Studies of metal ion interactions with peptides are proposed with the long range objective of understanding the role of these complexes in biological systems with regard to their regulatory functions, drug action and toxicity. Metal ions have been implicated as cofactors in strand scissions of DNA for a number of antitumor antibiotics. Coordination of metal ions to peptide hormones, neurotransmitters, and antibiotics are important in their reactions. Our goal is to determine the role of higher oxidation state metal ions in superoxide toxicity. We want to understand how redox reactions of metal peptide complexes can be used in the construction of DNA cleaving molecules, which act as antitumor agents.
Specific aims of this proposal include studies of (1) oxygen activation and superoxide reactions with copper and nickel peptides, (2) mechanisms of redox decomposition of Cu(III) and Ni(III) peptide complexes, (3) peptides and peptide derivatives that stabilize trivalent copper and trivalent nickel, (4) Pt(II) peptide complexes, (5) metal ion interactions and transfer reactions with peptide hormones and related peptides, and (6) the interaction of other metal ions with peptides. Factors which help to stabilize Cu(III) and Ni(III) peptides, as well as those which activate or catalyze their reactions, will be examined. The interaction of platinum(II) with peptides and the relationship between protein binding and toxic side effects will be studied. The nature, stability, oxidation states and kinetics of metal peptide complexes will be explored to help understand the biological transport, catalysis and toxicity of metal ions.
