Construction of Metal-Peptide Chimeras Targeted to DNA

无机、生物无机和有机金属化学项目的这一奖项支持了加州理工学院化学系杰奎琳·k·巴顿博士构建针对双螺旋DNA的金属肽复合物的研究。寡肽将被合成并偶联到对DNA主槽具有高结合亲和力的金属插入体上。这些插入物将定位附加的肽以特异性地与其他DNA位点结合。寡肽——源自DNA结合蛋白的识别元件，如噬菌体434和P（22）阻遏物以及Sp1的锌指结构域——以及含铑插入物将控制识别特性。插入物、肽和两者之间的连接将改变以靶向特定的DNA位点。通过金属嵌入层的光激活来切割DNA链，然后用化学足迹来确定结合位置。该项目的长期目标是开发一系列可预测序列特异性结合DNA的小金属肽复合物。这项研究将有助于理解蛋白质识别核酸的原理，并开发一些载体来影响蛋白质与核酸的选择性相互作用。研究结果将与治疗药物的设计和高级临床试验有关。

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 domain of Sp1--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. 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.