课题基金 / 基金详情

Deciphering the structure and dynamics of quadruplex DNA and DNA-ligand complexes

Deciphering the structure and dynamics of quadruplex DNA and DNA-ligand complexes
破译四链体 DNA 和 DNA-配体复合物的结构和动力学
批准号:
9304843
负责人:
Liliya A Yatsunyk
金额:
$41.05万
依托单位:
依托单位国家:
美国
项目类别:
财政年份:
2017
资助国家:
美国
项目状态:
已结题
起止时间:
2017-06-01 至 2020-08-31

项目摘要

项目成果

Liliya A Yatsunyk的其他基金

相似基金

相关文献

中文摘要
翻译
项目总结
英文摘要
PROJECT SUMMARY The proposed research will improve the selectivity and efficacy of anticancer therapies by contributing new knowledge about non-canonical G-quadruplex (GQ) DNA structure, and the interactions of GQs with small- molecule ligands. Bioinformatics studies have identified 370,000 sequences with G-quadruplex-forming potential in the human genome. There is now convincing biological evidence that GQs form in vivo and that these structures regulate a variety of cancer-related biological processes, such as telomere protection, oncogene expression, epigenetic modification, and DNA repair. Thus, GQ DNA has been firmly established as an important therapeutic target for cancer. Small molecules that bind selectively to GQ DNA have been identified, and some have been shown to inhibit tumor cells growth; however, exact mechanisms underlying this inhibition are not known. Such small-molecule ligands may ultimately become lead compounds for the generation of novel selective cancer drugs superior to conventional mutagenetic therapies. Unfortunately, DNA-centered drug discovery programs suffer from limited structural information available for GQs, especially in the presence of ligands. The situation is further complicated by high structural diversity of GQs, their contradictory biological functions, and our limited ability to target a specific GQ folding topology. To address these challenges, we propose to perform comprehensive crystallographic investigations focused on telomeric and oncogene promoter G-quadruplexes, both alone and in complex with a variety of small-molecule ligands. This work will be accompanied by spectroscopic and calorimetric studies of the thermodynamic parameters of ligand binding to GQ DNA (e.g., stoichiometry, affinity, selectivity, driving forces). The static structural view of GQs and GQ-ligand complexes will be complemented by rigorous kinetics studies of ligand-assisted GQ folding and structural rearrangements. Kinetic information can help us identify the timescale of G-quadruplex formation and thus biological processes that can be affected by the presence of these structures. Chemical and structural features of ligands essential for G-quadruplex binding or structural rearrangements will be identified from kinetics and structural studies. Furthermore, we propose chemical modification to the scaffold of N-methylmesoporphyrin IX (NMM), which we showed displays unprecedented selectivity for a parallel GQ fold, yet has modest binding affinity. The modifications should lead to new ligands that retain this selectivity but have improved binding affinity. Ligands that display selective GQ interactions in vitro will be tested in vivo for their biological effects, and genomic targets will be identified. Collectively, the proposed work will enhance our understanding of GQ structural plasticity, supply coordinates for drug discovery platforms, shed light on the origin of ligand selectivity for a specific DNA target, and guide the design of novel highly selective anticancer therapies while providing transformative training to Swarthmore undergraduate students.
期刊论文(5)
专著(0)
科研奖励(0)
会议论文
DOI: 10.1093/nar/gky290
发表时间: 2018-06-01
期刊: Nucleic acids research
影响因子: 14.9
作者: [Guédin A, Lin LY, Armane S, Lacroix L, Mergny JL, Thore S, Yatsunyk LA]
通讯作者: Yatsunyk LA
DOI: 10.1093/nar/gkaa1177
发表时间: 2021-01-11
期刊: Nucleic acids research
影响因子: 14.9
作者: [Li K, Yatsunyk L, Neidle S]
通讯作者: Neidle S
DOI: 10.3390/ijms19113686
发表时间: 2018-11-21
期刊: International journal of molecular sciences
影响因子: 5.6
作者: [Sabharwal NC, Chen J, Lee JHJ, Gangemi CMA, D'Urso A, Yatsunyk LA]
通讯作者: Yatsunyk LA
DOI: 10.1142/s1088424619300179
发表时间: 2019-12
期刊: Journal of porphyrins and phthalocyanines
影响因子: 1.5
作者: [Yett A, Lin LY, Beseiso D, Miao J, Yatsunyk LA]
通讯作者: Yatsunyk LA
Deciphering the structure and dynamics of non-canonical DNA implicated in cancer
  • 批准号:
    10046709
  • 项目类别:
  • 资助金额:
    $43.2万
  • 财政年份:
    2020
  • 负责人:
    Liliya A Yatsunyk
  • 依托单位:
海外基金