5Z9C

Solution NMR structures of BRD4 first bromodomain with small compound MMQO

5Z9C の概要

• エントリーDOI: 10.2210/pdb5z9c/pdb
• NMR情報: BMRB: 36163
• 分子名称: Bromodomain-containing protein 4, 8-methoxy-6-methylquinolin-4(1H)-one (2 entities in total)
• 機能のキーワード: brd4, bromodomain, inhibitor, hiv, bet, mmqo, signaling protein
• 由来する生物種: Homo sapiens (Human)
• 細胞内の位置: Nucleus: O60885
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 14136.35

構造登録者

Zeng, L.,Zhou, M.-M. (登録日: 2018-02-02, 公開日: 2018-02-14, 最終更新日: 2024-05-15)

主引用文献

Abner, E.,Stoszko, M.,Zeng, L.,Chen, H.C.,Izquierdo-Bouldstridge, A.,Konuma, T.,Zorita, E.,Fanunza, E.,Zhang, Q.,Mahmoudi, T.,Zhou, M.M.,Filion, G.J.,Jordan, A.
A New Quinoline BRD4 Inhibitor Targets a Distinct Latent HIV-1 Reservoir for Reactivation from Other "Shock" Drugs.
J. Virol., 92:-, 2018

PubMed Abstract: Upon HIV-1 infection, a reservoir of latently infected resting T cells prevents the eradication of the virus from patients. To achieve complete depletion, the existing virus-suppressing antiretroviral therapy must be combined with drugs that reactivate the dormant viruses. We previously described a novel chemical scaffold compound, MMQO (8-methoxy-6-methylquinolin-4-ol), that is able to reactivate viral transcription in several models of HIV latency, including J-Lat cells, through an unknown mechanism. MMQO potentiates the activity of known latency-reversing agents (LRAs) or "shock" drugs, such as protein kinase C (PKC) agonists or histone deacetylase (HDAC) inhibitors. Here, we demonstrate that MMQO activates HIV-1 independently of the Tat transactivator. Gene expression microarrays in Jurkat cells indicated that MMQO treatment results in robust immunosuppression, diminishes expression of c-Myc, and causes the dysregulation of acetylation-sensitive genes. These hallmarks indicated that MMQO mimics acetylated lysines of core histones and might function as a bromodomain and extraterminal domain protein family inhibitor (BETi). MMQO functionally mimics the effects of JQ1, a well-known BETi. We confirmed that MMQO interacts with the BET family protein BRD4. Utilizing MMQO and JQ1, we demonstrate how the inhibition of BRD4 targets a subset of latently integrated barcoded proviruses distinct from those targeted by HDAC inhibitors or PKC pathway agonists. Thus, the quinoline-based compound MMQO represents a new class of BET bromodomain inhibitors that, due to its minimalistic structure, holds promise for further optimization for increased affinity and specificity for distinct bromodomain family members and could potentially be of use against a variety of diseases, including HIV infection. The suggested "shock and kill" therapy aims to eradicate the latent functional proportion of HIV-1 proviruses in a patient. However, to this day, clinical studies investigating the "shocking" element of this strategy have proven it to be considerably more difficult than anticipated. While the proportion of intracellular viral RNA production and general plasma viral load have been shown to increase upon a shock regimen, the global viral reservoir remains unaffected, highlighting both the inefficiency of the treatments used and the gap in our understanding of viral reactivation Utilizing a new BRD4 inhibitor and barcoded HIV-1 minigenomes, we demonstrate that PKC pathway activators and HDAC and bromodomain inhibitors all target different subsets of proviral integration. Considering the fundamental differences of these compounds and the synergies displayed between them, we propose that the field should concentrate on investigating the development of combinatory shock cocktail therapies for improved reservoir reactivation.

PubMed: 29343578
DOI: 10.1128/JVI.02056-17

実験手法

SOLUTION NMR