Relevance of BET Family Proteins in SARS-CoV-2 Infection

Lara-Ureña, Nieves; García-Domínguez, Mario

doi:10.3390/biom11081126

Cited by 13 publications

(19 citation statements)

References 254 publications

(318 reference statements)

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“…RVX‐208 has an established favorable safety profile in clinical trials for cardiovascular indications and is now the focus of a clinical trial for COVID‐19 treatment compared to standard of care (Clinical trial identifier: NCT04894266) 28,38,39 . In addition to reducing SARS‐CoV‐2 infection, RVX‐208 may play a pivotal role in controlling hyperinflammatory immune responses that can cause long‐term tissue damage in patients 26,28,38,40,41 . BET inhibitors have also been reported to decrease the expression of immune inhibitory receptors, such as PD‐L1 and LAG3 which hinder T‐cell function 42 .…”

Section: Resultsmentioning

confidence: 99%

“…28,38,39 In addition to reducing SARS-CoV-2 infection, RVX-208 may play a pivotal role in controlling hyperinflammatory immune responses that can cause long-term tissue damage in patients. 26,28,38,40,41 BET inhibitors have also been reported to decrease the expression of immune inhibitory receptors, such as PD-L1 and LAG3 which hinder T-cell function. 42 High expression of LAG3 correlates with more severe disease in COVID-19 patients, with normalization of receptor levels witnessed during recovery.…”

Section: Targeting Ace2 Receptor Inhibits Binding By the S-ecto-egfpmentioning

confidence: 99%

“…It has recently been shown that transcription of ACE2 is regulated by bromodomain and extraterminal domain (BET) proteins that bind acetylated residues on histones to recruit transcriptional machinery 25,26 . Inhibitors of BET proteins have been shown to decrease ACE2 expression, spike protein binding, and SARS‐CoV‐2 infection in lung epithelial cells and cardiomyocytes 27,28 .…”

Section: Introductionmentioning

confidence: 99%

“…25 The SARS-CoV-2 envelope protein is additionally known to directly interact with BET proteins, but no associated effects have been reported for viral infection. 26 With the shift in focus of many laboratories toward COVID-19 research, an efficient and reliable method for purifying large amounts of glycosylated S protein is needed. We chose to use baculovirus-based recombinant spike protein expression in insect cells which provide Nglycosylation that mirrors mammalian cells, albeit with simpler side chains with terminal mannose residues instead of sialic acid residues.…”

Section: Introductionmentioning

confidence: 99%

“…Anti‐ACE2 antibodies can similarly attenuate viral entry and infection through the occupation of ACE2 receptors, thus blocking spike protein binding (i.e., ACE2 receptor blockade) 25 . The SARS‐CoV‐2 envelope protein is additionally known to directly interact with BET proteins, but no associated effects have been reported for viral infection 26 …”

Section: Introductionmentioning

confidence: 99%

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Insect cell expression and purification of recombinant SARS‐COV‐2 spike proteins that demonstrate ACE2 binding

Struble¹,

Smith²,

Lutz³

et al. 2022

Protein Science

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The COVID-19 pandemic caused by SARS-CoV-2 infection has led to socioeconomic shutdowns and the loss of over 5 million lives worldwide. There is a need for the identification of therapeutic targets to treat COVID-19. SARS-CoV-2 spike is a target of interest for the development of therapeutic targets.We developed a robust SARS-CoV-2 S spike expression and purification protocol from insect cells and studied four recombinant SARS-CoV-2 spike protein constructs based on the original SARS-CoV-2 sequence using a baculovirus expression system: a spike protein receptor-binding domain that includes the SD1 domain (RBD) coupled to a fluorescent tag (S-RBD-eGFP), spike ectodomain coupled to a fluorescent tag (S-Ecto-eGFP), spike ectodomain with six proline mutations and a foldon domain (S-Ecto-HexaPro(+F)), and spike ectodomain with six proline mutations without the foldon domain (S-Ecto-HexaPro(-F)). We tested the yield of purified protein expressed from the insect cell lines Spodoptera frugiperda (Sf9) and Trichoplusia ni (Tni) and compared it to previous research using mammalian cell lines to determine changes in protein yield. We demonstrated quick and inexpensive production of functional glycosylated spike protein of high purity capable of recognizing and binding to the angiotensin converting enzyme 2 (ACE2) receptor. To further confirm functionality, we demonstrate binding of eGFP fused construct of the spike ectodomain (S-Ecto-eGFP) to surface ACE2 receptors on lung epithelial cells by flow cytometry analysis and show that it can be decreased by means of receptor manipulation (blockade or downregulation).

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Section: Resultsmentioning

confidence: 99%

Section: Targeting Ace2 Receptor Inhibits Binding By the S-ecto-egfpmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Insect cell expression and purification of recombinant SARS‐COV‐2 spike proteins that demonstrate ACE2 binding

Struble¹,

Smith²,

Lutz³

et al. 2022

Protein Science

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Combining antiviral drugs with BET inhibitors is beneficial in combatting SARS‐CoV‐2 infection

Acharya

Kutateladze

Byrareddy

2022

Clinical and Translational Dis

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The COVID‐19 pandemic caused by the novel coronavirus SARS‐CoV‐2 has resulted in more than 500 million cases and 6 million deaths. Several antiviral therapies and vaccines have been developed to mitigate the spread of this infection. However, new approaches are required to battle emerging SARS‐CoV‐2 variants containing mutations that can reduce the vaccines' efficacy. The use of a combination of antiviral drugs with inhibitors of mammalian target of rapamycin (mTOR) signalling pathways has emerged as one of the promising novel approach. In this study, we have shown that SF2523, a dual activity small molecule that inhibits PI3K and BRD4, acts synergistically with the antiviral drugs remdesivir (RDV) and MU‐UNMC‐2. Our findings suggest that the mTOR pathways are necessary for SARS‐CoV‐2 pathogenesis in human cells and that targeting PI3K/BET (bromodomain and extra‐terminal domain proteins) alone or combined with antiviral therapies is beneficial in mitigating SARS‐CoV‐2 and its variants of concern (VOCs).

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SARS-CoV-2 E protein interacts with BRD2 and BRD4 SEED domains and alters transcription in a different way than BET inhibition

Lara-Ureña,

Gómez-Marín,

Pozuelo-Sánchez

et al. 2024

Cell. Mol. Life Sci.

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Bromodomain and extra-terminal (BET) proteins are relevant chromatin adaptors involved in the transcriptional control of thousands of genes. Two tandem N-terminal bromodomains are essential for chromatin attachment through acetyl-histone recognition. Recently, the BET proteins members BRD2 and BRD4 were found to interact with the SARS-CoV-2 envelope (E) protein, raising the question of whether the interaction constitutes a virus hijacking mechanism for transcription alteration in the host cell. To shed light on this question, we have compared the transcriptome of cells overexpressing E with that of cells treated with the BET inhibitor JQ1. Notably, E overexpression leads to a strong upregulation of natural immunity- and interferon response-related genes. However, BET inhibition results in the downregulation of most of these genes, indicating that these two conditions, far from causing a significant overlap of the altered transcriptomes, course with quite different outputs. Concerning the interaction of E protein with BET members, and differing from previous reports indicating that it occurs through BET bromodomains, we find that it relies on SEED and SEED-like domains, BET regions rich in Ser, Asp, and Glu residues. By taking advantage of this specific interaction, we have been able to direct selective degradation of E protein through a PROTAC system involving a dTAG-SEED fusion, highlighting the possible therapeutic use of this peptide for targeted degradation of a viral essential protein.

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Relevance of BET Family Proteins in SARS-CoV-2 Infection

Cited by 13 publications

References 254 publications

Insect cell expression and purification of recombinant SARS‐COV‐2 spike proteins that demonstrate ACE2 binding

Insect cell expression and purification of recombinant SARS‐COV‐2 spike proteins that demonstrate ACE2 binding

Combining antiviral drugs with BET inhibitors is beneficial in combatting SARS‐CoV‐2 infection

SARS-CoV-2 E protein interacts with BRD2 and BRD4 SEED domains and alters transcription in a different way than BET inhibition

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