandrogens) ( 1 , 3 ). We expect an antiandrogen-class effect on protection from COVID-19, which may be explained by mechanisms distinct from the androgen-mediated SARS-COV-2 cell entry mechanism ( 24 ). A non-immunosuppressive anti-inflammatory effect may occur, as the activation of the androgen receptor by dihydrotestosterone leads to increased IL-6 production in macrophages, delaying repair of injury ( 25 ).…”
Section: Discussionmentioning
confidence: 96%
“…1,3 We expect an antiandrogen-class effect on protection from COVID-19, which may be explained by mechanisms distinct from the androgen-mediated SARS-COV-2 cell entry mechanism. 22 A non-immunosuppressive anti-in ammatory effect may occur, as the activation of the androgen receptor by dihydrotestosterone leads to increased IL-6 production in macrophages, delaying repair of injury. 24 Furthermore, NSAA use was associated with a reduction in plasma IL-6 and TNF post-trauma, 25 and reduction in in ammatory response induced by radiation.…”
Section: Discussionmentioning
confidence: 99%
“…2,3 Early observations in COVID-19 pandemic have identified hyperandrogenic phenotypes as independent risk factors for disease severity in both males [4][5][6] and females. [7][8][9] Antiandrogens have mechanistic plausibility to work against SARS-CoV-2, 10,11 have demonstrated pre-clinical [12][13][14] and preliminary clinical efficacy against COVID-19, both when used continuously [15][16][17] or initiated during the course of the disease 18 .…”
Section: Introductionmentioning
confidence: 99%