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 July 22, 2019
Citation Information: J Clin Invest. 2019;129(8):3361-3373. https://doi.org/10.1172/JCI120633.
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Structure-guided drug design identifies a BRD4-selective small molecule that suppresses HIV

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 2

HIV suppression by ZL0580 in in vitro HIV-infected human CD4+ T cells.

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HIV suppression by ZL0580 in in vitro HIV-infected human CD4+ T cells. (...
(A) HIV infection of PHA-activated CD4+ T cells in normal PBMCs. PBMCs (n = 3) were stimulated with PHA (1 μg/mL) for 2 days, followed by infection with R5 HIV (US-1) in the absence or presence of ZL0580 (top) or ZL0454 (bottom) at various concentrations, as indicated. Three days after viral exposure, HIV infection in CD4+ T cells was measured by flow cytometry based on intracellular p24 staining. Representative FACS plots are shown. (B) Comparison of percentage of p24+CD4+ T cells in PBMCs. (C and D) Quantification of HIV DNA (C) and Gag RNA (D) in PBMCs following different treatments by qPCR. Data are shown as fold change of PHA/ZL0580 (4 μM) relative to PHA alone. (E) Representative FACS plots showing HIV infection (intracellular p24) of unactivated CD4+ T cells in PBMCs on day 6 after treatment. (F) Comparison of p24+ percentage in unactivated CD4+ T cells in PBMCs. (B–D and F) Mean ± SD from 3 PBMC donors. *P < 0.05; **P < 0.01, 1-way ANOVA (B and F) and paired Student’s t test (C and D).