Hydrolic Cleavage of RNA by Metal Complexes; A Fundamental Study in Catalysis

James BashkinCHE-9802660题目：金属络合物对RNA的水解性裂解；催化的基础研究摘要这项授予无机化学、生物无机化学和有机金属化学计划以及多学科活动数学和物理科学办公室(MPS/OMA)颁发的与工业(GOALI)奖的学术联系机会支持华盛顿大学化学系的James K.Bashkin博士对金属催化RNA切割机制的研究。RNA的破坏是一个具有基本生物化学意义的过程，也直接关系到基于基因组的新药物策略的发展。在这个方案中，RNA的破坏是通过无机催化剂通过磷酸二酯主链的酯交换来裂解RNA来完成的。例如，合适的催化剂来自铜(II)联吡啶，以及来自铜、锌和稀土的其他络合物。在这里，将使用一种新的底物来研究所有这些类别的催化剂切割RNA的机制，该底物含有嵌入在DNA聚合物中的单个RNA残基。这种新的底物被称为“嵌入式RNA”，或embRNA。EmbRNA底物保持了RNA聚合物的生物学相关性，但提供了RNA二聚体固有的简单性和实用性。此外，EmbRNA还允许评估RNA-金属结合的高度特异性特征，以确定它们对切割反应的重要性。这些特征包括电荷和疏水效应、金属的远程配位以及微妙的双金属机制。这项工作与开发抗击病毒感染和癌症的药物试剂有关。这种方法是为了了解反应机制，以便优化RNA切割以用于化疗。从这项工作中获得的机械信息将被提供给单独的项目，这些项目专注于核酶模拟物对RNA的序列特异性切割。参与该项目的研究生将通过在可靠的生物制药公司和孟山都公司的实习获得行业经验。可靠的生物制药公司还将提供核苷类似物和新核酶模拟物测试方面的资源和专业知识。

James BashkinCHE-9802660Title: Hydrolytic Cleavage of RNA by Metal Complexes; A Fundamental Study in CatalysisAbstractThis Grant Opportunities for Academic Liaison with Industry (GOALI) award in the Inorganic, Bioinorganic, and Organometallic Chemistry Program and the Mathematical and Physical Sciences Office of Multidisciplinary Activities (MPS/OMA) supports research on the mechanism of metal-catalyzed RNA cleavage by Dr. James K. Bashkin of the Chemistry Department, Washington University. 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 include 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. Graduate students involved in the project will gain industrial experience through internships at Reliable Biopharmaceutical and Monsanto Company. Reliable Biopharmaceutical will also provide resources and expertise on nucleoside analogues and testing of new ribozyme mimics.