DNA Recognition and Cleavage by Phenyl-Benzimidazole Modified Gly-Gly-His-Derived Metallopeptides

Abstract

Metallopeptides of the general form M(II)∙Gly1-Gly2-His induce DNA strand scission via minor groove interactions. This peptide system can serve as a nucleic acid-targeted cleavage agent – either as an appendage to other DNA binding agents, or as a stand alone complex. In an effort to further our knowledge of DNA recognition and cleavage, a novel series of phenyl-benzimidazole modified Gly-Gly-His-derived metallopeptides was synthesized via solid phase methods and investigated. The new systems allow the formation of additional contacts to the DNA minor groove through the incorporation of a DNA binding phenyl-benzimidazole moiety, thus strengthening the overall binding interaction and further stabilizing the metal complex-DNA association. In addition, how Lys side chains and an amidinium group influence the efficiency of DNA cleavage was also studied. DNA cleavage studies suggested that the phenyl-benzimidazole-modified Gly-Gly-His metallopeptides possess enhanced DNA cleavage abilities. In particular, when amidines are placed on the benzimidazole moieties, these moieties appeared to play an important role in increasing the DNA cleavage activity of the metal complex, most likely through an enhanced electrostatic attraction to the DNA.