SYNTHESIS OF DNA-BINDING PROTEIN MIMICS

DNA 结合蛋白模拟物的合成

• 批准号: 3466817
• 负责人: ROBERT W ARMSTRONG
• 金额: $ 8.17万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 1988
• 资助国家: 美国
• 起止时间: 1988-02-01 至 1993-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3466817
• 关键词: antineoplastic antibiotics; binding proteins; conformation; drug design /synthesis /production; drug screening /evaluation; endonuclease; glycoproteins; macromolecule; polysaccharides

This proposal describes the rational design and synthesis of substrates capable of recognizing DNA with a high degree of specificity for base-pair sequence and molecular conformation. The goal is to define the minimum requirements for DNA-binding proteins to recognize a specific base-pair sequence by using only those portions of the protein which are believed to be responsible for site-selective contacts. A portocol is established for the logical design and synthesis of a number of novel sugar-derived water-soluble "rigid" molecules which are capable of extending the distance required for each termini to reside in adjacent major- (or minor) grooves of B-DNA (33 - 34 Angstroms). The synthesis involves stereoselective C- glycosidations to construct the C-1-C-4' bond of deoxo- polysaccharides and 3,3 sigmatropic rearrangements for the construction of transoxo bipyranose derivatives. The target C- polysaccharides are "capped" with small peptides at each termini (Ca1 - Cg4) to afford C-glycoproteins of defined configuration. Several modes of binding are presented which are controlled by the symmetry of the terminal peptides and the size of the C- polysaccharide connecting them. Besides obtaining information on the parameters of binding recognition, the synthetic recognition fragments offer an array of existing multidisciplinary applications. These include the design of restriction endonucleases, their use as probes and mimics of other DNA-binding proteins and finally their potential as DNA- targeted antitumor agents.

该建议描述了理性的设计和合成 能够识别高度DNA的底物 基本对序列和分子构象的特异性。 目的是定义DNA结合的最低要求 蛋白质仅使用 据信是负责的蛋白质的那些部分 用于现场选择性触点。 建立了用于逻辑设计和合成 新型糖衍生的水溶性“刚性”分子的数量 能够延长每个的距离 终端居住在B-DNA的相邻主要（或次要）凹槽中 （33-34埃）。 合成涉及立体选择性c- 糖苷构建脱氧的C-1-C-4'键 多糖和3,3 sigmatropic重排 构造经氧双吡喃糖衍生物。 目标c- 多糖在每个末端用小肽“盖住” （CA1 -CG4）提供定义配置的C-糖蛋白。 提出了几种结合模式 末端肽的对称性和C-的大小 多糖连接它们。 除了获取有关绑定参数的信息 识别，合成识别片段提供了一系列 现有的多学科应用程序。 这些包括设计 限制性核酸内切酶，它们用作探针和模仿 其他DNA结合蛋白，最终作为DNA- 靶向抗肿瘤剂。