Construction of Metal-Peptide Chimeras Targeted to DNA

该奖项在无机，生物无机和有机化学 该计划支持杰奎琳·K博士的研究。系里的巴顿 化学，加州理工学院，为建设 靶向双螺旋DNA的金属-肽复合物。 寡肽 将被合成并偶联到具有高 对DNA大沟的结合亲和力。 这些嵌入物将 定位附加的肽以特异性地结合到其他DNA位点。 寡肽--它们来自于 DNA结合蛋白，如噬菌体434和P（22）阻遏物和锌 Sp1和ADR 1的指状结构域--以及含铑的 嵌入剂将控制识别特性。的 嵌入剂、肽和两者之间的连接将变化， 靶向特定的DNA位点。 DNA链的切割， 金属嵌入剂的光活化，然后化学 足迹法将用于确定绑定位置。 长期 该项目的目标是开发一系列小金属肽 以可预测的序列特异性结合DNA的复合物。 另外，通过引入第二金属的配位位点， 锌离子进入附加肽，锌离子和金属肽依赖 将探索DNA磷酸二酯骨架的水解裂解。 这项研究将有助于理解的原则， 识别核酸的蛋白质，以及开发一些 载体以实现蛋白质与核酸的选择性相互作用。 结果将与治疗剂的设计相关， 先进的临床试验。

This award in the Inorganic, Bioinorganic, and Organometallic Chemistry Program supports research by Dr. Jacqueline K. Barton of the Department of Chemistry, California Institute of Technology, for the construction of metal-peptide complexes targeted to double helical DNA. Oligopeptides will be synthesized and coupled onto metallointercalators which have high binding affinity for the major groove of DNA. These intercalators will position the appended peptide to bind specifically to other DNA sites. The oligopeptides-- which are derived from the recognition elements of DNA binding proteins such as phage 434 and P(22) repressors and the zinc finger domains of Sp1 and ADR1--as well as the rhodium-containing intercalators will govern the recognition characteristics. The intercalator, peptide, and the linkage between the two will be varied to target specific DNA sites. Cleavage of the DNA strand by photoactivation of the metallointercalator followed by chemical footprinting will be used to determine binding locations. The long term goal of the project is the development of an array of small metal-peptide complexes which bind DNA with predicatable sequence-specificities. Additionally, by incorporating a coordination site for a secondary metal ion into the appended peptide, zinc ion and metal-peptide-dependent hydrolytic cleavage of the DNA phosphodiester backbone will be explored. This research will contribute to understanding the principles of recognition of nucleic acids by proteins, as well as develop some vehicles to effect selective interaction of proteins with nucleic acids. The results will be relevant to the design of therapeutic agents and advanced clinical testing.