title: Histidine-Rich Oligopeptides To Lessen Copper-Mediated Amyloid-β Toxicity.
abstract: Brain copper imbalance plays an important role in amyloid-β aggregation, tau hyperphosphorylation, and neurotoxicity observed in Alzheimer's disease (AD). Therefore, the administration of biocompatible metal-binding agents may offer a potential therapeutic solution to target mislocalized copper ions and restore metallostasis. Histidine-containing peptides and proteins are excellent metal binders and are found in many natural systems. The design of short peptides showing optimal binding properties represents a promising approach to capture and redistribute mislocalized metal ions, mainly due to their biocompatibility, ease of synthesis, and the possibility of fine-tuning their metal-binding affinities in order to suppress unwanted competitive binding with copper-containing proteins. In the present study, three peptides, namely HWH, HK(C) H, and HAH, have been designed with the objective of reducing copper toxicity in AD. These tripeptides form highly stable albumin-like complexes, showing higher affinity for Cu(II) than that of Aβ(1-40). Furthermore, HWH, HK(C) H, and HAH act as very efficient inhibitors of copper-mediated reactive oxygen species (ROS) generation and prevent the copper-induced overproduction of toxic oligomers in the initial steps of amyloid aggregation in the presence of Cu(II) ions. These tripeptides, and more generally small peptides including the sequence His-Xaa-His at the N-terminus, may therefore be considered as promising motifs for the future development of new and efficient anti-Alzheimer drugs.
authors.affiliation: Department of Inorganic and Organic Chemistry, University of Barcelona, Martí i Franquès 1-11, 08028, Barcelona, Spain. ana.caballero@ub.edu.
authors.forename: Ana B
authors.identifier: 0000-0001-9294-9085
authors.initials: AB
authors.lastname: Caballero
authors.affiliation: Department of Inorganic and Organic Chemistry, University of Barcelona, Martí i Franquès 1-11, 08028, Barcelona, Spain.
authors.forename: Laia
authors.initials: L
authors.lastname: Terol-Ordaz
authors.affiliation: Department of Physical Chemistry, Faculty of Pharmacy and, Institute of Nanoscience and Nanotechnology (IN2UB), University of Barcelona, Avda. Joan XXIII 27-31, 08028, Barcelona, Spain.
authors.forename: Alba
authors.initials: A
authors.lastname: Espargaró
authors.affiliation: Department of Inorganic and Organic Chemistry, University of Barcelona, Martí i Franquès 1-11, 08028, Barcelona, Spain.
authors.forename: Guillem
authors.initials: G
authors.lastname: Vázquez
authors.affiliation: Department of Inorganic and Organic Chemistry, University of Barcelona, Martí i Franquès 1-11, 08028, Barcelona, Spain.
authors.forename: Ernesto
authors.initials: E
authors.lastname: Nicolás
authors.affiliation: Department of Physical Chemistry, Faculty of Pharmacy and, Institute of Nanoscience and Nanotechnology (IN2UB), University of Barcelona, Avda. Joan XXIII 27-31, 08028, Barcelona, Spain.
authors.forename: Raimon
authors.initials: R
authors.lastname: Sabaté
authors.affiliation: Department of Inorganic and Organic Chemistry, University of Barcelona, Martí i Franquès 1-11, 08028, Barcelona, Spain. patrick.gamez@qi.ub.es.|Institució Catalana de Recerca i Estudis Avançats (ICREA), Passeig Lluís Companys 23, 08010, Barcelona, Spain. patrick.gamez@qi.ub.es.
authors.forename: Patrick
authors.identifier: 0000-0003-2602-9525
authors.initials: P
authors.lastname: Gamez
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy / Q000378:metabolism; D000682:Amyloid / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D003300:Copper / Q000378:metabolism*; D006639:Histidine / Q000031:analogs & derivatives* / Q000494:pharmacology*; D006801:Humans; D009842:Oligopeptides / Q000737:chemistry* / Q000494:pharmacology*; D010446:Peptide Fragments / Q000378:metabolism*; D066329:Protein Aggregates / Q000187:drug effects; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D000682:Amyloid; D016229:Amyloid beta-Peptides; D009842:Oligopeptides; D010446:Peptide Fragments; D066329:Protein Aggregates; D017382:Reactive Oxygen Species; C078592:amyloid beta-protein (1-40); D006639:Histidine; D003300:Copper
keywords: aggregation; amyloid oligomers; copper; metal homeostasis; neurodegenerative disease; oxidative stress