IDR-targeting compounds suppress HPV genome replication via disruption of phospho-BRD4 association with DNA damage response factors

  • Mol Cell. 2023 Dec 12:S1097-2765(23)00967-X. doi: 10.1016/j.molcel.2023.11.022.
Shwu-Yuan Wu  1 ,  Hsien-Tsung Lai  2 ,  N Sanjib Banerjee  3 ,  Zonghui Ma  4 ,  Juan F Santana  5 ,  Shuguang Wei  6 ,  Xisheng Liu  3 ,  Meirong Zhang  7 ,  Jian Zhan  7 ,  Haiying Chen  4 ,  Bruce Posner  6 ,  Yadong Chen  7 ,  David H Price  5 ,  Louise T Chow  3 ,  Jia Zhou  8 ,  Cheng-Ming Chiang  9
Affiliations
  • 1. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
  • 2. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
  • 3. Department of Biochemistry and Molecular Genetics, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
  • 4. Chemical Biology Program, Department of Pharmacology and Toxicology, University of Texas Medical Branch (UTMB), Galveston, TX 77555, USA.
  • 5. Department of Biochemistry and Molecular Biology, The University of Iowa, Iowa City, IA 52242, USA.
  • 6. Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
  • 7. State Key Laboratory of Natural Medicines, Department of Organic Chemistry, China Pharmaceutical University, Nanjing 210009, P.R. China.
  • 8. Chemical Biology Program, Department of Pharmacology and Toxicology, University of Texas Medical Branch (UTMB), Galveston, TX 77555, USA. Electronic address: [email protected].
  • 9. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA. Electronic address: [email protected].
PMID: 38103559 DOI: 10.1016/j.molcel.2023.11.022
Abstract

Compounds binding to the bromodomains of bromodomain and extra-terminal (BET) family proteins, particularly BRD4, are promising Anticancer agents. Nevertheless, side effects and drug resistance pose significant obstacles in BET-based therapeutics development. Using high-throughput screening of a 200,000-compound library, we identified small molecules targeting a phosphorylated intrinsically disordered region (IDR) of BRD4 that inhibit phospho-BRD4 (pBRD4)-dependent human papillomavirus (HPV) genome replication in HPV-containing keratinocytes. Proteomic profiling identified two DNA damage response factors-53BP1 and BARD1-crucial for differentiation-associated HPV genome amplification. pBRD4-mediated recruitment of 53BP1 and BARD1 to the HPV origin of replication occurs in a spatiotemporal and BRD4 long (BRD4-L) and short (BRD4-S) isoform-specific manner. This recruitment is disrupted by phospho-IDR-targeting compounds with little perturbation of the global transcriptome and BRD4 chromatin landscape. The discovery of these protein-protein interaction inhibitors (PPIi) not only demonstrates the feasibility of developing PPIi against phospho-IDRs but also uncovers Antiviral agents targeting an epigenetic regulator essential for virus-host interaction and Cancer development.

Keywords
53BP1; BARD1; BET; BRD4; DDR; HPV; IDR; PPI inhibitors; antiviral; compound.
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