HYDROLYTIC CLEAVAGE OF RNA BY METAL COMPLEXES, FUNDAMENTAL STUDY IN CATALYSIS

金属配合物对 RNA 的水解裂解，催化基础研究

• 批准号: 6336749
• 负责人: James K. Bashkin
• 金额: $ 0.53万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-08-01 至 2001-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6336749
• 关键词: biological products; biomedical resource; nucleic acids; spectrometry

The destruction of RNA is a process of fundamental biochemical importance, and also has direct bearing on the development of new genomic-based drug strategies. The destruction of RNA is accomplished in this proposal by inorganic catalysts that cleave RNA through transesterification of its phosphodiester backbone. For example, appropriate catalysts are derived from Cu(II)terpyridine, as well as from other complexes of copper, zinc and the lanthanides. Here, the mechanism of RNA cleavage by all of these classes of catalyst will be studied using a new substrate containing a single RNA residue embedded in a DNA polymer. The new substrate is called "embedded RNA", or embRNA. The embRNA substrate maintains the biological relevance of RNA polymers but provides the simplicity and practicality inherent to RNA dimers. EmbRNA furthermore allows highly specific features of RNA-metal binding to be assessed for their importance to the cleavage reaction. These features in clud e charge and hydrophobic effects, remote coordination of metals, and subtle two-metal mechanisms. The work has relevance to development of pharmaceutical reagents to fight viral infections and cancer. The approach is to gain an understanding of the reaction mechanism so that RNA cleavage can be optimized for use in chemotherapy. The mechanistic information gained from this work will feed into separate projects that focus on the sequence-specific cleavage of RNA by ribozyme mimics. Mass spectrometry is used for characterizing these materials.

RNA的破坏是一个基本的生化过程 的重要性，也直接关系到新产品的开发 基于基因组的药物策略。 RNA的破坏完成 在这个提议中，通过无机催化剂切割RNA 其磷酸二酯主链的酯交换反应。 例如， 合适的催化剂衍生自三联吡啶铜(II)，以及 来自铜、锌和镧系元素的其他络合物。 在这里， 所有这些类别的催化剂切割 RNA 的机制将是 使用含有嵌入的单个 RNA 残基的新基质进行研究 在 DNA 聚合物中。 新的底物被称为“嵌入的RNA”，或者 embRNA。 embRNA 底物保持了生物相关性 RNA 聚合物，但提供了固有的简单性和实用性 RNA二聚体。 EmbRNA还允许高度特异性的特征 评估 RNA-金属结合对切割的重要性 反应。 这些特征包括电荷和疏水效应， 金属的远程协调，以及微妙的二金属机制。 这 工作与开发药物试剂以对抗 病毒感染和癌症。 方法是为了获得理解 反应机制，以便可以优化 RNA 切割 用于化疗。 由此获得的机械信息 工作将纳入单独的项目，重点关注 通过核酶模拟物对 RNA 进行序列特异性切割。 大量的 光谱测定法用于表征这些材料。