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

James BashkinCHE-9802660标题：金属络合物对RNA的水解裂解;催化作用的基础研究摘要无机、生物无机和有机化学项目和多学科活动数学和物理科学办公室（MPS/OMA）的学术与工业联络（GOALI）奖支持James K.他是华盛顿大学化学系的Bashkin。 RNA的破坏是一个具有基本生化重要性的过程，也直接关系到基于基因组的新药物策略的开发。 在该方案中，RNA的破坏是通过无机催化剂完成的，所述无机催化剂通过其磷酸二酯骨架的酯交换来切割RNA。 例如，合适的催化剂衍生自Cu（II）三联吡啶，以及衍生自铜、锌和镧系元素的其它络合物。 在这里，所有这些类别的催化剂的RNA切割的机制将使用一种新的基板含有一个单一的RNA残基嵌入在DNA聚合物进行研究。 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。 这项工作与开发药物试剂以对抗病毒感染和癌症有关。 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械信息将投入到专注于核酶模拟物对RNA的序列特异性切割的单独项目中。 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。 Reliable Biopharmaceutical还将为核苷类似物和新型核酶模拟物的测试提供资源和专业知识。

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.