The antiviral action of BET protein on SARS-CoV-2 infection

Scientists have created novel therapeutics and vaccines to combat the ongoing coronavirus epidemic of 2019 (COVID-19), which is caused by the rapid spread in severe acute respiratory disease coronavirus-2 (SARS-CoV-2). The COVID-19 vaccines are effective against the original SARS CoV-2 strain, which was first discovered in Wuhan, China in December 2019. However, the virus’s evolution has affected their effectiveness. Therefore, it is crucial to develop more effective therapies to reduce the rate of infection and mortality that are caused by new variants of the SARS-CoV-2 virus.

Characterization and Function of BET Protein

BRD2, BRD3, BRD4, BRDT are members of the bromodomain extraterminal domain (BET) family of proteins. Characteristic characteristics of BET protein family members include the presence of two highly conserved N-terminal bromodomains (BDs) and an extraterminal (ET) domain. Previous studies have shown that BETs interact directly with histones as well as the cellular transcriptional machinery.

One of the main purposes of BDs is that they act as bonafide reader domains for acetylated Lysines within histone and nonhistone proteins. These proteins were the targets for small-molecule BET inhibitors (e.g. JQ1). Studies in the past have revealed that the ET domain has less protein binding properties than BDs.

Numerous functions in the cells are affected by BET proteins, such as cell proliferation, chromatin remodeling, and gene expression. Among the BETs proteins, BRD4 has been an extensively studied protein that exists in different splice isoforms that include long (BRD4L) and short (BRD4S) isoforms. Only osteosarcoma cells contained a third or intermediate isoform. Scientists have discovered that BRD2, BRD3, and BRD4 interact with herpesvirus viral proteins flaviviruses, papillomaviruses, and flavi.

The role of BETs and Viral Infection

SARS-CoV-2 patients often have impaired the type I interferon-I (IFN-I), and an overproduction of proinflammatory chemical. BRD4 has been identified as an antiviral gene, and a potent coactivator of proinflammatory chemicals. In this context, scientists have reported that BRD4 coactivates interferon-stimulated genes (ISGs) in the lungs during viral infection by employing P-TEFb. Additionally, it also stimulates pro-inflammatory responses in chronic obstructive pulmonary diseases as well as lung fibrosis and asthma.

A prior study has shown that BET inhibitors can successfully attenuate transcriptional activation of the antiviral response in the influenza A infection. A recent study also identified BRD4 (and BRD2) as high-confidence interlocutors of the SARS-CoV-2’s E protein.

Most importantly, BRD2 functions as a transcriptional regulator of angiotensin-converting enzyme 2 (ACE2), which is the entry point of the SARS-CoV-2 virus. The studies have also revealed that the deletion of the BRD2 gene or a prophylactic application of BET inhibitors reduces ACE2 expression and, hence, reduces the risk of infection.

With regard to the past shards of evidence on BRD2 and BRD4 related to viral infections, researchers have evaluated the function of all relevant BET proteins during COVID-19 infection. In this regard they have discovered that inhibition of BET proteins following virus invasion or knockout of BRD3 or BRD4 genes in cells leads to an increase in ACE2, which dramatically increases the replication of viruses. This study is available on the bioRxiv* preprint server.

SARS-CoV-2 E Protein, as well as BET Protein of The Host

In this study, researchers have suggested that BET proteins (BRD4 > BRD3 > BRD2) have prominent antiviral capabilities, particularly after SARS-CoV-2 invades the host cell. In addition, BET proteins can hinder COVID-19’s infection in the post-entry phase as they are crucial to fully activate the interferon type 1 response and the proinflammatory IL-6 cytokine. In addition, researchers stated that viral replication intensifies after the inactivation of BET proteins through a chemical or genetic method.

The present study identified a new function for the SARS-CoV-2 E protein, i.e. it inhibits interferon and ISG expression. Researchers found that viral E protein when acetylated can inhibit the antiviral function by binding with the second bromodomain (BRD4). The study revealed that BRD2 was the most pro-viral of the BET proteins due to its ability to regulate the expression of ACE2.

BRD4 also has an antiviral function due to its function as a co-activator within the induction interferon genes. Although BRD2 and BRD4 share 70% of their sequences in their N-terminus, the differences are in their domain structure.

BET proteins are the positive regulators of ACE2 expression A. RT-qPCR of ACE2 DNA isolated from Calu3 cells that have BET KOs. Data are shown relative to RNP-only cells. The average of three independent experiments, each in triplicate +SEM, are displayed. They are compared with RNP-only samples using ANOVA: ****p0.0001. B. Viability of A549-ACE2 cells treated DMSO (vehicle) JQ1 (500nM), the dBET6 (500nM) and AbBV-744 (500nM) for 48 hours relative to DMSO. C. Viability of Calu3 cells treated with DMSO (vehicle) JQ1 (500nM) and dBET6 (500nM) for 48 hours in comparison to DMSO.

Scientists also found an increase in viral replication, hypothermic and hyperthermic conditions, as well in severe weight loss and gut inflammation in the SARS/CoV-2 infected K18-hACE2 mice model.

The results are in line with a previous study that reported therapeutic application of BET inhibitors on K18-hACE2 mice resulted in severe lung pathology as well as significant viral RNA in the lung. The current study highlights the significance of BET proteins as regulators of the expression of antiviral genes.


The current study highlights the effect of the therapeutic application of BET inhibitors during COVID-19 infection. Researchers have shed light on the antiviral function of BET proteins during the course of the infection. BET inhibitors are not recommended for use in the course of SARS-CoV-2 infections since they can increase the viral burden.

*Important Notice

bioRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.

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Gemma Wilson

Gemma is a journalism graduate with keen interest in covering business news – specifically startups. She has as a keen eye for technologies and has predicted quite a few successful startups over the last couple of years.

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