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.

Current progress, challenges and future prospects of diagnostic and therapeutic interventions in Alzheimer's disease

“…25,95 Therefore, the design of peptide-or peptidomimeticbased metal chelators/sequestrators has been an active area of research, although most of the reported chelators lack multifunctional features. 96,97 We developed the multifunctional peptidomimetic P6 by conjugating the copper-chelating natural tripeptide Gly-His-Lys (GHK) found in humans and the peptoid-based Ab aggregation modulator P5 (Fig. 7a and b).…”

Drastic Effect of the Peptide Sequence on the Copper‐Binding Properties of Tripeptides and the Electrochemical Behaviour of Their Copper(II) Complexes

“…Possible configurations were built considering the information obtained from NMR experiments, [48] which indicated that the probable coordinating sites are the N term ,H is1, His3, and N À from the deprotonated amide of the backboneo rt he Of rom the carbonyl group of the backbone. Possible configurations were built considering the information obtained from NMR experiments, [48] which indicated that the probable coordinating sites are the N term ,H is1, His3, and N À from the deprotonated amide of the backboneo rt he Of rom the carbonyl group of the backbone.…”

“…To determine which coordination mode provides the electrochemicalp roperties observed for these complexes,a nd to assessh ow much different coordination environments would influence the electrochemical behaviour,D FT (B3LYP-D3) calculationsw erec arried out for differentc onfigurations. Possible configurations were built considering the information obtained from NMR experiments, [48] which indicated that the probable coordinating sites are the N term ,H is1, His3, and N À from the deprotonated amide of the backboneo rt he Of rom the carbonyl group of the backbone. Since minor differences are expected among the two complexes, the exploration of different binding modes was first investigated for Cu II -HAH.F ourm ajor configurations werec onsidered from ac omputationalp oint of view: 1) configuration 1,i nvolving the N term ,H is1, His3, the carboxylate group, and the carbonyl Oo fA la2;2 )configuration 2,i nvolvingt he N term ,d eprotonated amide, the carbonyl Oo fA la2, and His3; 3) configuration 3,c orresponding to the ATCUN motif (see Scheme 1) and involving the N term ,H is3, andt he two deprotonated Na mides;a nd finally,4 )configuration 4,w ith His1, His3, the deprotonated N À amide, and the carbonyl Oo f Ala2 as binding sites.…”

Amyloid plaques beyond Aβ: a survey of the diverse modulators of amyloid aggregation

“…However, in a longer 52-week trial, PBT2 did not reduce plaque burden or improve cognitive function to a statistically significant extent. Recently, Caballero and co-workers have designed peptide fragments containing one to two histidine residues which showed higher affinity for Cu 2+ ions than the Aβ40 peptide, and also showed reduced amyloid toxicity and reduced copper-generated ROS (Caballero et al 2016 ) (Fig. 3 i).…”

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Fig. 3 Proposed molecules targeting Aβ aggregation: a heparin-based N-acetyl-glucosamine monosaccharide (Kisilevsky et al 2003 ); b Enoxaparin, a low-molecular-weight heparin (Bergamaschini et al 2004 ); c RNA aptamer β55 (Ylera et al 2002 ), with bases colored as shown; d RNA aptamer E2 (Rahimi et al 2009 ); e the statin Atorvastatin (Lipitor); f doxcosahexaenoic acid (DHA); g clioquinol; h PBT2; i tripeptide H-W-H (Caballero et al 2016 )

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