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

Author

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

Subjects
Control, Drug therapy, Analysis, Health aspects, Epigenetic inheritance -- Analysis -- Health aspects, Efavirenz -- Analysis -- Health aspects, Protein binding -- Analysis -- Health aspects, Highly active antiretroviral therapy -- Analysis -- Health aspects, Raltegravir -- Analysis -- Health aspects, HIV -- Drug therapy -- Analysis -- Control -- Health aspects, Virus diseases -- Drug therapy -- Analysis -- Control -- Health aspects, Infection -- Drug therapy -- Analysis -- Health aspects, Genomes -- Analysis -- Health aspects, Proteins -- Analysis -- Health aspects, Antiretroviral agents, Genomics, Chromatin, Viremia
Abstract

Introduction HIV infection continues to cause a global pandemic. Antiretroviral therapy (ART) can effectively suppress active HIV replication and has improved survival and quality of life of HIV-infected individuals. However, [...], 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.

Published
2019
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15. Knowledge, Attitudes and Perception toward COVID-19 Vaccines among Adults in Jazan Province, Saudi Arabia

Author

Alamer, Edrous, primary, Hakami, Faisal, additional, Hamdi, Sulaiman, additional, Alamer, Afnan, additional, Awaf, Mohammed, additional, Darraj, Hussam, additional, Abutalib, Yumna, additional, Madkhali, Ebtisam, additional, Alamer, Rahaf, additional, Bakri, Nawaf, additional, Qadri, Marwa, additional, Algaissi, Abdullah, additional, and Alhazmi, Abdulaziz, additional

Published
2021
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