2. Academic Validation
  3. Mechanistic insights and in vivo HIV suppression by the BRD4-targeting small molecule ZL0580

Mechanistic insights and in vivo HIV suppression by the BRD4-targeting small molecule ZL0580

  • bioRxiv. 2025 Aug 14:2025.08.14.670267. doi: 10.1101/2025.08.14.670267.
Naveen Kumar 1,  Zonghui Ma 2,  Fuquan Long 1 3,  Srinivasa Reddy Bonam 1,  Hsien-Tsung Lai 4,  Shwu-Yuan Wu 4,  Haiying Chen 2,  Nicholas C Hazell 1,  Jiani Bei 1,  Xuefeng Liu 5,  Zhi Wei 6,  Cheng-Ming Chiang 4,  Jia Zhou 2,  Haitao Hu 1 7
Affiliations

Affiliations

  • 1 Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, Texas, USA 77555.
  • 2 Chemical Biology Program, Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, Texas, USA 77555.
  • 3 Department of Sexually Transmitted Disease, Center of Infectious Skin Disease, Shanghai Skin Disease Hospital, School of Medicine, Tongji University, Shanghai, China 200040.
  • 4 Simmons Comprehensive Cancer Center, Department of Biochemistry, and Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, TX, USA 75390.
  • 5 Department of Pathology, The Ohio State University College of Medicine, Columbus, OH, USA 43210.
  • 6 Department of Computer Science, of Computer Science, New Jersey Institute of Technology, Newark, NJ, USA 07102.
  • 7 Institute for Human Infections and Immunity, University of Texas Medical Branch, Galveston, Texas, USA 77555.
PMID: 40832229 DOI: 10.1101/2025.08.14.670267
Abstract

Epigenetic suppression and durable silencing of HIV represent a promising strategy to achieve ART-free remission, consistent with the "block and lock" HIV cure paradigm. BRD4 is a host epigenetic reader and plays a critical role in HIV transcriptional regulation. We previously identified ZL0580, a first-in-class BRD4-selective small molecule distinct from the pan-BET inhibitor JQ1, which induces HIV epigenetic suppression. However, detailed molecular mechanisms, pharmacokinetics (PK), and in vivo HIV-suppressive efficacy of ZL0580 remain undefined. Here, we show that ZL0580 selectively targets BRD4 bromodomain 1 (BD1) through interaction with a key glutamic acid residue (E151), as determined by structural modeling and mutagenesis. Transcriptomic profiling by RNA-seq reveals that ZL0580 and JQ1 induce opposing gene expression programs, consistent with their distinct effects on HIV proviral transcription and latency. In a humanized mouse model of HIV Infection, ZL0580 monotherapy, or in combination with ART, potently suppressed active HIV replication, reducing the plasma viremia to nearly undetectable levels, and delayed viral rebound following treatment interruption. Collectively, these findings establish ZL0580 as an epigenetic suppressor of HIV in vivo and provide proof-of-concept for its potential as a "block and lock" HIV cure candidate, warranting further optimization and development.

Keywords

BRD4; HIV; ZL0580; epigenetic suppression; in vivo activity.

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