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

题目：金属配合物对RNA的水解裂解；摘要：华盛顿大学化学系James K. Bashkin博士在金属催化RNA裂解机制方面的研究获得了无机、生物无机和有机金属化学项目和数学与物理科学多学科活动办公室（MPS/OMA）颁发的学术与工业联络机会（GOALI）奖。RNA的破坏是一个重要的基本生化过程，也直接关系到新的基于基因组的药物策略的发展。RNA的破坏是由无机催化剂完成的，通过磷酸二酯主链的酯交换裂解RNA。例如，从铜（II）三吡啶以及铜、锌和镧系元素的其他配合物中衍生出合适的催化剂。在这里，所有这些类型的催化剂的RNA裂解机制将研究使用一个新的底物包含一个单一的RNA残基嵌入DNA聚合物。这种新的底物被称为“嵌入RNA”或embRNA。embRNA底物维持了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还允许对rna -金属结合的高度特异性特征进行评估，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。这项工作与开发抗病毒感染和癌症的药物试剂有关。该方法是为了了解反应机制，以便RNA切割可以优化用于化疗。从这项工作中获得的机制信息将提供给专注于核酶模拟物对RNA序列特异性切割的单独项目。参与该项目的研究生将通过在可靠生物制药公司和孟山都公司实习获得工业经验。可靠的生物制药公司还将提供核苷类似物和新型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.