Combined cupric- and cuprous-binding peptides are effective in preventing IL-8 release from endothelial cells and redox reactions.
Copper mobilization and subsequent redox reactions have been implicated in the pathogenesis of numerous inflammation-based diseases. Reduction of the cupric ion (Cu(2+)) to the cuprous ion (Cu(+)) is necessary for the production of copper-induced reactive oxygen species (ROS). Peptides, designed to bind both Cu(2+) and Cu(+) and have the ability to prevent copper redox reactions, were studied. The peptides DAHGMTCANC and DAHKGMTCANC 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 DAHGMTCARC 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(+)/Cu(2+)-binding peptides might be beneficial in the treatment of ROS-related diseases associated with copper.
Rael
Leonard T
LT
Swedish Medical Center, Trauma Research Laboratory, 501 East Hampden Avenue, Room 4-454, Englewood, CO 80113, USA.
Rao
Nagaraja K R
NK
Thomas
Gregory W
GW
Bar-Or
Raphael
R
Curtis
C Gerald
CG
Bar-Or
David
D
D002478:Cells, Cultured; D003300:Copper / Q000008:administration & dosage*; D004305:Dose-Response Relationship, Drug; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D016209:Interleukin-8 / Q000378:metabolism*; D010084:Oxidation-Reduction / Q000187:drug effects; D010455:Peptides / Q000008:administration & dosage*; D017382:Reactive Oxygen Species / Q000378:metabolism*; D017392:Thiobarbituric Acid Reactive Substances / Q000378:metabolism*
D016209:Interleukin-8; D010455:Peptides; D017382:Reactive Oxygen Species; D017392:Thiobarbituric Acid Reactive Substances; D003300:Copper