English   español  
Please use this identifier to cite or link to this item: http://hdl.handle.net/10261/174175
Share/Impact:
Statistics
logo share SHARE logo core CORE   Add this article to your Mendeley library MendeleyBASE

Visualizar otros formatos: MARC | Dublin Core | RDF | ORE | MODS | METS | DIDL
Exportar a otros formatos:
Title

A new quinoline BRD4 inhibitor targets a distinct latent HIV-1 reservoir for reactivation from other “shock” drugs

AuthorsAbner, Erik; Stoszko, Mateusz; Zeng, Lei; Chen, Heng-Chang; Izquierdo-Bouldstridge, Andrea; Konuma, Tsuyoshi; Zorita, Eduard; Fanunza, Elisa; Zhang, Qiang; Mahmoudi, Tokameh; Zhou, Ming-Ming; Filion, Guillaume J.; Jordan, Albert
KeywordsBETi
BRD4
HIV latency
LRAs
Issue DateMay-2018
PublisherAmerican Society for Microbiology
CitationJournal of Virology 92(10): e02056-17 (2018)
AbstractUpon 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.
Publisher version (URL)https://doi.org/10.1128/JVI.02056-17
URIhttp://hdl.handle.net/10261/174175
DOI10.1128/JVI.02056-17
ISSN0022-538X
E-ISSN1098-5514
Appears in Collections:(IBMB) Artículos
Files in This Item:
File Description SizeFormat 
accesoRestringido.pdf15,38 kBAdobe PDFThumbnail
View/Open
Show full item record
Review this work
 

Related articles:


WARNING: Items in Digital.CSIC are protected by copyright, with all rights reserved, unless otherwise indicated.