Histidine‐Rich Oligopeptides To Lessen Copper‐Mediated Amyloid‐β Toxicity. Issue 21 (13th April 2016)

• Record Type: Journal Article
• Authors: Caballero, Ana B.; Terol‐Ordaz, Laia; Espargaró, Alba; Vázquez, Guillem; Nicolás, Ernesto; Sabaté, Raimon; Gamez, Patrick
• Is Part Of: Chemistry. Volume 22:Issue 21(2016)
• Page Start: 7268
• Page End: 7280
• Publication Date: 2016-04-13
• Subjects: aggregation -- amyloid oligomers -- copper -- metal homeostasis -- neurodegenerative disease -- oxidative stress; Chemistry -- Periodicals; 540
• DOI: 10.1002/chem.201600286
• Languages: English
• ISSNs: 0947-6539

Abstract

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, namelyHWH, HK C H, andHAH, 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, andHAH 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. Abstract : Copper capture : Tripeptides of the type His‐Xaa‐His exhibit high affinity for copper(II) ions, and can therefore compete with amyloid‐β in binding this metal (see figure). Furthermore, these histidine‐rich small peptides are capable of reducing the redox activity of the captured divalent ions.