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

RNA的破坏是一个基本的生物化学过程， 重要性，也直接关系到新的发展。 基于基因组的药物策略 RNA的破坏完成了 在这个提议中，通过无机催化剂， 其磷酸二酯骨架的酯交换。 比如说， 合适的催化剂衍生自Cu（II）三联吡啶，以及 与铜、锌和镧系元素的其他络合物不同。 这里 所有这些类型的催化剂切割RNA的机制将是 研究使用一种新的基板含有一个单一的RNA残基嵌入 DNA聚合物中。 这种新的底物被称为“嵌入的RNA”， embRNA。 embRNA底物保持了以下生物学相关性： RNA聚合物，但提供了固有的简单性和实用性， RNA二聚体。 此外，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， 金属的远程配位和微妙的双金属机制。 的 工作有相关的药物试剂的发展，以打击 病毒感染和癌症。 方法是了解 的反应机制，使RNA切割可以优化， 用于化疗。 由此获得的机械信息 工作将纳入单独的项目，重点是 核酶模拟物对RNA的序列特异性切割。 质量 光谱法用于表征这些材料。

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.