Abstract
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus responsible for COVID-19, employs two key host proteins to gain entry and replicate within cells, angiotensin-converting enzyme 2 (ACE2) and the cell surface transmembrane protease serine 2 (TMPRSS2). TMPRSS2 was first characterized as an androgen-regulated gene in the prostate. Supporting a role for sex hormones, males relative to females are disproportionately affected by COVID-19 in terms of mortality and morbidity. Several studies, including one employing a large epidemiological cohort, suggested that blocking androgen signaling is protective against COVID-19. Here, we demonstrate that androgens regulate the expression of ACE2, TMPRSS2, and androgen receptor (AR) in subsets of lung epithelial cells. AR levels are markedly elevated in males relative to females greater than 70 y of age. In males greater than 70 y old, smoking was associated with elevated levels of AR and ACE2 in lung epithelial cells. Transcriptional repression of the AR enhanceosome with AR or bromodomain and extraterminal domain (BET) antagonists inhibited SARS-CoV-2 infection in vitro. Taken together, these studies support further investigation of transcriptional inhibition of critical host factors in the treatment or prevention of COVID-19.
Highlights
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus responsible for COVID-19, employs two key host proteins to gain entry and replicate within cells, angiotensin-converting enzyme 2 (ACE2) and the cell surface transmembrane protease serine 2 (TMPRSS2)
We discovered that the bromodomain and extraterminal domain (BET) inhibitor JQ1 and degrader ZBC260 consistently down-regulated ACE2 in Calu-3 (SI Appendix, Fig. S1A) and TMPRSS2 and ACE2 in Caco-2 cells (SI Appendix, Fig. S1B), suggesting that BET proteins may play a role in regulating SARS-CoV-2 entry factor expression
ACE2 and TMPRSS2 were shown to be the key mediators of SARS-CoV-2 viral entry early in the COVID-19 pandemic, but which cells of the upper airway tract express them and mechanisms governing their expression in the lung were not defined [3, 4]
Summary
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus responsible for COVID-19, employs two key host proteins to gain entry and replicate within cells, angiotensin-converting enzyme 2 (ACE2) and the cell surface transmembrane protease serine 2 (TMPRSS2). Transcriptional repression of the AR enhanceosome with AR or bromodomain and extraterminal domain (BET) antagonists inhibited SARS-CoV-2 infection in vitro Taken together, these studies support further investigation of transcriptional inhibition of critical host factors in the treatment or prevention of COVID-19. The genome of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the coronavirus responsible for COVID-19, is a positive, single-stranded RNA that encodes nonstructural and structural proteins required for the viral life cycle. Results in this study show that targeting the transcriptional regulation of host entry factors TMPRSS2 and ACE2 is a viable treatment strategy to prevent SARS-CoV-2 infection. AR inhibitors are already approved in the clinic for treatment of prostate cancer and are under investigation in COVID-19 patients; BET inhibitors are in clinical development for other indications and could be rapidly repurposed for COVID-19
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