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

RNA的破坏是一个基本的生化过程 重要性，也直接关系到新世纪的发展 基于基因组的药物策略。核糖核酸的破坏完成了 在这项提案中，由无机催化剂通过裂解RNA 它的磷酸二酯主链的酯交换反应。例如, 合适的催化剂来源于铜(II)联吡啶以及 从铜、锌和稀土的其他络合物中分离出来。在这里， 所有这些类别的催化剂切割RNA的机制都将是 使用包含单个嵌入的RNA残基的新底物进行研究 在DNA聚合物中。这种新的底物被称为“嵌入的RNA”，或 EmbRNA。EmbRNA底物保持了 RNA聚合物，但提供了以下固有的简单和实用 RNA二聚体。EmbRNA还允许高度特定的特征 RNA-金属结合对切割的重要性有待评估 反应。这些特征表现在杂化和疏水效应上， 金属的远程配位，以及微妙的双金属机制。这个 这项工作关系到抗击药物试剂的发展 病毒感染和癌症。方法是获得一种理解 反应机理，从而使RNA裂解可以被优化 在化疗中使用。从这个过程中获得的机械信息 工作将提供给单独的项目，这些项目专注于 核酶模拟序列特异性切割RNA。质量 光谱是用来表征这些材料的。

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.