Deciphering the structure and dynamics of non-canonical DNA implicated in cancer

破译与癌症相关的非规范 DNA 的结构和动力学

基本信息

批准号：
10046709
负责人：
Liliya A Yatsunyk
金额：
$ 43.2万
依托单位：
SWARTHMORE COLLEGE
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-01 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10046709
关键词：
Address Affect Affinity Antineoplastic Agents Architecture Area Binding Binding Sites Bioinformatics Biological Biological Process Cancer Intervention Cause of Death Chemical Structure Clinical Communities Complement Complex Crystallization DNA DNA Damage DNA Sequence DNA Structure Development G-Quartets Gene Expression Regulation Goals Grant Human Genome Investigation KRAS2 gene Kinetics Knowledge Lead Ligand Binding Ligands Light Malignant Neoplasms Mentorship Molecular Molecular Conformation Neoplasm Metastasis Nucleic Acids Nucleotides Oncogenes Oncoproteins Physiological Probability Publications Publishing RAS genes RNA Recovery Regulation Reporting Research Resolution Roentgen Rays Scientist Structure Students Telomere Maintenance Telomere Maintenance Gene Thermodynamics Time Training Vascular Endothelial Growth Factors Work anti-cancer therapeutic biophysical properties cancer therapy cell growth design driving force drug candidate drug discovery improved in vivo interdisciplinary collaboration neoplastic cell novel nucleic acid structure programs promoter side effect small molecule stoichiometry targeted treatment telomere therapeutic target three dimensional structure tumor growth undergraduate student

项目摘要

PROJECT SUMMARY The proposed research will improve the selectivity and efficacy of anticancer therapies by contributing new knowledge about non-canonical nucleic acid structures, G-quadruplexes (GQ) and i-motifs, and details of their interactions with small-molecule ligands. Bioinformatics studies have identified 700,000 sequences with GQ- forming potential in the human genome. The C-rich opposite strands are proposed to form i-motifs. There is now convincing biological evidence that GQs and i-motifs form in vivo and that these structures complement each other in regulating a variety of cancer-related biological processes. GQ nucleic acids have been firmly established as an important therapeutic target for cancer. The same evidence for i-motifs is steadily accumulating. Small molecules that bind selectively to GQ DNA and RNA and to i-motifs have been identified, and some have been shown to inhibit tumor cells growth; however, exact mechanisms underlying this inhibition are not known. Additionally, the number of selective i-motif ligands is low. Such ligands may ultimately become lead compounds for cancer intervention superior to conventional mutagenetic therapies. Nucleic acid-centered drug discovery programs suffer from limited structural information for GQs and i-motifs, especially in the presence of ligands. As of now, no structure of an i-motif-ligand complex has been reported. The situation is further complicated by high structural diversity of both GQs and i-motifs, their contradictory biological functions, and our limited ability to target their specific folding topology (e.g., parallel vs antiparallel GQs). To address these challenges, we propose to perform comprehensive crystallographic investigation of telomeric and oncogene promoter GQs and i-motifs, both alone and in complex with novel and commercially available selective small-molecule ligands. The diversity of interactions which provide stability to GQs and i-motifs will be determined. The details of ligand binding sites, as well as chemical and structural features of ligands essential for their affinity and selectivity will be identified. This work will be complemented by spectroscopic and calorimetric studies of the thermodynamic parameters of ligand binding. For GQ DNA, that is much more explored, structural studies will be complemented by rigorous kinetic exploration of ligand-assisted GQ folding. Kinetic information can help us identify the timescale of GQ formation and, thus, biological processes that can be affected by the presence of these structures. Collectively, the proposed work will enhance our understanding of GQ and i-motif structural plasticity, supply coordinates for drug discovery platforms, shed light on the origin of ligand selectivity for a specific DNA or RNA target, and guide the design of novel anticancer therapies all while providing transformative training to Swarthmore undergraduates.

项目概要拟议的研究将通过贡献新的方法来提高抗癌疗法的选择性和疗效关于非规范核酸结构、G-四链体 (GQ) 和 i-基序及其详细信息的知识生物信息学研究已经鉴定出 700,000 个具有 GQ- 的序列。富含C的相反链被认为可以形成i-基序。生物学证据表明 GQ 和令人信服的 i 基序在体内形成，并且这些结构相互补充其他GQ核酸在调节多种癌症相关的生物过程方面也得到了牢固的证实。 i-motifs 已被确定为重要的治疗靶点。已鉴定出选择性结合 GQ DNA 和 RNA 以及 i-motif 的小分子，有些已被证明可以抑制肿瘤细胞的生长；然而，这种抑制的确切机制尚不清楚。此外，选择性 i-基序配体的数量最终可能会减少。用于癌症干预的先导化合物优于传统的诱变疗法。以核酸为中心的药物发现项目受到 GQ 和 i-motif 结构信息有限的困扰，特别是在配体存在的情况下，到目前为止，还没有报道 i-基序-配体复合物的结构。由于 GQ 和 i-motif 的高度结构多样性以及它们的矛盾性，情况变得更加复杂。生物功能，以及我们针对其特定折叠拓扑的有限能力（例如，平行与反平行） GQ）。为了应对这些挑战，我们建议对端粒进行全面的晶体学研究和癌基因启动子 GQ 和 i-基序，无论是单独的还是与新型和市售的复合物为 GQ 和 i 基序提供稳定性的相互作用的多样性将是。确定配体结合位点的详细信息以及配体的化学和结构特征。因为它们的亲和力和选择性将得到光谱和选择性的补充。对于 GQ DNA 来说，配体结合的热力学参数的量热研究远不止这些。随着配体辅助 GQ 折叠的严格动力学探索，结构研究将得到补充。动力学信息可以帮助我们识别 GQ 形成的时间尺度，从而识别可以总的来说，拟议的工作将增强我们的理解。 GQ 和 i-motif 结构可塑性，药物发现平台的供应坐标，揭示了针对特定 DNA 或 RNA 靶点的配体选择性，并指导新型抗癌疗法的设计为斯沃斯莫尔本科生提供变革性培训。