Preprint Article Version 2 Preserved in Portico This version is not peer-reviewed

TMPRSS2 Transcriptional Inhibition as a Therapeutic Strategy for COVID-19

Version 1 : Received: 24 March 2020 / Approved: 24 March 2020 / Online: 24 March 2020 (14:26:57 CET)
Version 2 : Received: 27 April 2020 / Approved: 28 April 2020 / Online: 28 April 2020 (09:39:02 CEST)

How to cite: Wang, X.; Dhindsa, R.; Povysil, G.; Zoghbi, A.; Motelow, J.; Hostyk, J.; Nickols, N.; Rettig, M.; Goldstein, D.B. TMPRSS2 Transcriptional Inhibition as a Therapeutic Strategy for COVID-19 . Preprints 2020, 2020030360 (doi: 10.20944/preprints202003.0360.v2). Wang, X.; Dhindsa, R.; Povysil, G.; Zoghbi, A.; Motelow, J.; Hostyk, J.; Nickols, N.; Rettig, M.; Goldstein, D.B. TMPRSS2 Transcriptional Inhibition as a Therapeutic Strategy for COVID-19 . Preprints 2020, 2020030360 (doi: 10.20944/preprints202003.0360.v2).

Abstract

There is an urgent need to identify effective therapies for COVID-19. The SARS-CoV-2 host factor protease TMPRSS2 is required for viral entry and thus an attractive target for therapeutic intervention. In mouse, knockout of tmprss2 led to protection against SARS-CoV-1 with no deleterious phenotypes, and in human populations genetic loss of TMPRSS2 does not appear to be selected against. Here, we mined publicly available gene expression data to identify several compounds that down-regulate TMPRSS2. Recognizing the need for immediately available treatment options, we focused on FDA-approved drugs. We found 20 independent studies that implicate estrogenic and androgenic compounds as transcriptional modulators of TMPRSS2, suggesting these classes of drugs may be promising therapeutic candidates for clinical testing and observational studies of COVID-19. We also note that expression of TMPRSS2 is highly variable and skewed in humans, with a minority of individuals having extremely high expression. Combined with literature showing that inhibition of TMPRSS2 protease activity reduces SARS-CoV-2 viral entry in human cells, our results raise the hypothesis that modulation of TMPRSS2 expression is a promising therapeutic avenue for COVID-19.

Subject Areas

SARS-CoV-2; transcriptional inhibition; COVID-19; drug repurposing; TMPRSS2

Comments (1)

Comment 1
Received: 28 April 2020
Commenter: Xinchen Wang
Commenter's Conflict of Interests: Author
Comment: 1) Shorter, more concise version with some text & figures moved to Supplement. 
2) More detailed discussion section
3) New title
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