Copper mobilization and subsequent redox reactions have been implicated in the pathogenesis of numerous inflammation-based diseases. Reduction of the cupric ion (Cu2+) to the cuprous ion (Cu+) is necessary for the production of copper-induced reactive oxygen species (ROS). Peptides, designed to bind both Cu2+ and Cu+ and have the ability to prevent copper redox reactions, were studied. The peptides DAHGMTCA (N) under barC and DAHKGMTCA (N) under barC were effective at preventing the formation of thiobarbituric acid-reactive species (TBARS) in a copper/ascorbate solution at a 1:1 peptide/Cu ratio. This was observed in the reducing potential of the copper/ascorbate solutions containing these peptides at a 1:1 ratio based on oxidation-reduction potential (ORP) measurements. The peptide DAHGMTCA (R) under barC was effective at a 2:1 ratio, but not at a 1:1 ratio in which an increase in the oxidation potential was observed. This suggests that a positively charged amino acid such as arginine (R) in the Cu+-binding motif interferes with metal chelation. All peptides tested were effective at preventing IL-8 release from phorbol 12-myristate 13-acetate (PMA)/copper-stimulated human umbilical vein endothelial cells (HUVEC). The use of Cu+/Cu2+-binding peptides might be beneficial in the treatment of ROS-related diseases associated with copper. (c) 2007 Elsevier Inc. All rights reserved.