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Structure-guided drug design identifies a BRD4-selective small molecule that suppresses HIV
Qingli Niu, … , Jia Zhou, Haitao Hu
Qingli Niu, … , Jia Zhou, Haitao Hu
Published August 1, 2019; First published July 22, 2019
Citation Information: J Clin Invest. 2019;129(8):3361-3373. https://doi.org/10.1172/JCI120633.
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Categories: Research Article AIDS/HIV

Structure-guided drug design identifies a BRD4-selective small molecule that suppresses HIV

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Abstract

HIV integrates its provirus into the host genome and establishes latent infection. Antiretroviral therapy (ART) can control HIV viremia, but cannot eradicate or cure the virus. Approaches targeting host epigenetic machinery to repress HIV, leading to an aviremic state free of ART, are needed. Bromodomain and extraterminal (BET) family protein BRD4 is an epigenetic reader involved in HIV transcriptional regulation. Using structure-guided drug design, we identified a small molecule (ZL0580) that induced epigenetic suppression of HIV via BRD4. We showed that ZL0580 induced HIV suppression in multiple in vitro and ex vivo cell models. Combination treatment of cells of aviremic HIV-infected individuals with ART and ZL0580 revealed that ZL0580 accelerated HIV suppression during ART and delayed viral rebound after ART cessation. Mechanistically different from the BET/BRD4 pan-inhibitor JQ1, which nonselectively binds to BD1 and BD2 domains of all BET proteins, ZL0580 selectively bound to BD1 domain of BRD4. We further demonstrate that ZL0580 induced HIV suppression by inhibiting Tat transactivation and transcription elongation as well as by inducing repressive chromatin structure at the HIV promoter. Our findings establish a proof of concept for modulation of BRD4 to epigenetically suppress HIV and provide a promising chemical scaffold for the development of probes and/or therapeutic agents for HIV epigenetic silencing.

Authors

Qingli Niu, Zhiqing Liu, Edrous Alamer, Xiuzhen Fan, Haiying Chen, Janice Endsley, Benjamin B. Gelman, Bing Tian, Jerome H. Kim, Nelson L. Michael, Merlin L. Robb, Jintanat Ananworanich, Jia Zhou, Haitao Hu

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Figure 1

Discovery of a small molecule suppressing HIV in J-Lat cells.

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Discovery of a small molecule suppressing HIV in J-Lat cells.
(A) Screen...
(A) Screening of compounds (C1–C62) designed as new BRD4 modulators in J-Lat cells (10.6). Cells were stimulated with PMA (1 μg/mL) to activate HIV and treated with individual compounds (10 μM) for 24 hours (PMA/C1–C62). Cell only (NC), PMA, and PMA/JQ1 (10 μM) were included as controls (labeled as 1, 2, and 63). HIV activation was measured by flow cytometry (GFP+%). (B) Chemical structure of ZL0580. (C and D) Dose-dependent suppression of PMA-induced HIV activation by ZL0580. Cells were treated with PMA and ZL0580 (0 μM, 1 μM, 10 μM, 20 μM) for 24 hours. NC or PMA/JQ1 (10 μM) was included as a control. Representative FACS plots for GFP expression (C) and cumulative data for percentage of GFP+ in J-Lat cells of 3 experimental repeats (D) (mean ± SD) are shown. (E) Comparison of HIV transcription. HIV RNAs (Gag and 3′ LTR) were quantified by qPCR in cells 24 hours after treatment. Results are shown as fold change relative to NC. (F and G) Kinetics of ZL0580-induced HIV suppression in PMA-activated (F) or resting (G) J-Lat cells. Cells were treated as indicated for 24 hours. HIV 3′ LTR RNA was quantified on days 2, 7, and 14 after treatment. Data are shown as fold change relative to NC for each time point. Asterisks denote comparison of PMA/ZL0580 or PMA/JQ1 with PMA (F) or comparison of ZL0580 or JQ1 with NC (G). Error bars in E–G represent SD of PCR duplicate. (H) Unstimulated J-Lat cells were treated with NC or ZL0580 (10 μM), followed by stimulation with SAHA or prostratin 3 days after treatment. HIV reactivation was measured based on 3′ LTR RNA, and results are shown as fold change relative to NC. All experiments were repeated at least 3 times. *P < 0.05; **P < 0.005, 1-way ANOVA (D) and paired Student’s t test (E–H).
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