Construction of Metal-Peptide Chimeras Targeted to DNA

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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.