2. Academic Validation
  3. Structure-guided drug design identifies a BRD4-selective small molecule that suppresses HIV

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

  • J Clin Invest. 2019 Jul 22;129(8):3361-3373. doi: 10.1172/JCI120633.
Qingli Niu 1 2,  Zhiqing Liu 3,  Edrous Alamer 1 2,  Xiuzhen Fan 1 2,  Haiying Chen 3,  Janice Endsley 1 2,  Benjamin B Gelman 4,  Bing Tian 5,  Jerome H Kim 6,  Nelson L Michael 7 8,  Merlin L Robb 7 8,  Jintanat Ananworanich 7 8 9,  Jia Zhou 3,  Haitao Hu 1 2
Affiliations

Affiliations

  • 1 Department of Microbiology and Immunology, University of Texas Medical Branch (UTMB), Galveston, Texas, USA.
  • 2 Institute for Human Infections and Immunity, Sealy Institute for Vaccine Sciences.
  • 3 Chemical Biology Program, Department of Pharmacology and Toxicology.
  • 4 Department of Pathology, and.
  • 5 Department of Internal Medicine, Sealy Center for Molecular Medicine, UTMB, Galveston, Texas, USA.
  • 6 International Vaccine Institute, Gwanak-gu, Seoul, South Korea.
  • 7 US Military HIV Research Program, Walter Reed Army Institute of Research, Silver Spring, Maryland, USA.
  • 8 Henry M. Jackson Foundation for the Advancement of Military Medicine, Bethesda, Maryland, USA.
  • 9 Department of Global Health, The University of Amsterdam, Amsterdam, Netherlands.
PMID: 31329163 DOI: 10.1172/JCI120633
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.

Keywords

AIDS/HIV; Drug therapy; Epigenetics.

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