DEVELOPMENT OF MODULAR NUCLEIC ACID SURROGATES

模块化核酸替代物的开发

• 批准号: 2406564
• 负责人: PHILIP P GARNER
• 金额: $ 15.75万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-08-01 至 2000-07-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2406564
• 关键词: DNA; RNA; X ray crystallography; affinity chromatography; chemical binding; computer assisted sequence analysis; conformation; molecular dynamics; nuclear magnetic resonance spectroscopy; nucleic acid chemical synthesis; nucleic acid sequence; nucleic acid structure; nucleobase analog; peptide chemical synthesis; protein engineering; protein structure

The overall aim of this project is to develop a new class of nucleic acid surrogates capable of sequence specific binding to single stranded DNA & RNA as well as double-stranded DNA targets. The repeating structural units for the proposed modules include peptide- and peptidomimetic-based nucleic acid surrogates. Once synthesized (in suitably protected form), the nucleobase-containing modules will be linked together via peptide and/or amide bonds to give the required oligomeric structures having defined nucleobase sequences. For each structural type, the research plan will entail: (1) computational evaluation of each surrogate to see if it can accommodate hybridization to complementary nucleic acid targets, (2) molecular synthesis and characterization of oligomeric structures having defined sequences of nucleobases, and finally (3) physicochemical evaluation of the hybridization potential of the resulting surrogates with specific nucleic acid target sequences. Iteration of this rational approach (design, synthesis, & evaluation) is expected to lead to nucleic acid surrogates that bind specifically to their nucleic acid target sequences. Alternatively, a combinatorial synthesis/affinity chromatography approach will be used to produce mixed residue surrogates capable of sequence specific triplex formation and molecular recognition of unusual nucleic acid tertiary structures (loops, junctions, etc.). If successful, this research project could lead to more effective antisense/antigene probes and/or drug carriers for use as genetically-based medicines in the treatment of viral infections and cancer.

该项目的总体目标是开发一种新的核 能够序列特异性结合单个 链DNA和RNA以及双链DNA靶标。 的 所提出的模块的重复结构单元包括肽- 和基于肽模拟的核酸替代物。一旦合成 (in适当保护的形式），含核碱基的模块将 通过肽和/或酰胺键连接在一起， 需要具有确定的核碱基序列的寡聚结构。 对于每种结构类型，研究计划将包括：（1） 每个代理的计算评估，看看它是否可以 适应与互补核酸靶的杂交，（2） 低聚物结构的分子合成和表征 具有确定的核碱基序列，以及最后（3） 杂交潜力的物理化学评价 产生具有特定核酸靶序列的替代物。 这种理性方法的迭代（设计、合成和 评估）预期将导致核酸替代物， 特别是它们的核酸靶序列。 可选择地， 一种组合合成/亲和层析方法将 用于产生能够排序的混合残基替代物 特异性三链体形成和异常分子识别 核酸三级结构（环、连接等）。如果 如果成功，这项研究项目可能会导致更有效的 反义/反基因探针和/或药物载体 治疗病毒感染的基因药物， 癌