@article{f762fc86b4c547d0af821cfcaecbef9d,
title = "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.",
author = "Qingli Niu and Zhiqing Liu and Edrous Alamer and Xiuzhen Fan and Haiying Chen and Janice Endsley and Gelman, {Benjamin B.} and Bing Tian and Kim, {Jerome H.} and Michael, {Nelson L.} and Robb, {Merlin L.} and Jintanat Ananworanich and Jia Zhou and Haitao Hu",
note = "Funding Information: We thank human participants for providing cell samples, Istvan Boldogh for help with the ChIP assay, and Allan Brasier for help with the TR-FRET assay. The reagents J-Lat (clone 10.6, catalog 9849) and anti-Tat Ab (catalog 160189) were obtained through the AIDS Reagent Program. The study was funded by UTMB{\textquoteright}s startup fund and grants from the NIH (R21AI110214) and the Robert Map-plethorpe Foundation (to HH) and was supported by NIH grant R01AI132674. During this study, QN was also affiliated with the Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, and was sponsored by the China Scholarship Council (no. 201603250037). ZL was supported by the Crohn{\textquoteright}s & Colitis Foundation of America (grant 548813). The content of this publication does not necessarily reflect the views or policies of the NIH, the U.S. Army, or the Department of Defense, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government. The investigators have adhered to the policies for the protection of human subjects as prescribed in AR-70. Funding Information: We thank human participants for providing cell samples, Istvan Boldogh for help with the ChIP assay, and Allan Brasier for help with the TR-FRET assay. The reagents J-Lat (clone 10.6, catalog 9849) and anti-Tat Ab (catalog 160189) were obtained through the AIDS Reagent Program. The study was funded by UTMB{\textquoteright}s startup fund and grants from the NIH (R21AI110214) and the Robert Mapplethorpe Foundation (to HH) and was supported by NIH grant R01AI132674. During this study, QN was also affiliated with the Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, and was sponsored by the China Scholarship Council (no. 201603250037). ZL was supported by the Crohn{\textquoteright}s & Colitis Foundation of America (grant 548813). The content of this publication does not necessarily reflect the views or policies of the NIH, the U.S. Army, or the Department of Defense, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government. The investigators have adhered to the policies for the protection of human subjects as prescribed in AR-70. Publisher Copyright: {\textcopyright} 2019, American Society for Clinical Investigation.",
year = "2019",
month = aug,
day = "1",
doi = "10.1172/JCI120633",
language = "English",
volume = "129",
pages = "3361--3373",
journal = "Journal of Clinical Investigation",
issn = "0021-9738",
number = "8",
}