Distinct mechanisms for TMPRSS2 expression explain organ-specific inhibition of SARS-CoV-2 infection by enzalutamide.
Nat Commun
; 12(1): 866, 2021 02 08.
Article
in English
| MEDLINE | ID: covidwho-1069107
Preprint
This scientific journal article is probably based on a previously available preprint. It has been identified through a machine matching algorithm, human confirmation is still pending.
See preprint
This scientific journal article is probably based on a previously available preprint. It has been identified through a machine matching algorithm, human confirmation is still pending.
See preprint
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.
Full text:
Available
Collection:
International databases
Database:
MEDLINE
Main subject:
Organ Specificity
/
Phenylthiohydantoin
/
Serine Endopeptidases
/
SARS-CoV-2
/
COVID-19
Type of study:
Experimental Studies
/
Observational study
/
Prognostic study
Limits:
Animals
/
Humans
/
Male
Language:
English
Journal:
Nat Commun
Journal subject:
Biology
/
Science
Year:
2021
Document Type:
Article
Affiliation country:
S41467-021-21171-x
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