DESIGN OF SEQUENCE SPECIFIC METAL POLYAMIDE CONJUGATES

California Institute Of Technology, Pasadena CA

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Abstract

The design of the first sequence-specific conjugates of DNA-targeting transition metal complexes and hairpin polyamides that bind to a predetermined sequence within the DNA minor groove is described. Pyrrole-imidazole-hydroxypyrrole polyamide hairpins that are specifically designed to recognize a single nucleotide sequence will be used as a recognition system, delivering the transition metal complexes to the desired polynucleotide site. Subsequent formation of a covalent bond between DNA and the transition metal complex will secure the conjugate in the desired nucleotide site. Such a combination of hydrogen-bonding and covalent bonds is expected to inhibit the progressive movement of polymerase II and III thereby interfering with the mechanism of gene expression. Three different transition metal complexes, Pt(II), Pt(IV) and molybdenocene will be prepared and their binding affinity and sequence specificity will be investigated by NMR and various nucleic acid techniques.