METALLOPEPTIDE DNA INTERACTIONS - SITE-SELECTIVITY BASED ON AMINO-ACID-COMPOSITION AND CHIRALITY

DNA cleavage by synthetic tripeptides of the form NH2-Xaa-Xaa-His-CONH2 was investigated in the presence of Ni(II) and the oxygen activating agent oxone. Studies with Ni(II). Gly-Gly-His, Ni(II). Lys-Gly-His, and Ni(II). Arg-Gly-His indicated that each metallopeptide is capable of inducing strand scission via a non-diffusible oxidant at mixed A/T-rich regions, albeit with an avoidance of homopolymeric A/T sites, in a reaction that can be inhibited by the minor groove binding drug distamycin. Additional metallopeptides containing substitutions of D-His for L-His and neutral metallopeptides containing Asn residues demonstrate the ability to alter site-selectivity through subtle structural changes; the metallopeptide Ni(II). Gly-D-Asn-His displayed a selectivity for 5'-CCT sites while other substitutions varied with respect to their levels of site discrimination in comparison to Ni(II). Gly-Gly-His. These observations indicate that the metallopeptides in question are sensitive to DNA structure and are capable of interacting selectively with the minor groove, suggesting the possibility of exploiting the chemical diversity and chirality of peptides in the further design of site-selective DNA binding and modifying agents.