https://www.biorxiv.org/content/10.1101/2021.11.14.468537v1
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8609896/
Summary
"Inhibitors of Bromodomain and Extra-terminal domain (BET) proteins are possible antiSARS-CoV 2 prophylactics as they downregulate angiotensin-converting enzyme 2 (ACE2). Here, we show that BET proteins should not be inactivated therapeutically as they are critical antiviral factors at the post-entry level. Knockouts of BRD3 or BRD4 in cells overexpressing ACE2 exacerbate SARS-CoV-2 infection; the same is observed when cells with endogenous ACE2 expression are treated with BET inhibitors during infection, and not before. Viral replication and mortality are also enhanced in BET inhibitor-treated mice overexpressing ACE2. BET inactivation suppresses interferon production induced by SARS-CoV-2, a process phenocopied by the envelope (E) protein previously identified as a possible “histone mimetic.” E protein, in an acetylated form, directly binds the second bromodomain of BRD4. Our data support a model where SARSCoV-2 E protein evolved to antagonize interferon responses via BET protein inhibition; this neutralization should not be further enhanced with BET inhibitor treatment."
Discussion
"Since the beginning of the pandemic, there has been growing interest in the prophylactic application of BET inhibitors to prevent SARS-CoV-2 infection as they reduce ACE2 expression. All previous studies relied on multi-day pretreatment of cell lines, organoids, and primary cells with BET inhibitors to inhibit infection (Gilham et al., 2021; Mills et al., 2021; Qiao et al., 2020; Tian et al., 2021). In contrast, our study focuses on the concurrent administration of BET inhibitors, JQ1 and ABBV-744, at the time of infection. Similar to our observations, Mills et al. found that therapeutic application of K18-hACE2 mice with BET inhibitor, INCB054329, resulted in severe lung pathology and significant viral RNA in the lung. We demonstrate the therapeutic application of the BET inhibitors worsens viral pathogenesis as evidenced by hypothermic and hyperthermic conditions, severe weight loss, and inflammation of gut, underscoring the clinical significance of post entry restriction of SARS-CoV-2 by BET proteins.
Our study sheds new light on the antiviral function of BET proteins during SARS-CoV-2 nfection, highlighting their contrasting functions at different stages of the viral life cycle. Whether SARS-CoV-2 evolved the anti-BET protein function of the E protein because of the unique influence of BRD2 on ACE2 receptor levels or the necessity for a more surgical inactivation of BET proteins as transcriptional coactivators necessary for antagonizing the virus remains to be determined. Because most BET inhibitors do not distinguish between the different BET proteins and inhibit all of them indiscriminately, our study urges caution with the clinical use, prophylactic or therapeutic, of pan-BET inhibitors in people at risk or afflicted with COVID-19."
