STRUCTURAL AND DYNAMIC ASPECTS OF DRUG/DNA INTERACTIONS

药物/DNA 相互作用的结构和动力学方面

• 批准号: 2865151
• 负责人: DAVID E WEMMER
• 金额: $ 1.23万
• 依托单位: UNIVERSITY OF CALIFORNIA BERKELEY
• 依托单位国家: 美国
• 财政年份: 1989
• 资助国家: 美国
• 起止时间: 1989-12-01 至 2000-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2865151
• 关键词: STRUCTURAL; DYNAMIC; ASPECTS; DRUG; DNA

DESCRIPTION: The goal of this project is to continue to improve understanding of ligands which interact with DNA in a sequence specific manner, and to improve the design of such molecules. Ligands designed to target any particular DNA sequence with both high affinity and specificity would be very useful in biochemistry and molecular biology, and also potentially as therapeutic agents. the investigator's focus has been derivatives of the natural product distamycin, containing three pyrrole rings, which has a preference for binding in the minor groove at sequences containing four sequential A,T pairs. He has demonstrated that synthetic derivatives containing imidazole rings bind selectively at specific sequences containing both A,T and G,C pairs, utilizing hydrogen bonding to recognize the amino group of guanosine in the minor groove. Different combinations of these 'recognition modules' have been demonstrated to bind specifically at a number of different DNA sequences, including mostly G,C pairs. Linking such modules has allowed recognition of sites up to 13 base pairs in long. Work proposed will extend studies of linked ligands for recognition of general, mixed A,T and G,C sequences. Linking different recognition modules for enhancing specificity in binding has been shown, and good linkers have been found. For some binding modes the linkers affect the binding affinity and specificity. Dr. Wemmer will study several linked ligand complexes by NMR to understand the interactions with DNA, which will allow development of optimal designs. Linkers for hairpin complexes and extended complexes, with the linker partially controlling the preferred binding mode, and inflexible extensions will be examined. A particularly important area in the next period will be to better understand the factors which control specificity in binding of these designed ligands. The ligands which have been designed do in fact bind with significant preference for the selected target sites. However, there is a substantial range of discrimination between correct and incorrect or mismatched sites. The problem of discrimination seems to increase as the number of G:C pairs in the target site increases. Dr. Wemmer has two challenges, first to understand the origin of these effects, and second to control them. Meeting these challenges will also require developing new methods for determining the specificity for ligands which recognize long target sequences. A final area of work will be to link the minor groove binding agents to other molecules which can be used for sensitive detection, or to carry out chemistry on the target DNA.

说明：本项目的目标是继续改进 了解与DNA在特定序列中相互作用的配体 的方式，并改善这种分子的设计。 配体设计用于 以高亲和力和特异性靶向任何特定DNA序列 在生物化学和分子生物学中非常有用， 可能作为治疗剂。 调查人员的重点是 天然产物偏端霉素的衍生物，含有三个吡咯 环，其具有在序列处的小沟中结合的偏好 包含四个连续的A，T对。 他证明了合成的 含有咪唑环的衍生物选择性地结合在特定的 含有A，T和G，C对的序列，利用氢键键合， 识别小沟中鸟苷的氨基。 不同 这些“识别模块”的组合已经被证明可以结合 特别是在许多不同的DNA序列上，主要包括G，C 对. 连接这些模块，可以识别多达13个基地的网站 长对。 所提出的工作将扩展连接配体的研究，用于识别 一般的，混合的A，T和G，C序列。 连接不同的识别模块 用于增强结合的特异性，并且良好的接头具有 对于某些结合模式，接头影响结合亲和力 和特异性。 Wemmer博士将研究几种连接的配体复合物， 核磁共振，以了解与DNA的相互作用，这将允许开发 最优设计 用于发夹复合物和延伸复合物的接头， 接头部分控制优选的结合模式，并且是不可弯曲的 扩展将被审查。 下一个时期一个特别重要的领域是， 了解控制这些结合特异性的因素 设计的配体。 已经设计的配体实际上与 对所选目标部位的显著偏好。 但有一个 正确和不正确之间的大量区别，或 不匹配的网站。 歧视问题似乎随着 靶位点中G：C对的数量增加。 韦默医生有两个 挑战，首先是了解这些影响的起源，其次是 控制他们。 应对这些挑战还需要开发新的 确定识别长链的配体的特异性的方法 靶序列。 最后一个工作领域是将小沟结合剂与 可用于灵敏检测或进行 目标DNA上的化学反应