Inhibition of Cu‐Amyloid‐β by using Bifunctional Peptides with β‐Sheet Breaker and Chelator Moieties

Abstract

Breaking the mold: Inhibition of toxic amyloid-β (Aβ) aggregates and disruption of Cu-Aβ with subsequent redox-silencing of Cu have been considered promising strategies against Alzheimer's disease. The design and proof of concept of simple peptides containing a Cu-chelating/redox-silencing unit and an Aβ-aggregation inhibition unit (β-sheet breaker) is described (see scheme).

Design of nonapeptide LVFFARKHH: A bifunctional agent against Cu2+‐mediated amyloid β‐protein aggregation and cytotoxicity

“…Due to the fluorescent property of tyrosine (Tyr), its intrinsic fluorescence can be used as a probe for conformational changes and bioactivity of proteins, including Aβ . Moreover, the Tyr fluorescence of Aβ 40 can be quenched on Cu 2+ binding, unless the Cu 2+ was deprived from Aβ 40 by metal‐chelators .…”

“…It has been known that peptides containing histidine (H) residues can coordinate with Cu 2+ through the N atom of imidazole group . For this reason, Aβ 12–20 and Aβ 13–20 were used as bifunctional peptides to inhibit the aggregation of Aβ‐Cu 2+ complexes . Inspired by the investigations, we have herein proposed a new peptide sequence by introducing H residues to LK7 to reduce its tendency of self‐assembly (and the cytotoxicity of the aggregates) and introduce a new function, metal‐chelating capability.…”

N‐Terminal Cu‐Binding Motifs (Xxx‐Zzz‐His, Xxx‐His) and Their Derivatives: Chemistry, Biology and Medicinal Applications

“…[42] This agrees with most of the reported studies showingt hat Cu-XZH complex are not able to catalyze the oxidation of ascorbate efficiently.T his is confirmed by the measurementso ft he HOC productionb yC u II -XZH in the presence of ascorbate/O 2 ;compared to Cu II in buffer,orC u-peptide complexes like Cu II -Ab [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16] or Cu II -a-synuclein, the HOC production by Cu II -XZH was virtually absent. [2,22,39,41,[43][44][45] However,i ntroducing aH is-His motif nearby the ATCUN site can help Cu II -reduction by ascorbate, by coordination and stabilization of Cu I in the His-His motif. [46][47][48] Specifically, in the Nterminal peptideo ft he Ctr1 membrane copperr eceptor, containing an XZH motif followed by aH Hc ouple (MDHSHHMG…), the additiono fs toichiometric amounts of ascorbater esulted in ap artial reduction of the d-d band intensity.T his effect was assigned to the HH motif, which is able to bind Cu I ,a nd hence to stabilizei ta fter reduction.…”

A new water-soluble Cu(II) chelator that retrieves Cu from Cu(amyloid-β) species, stops associated ROS production and prevents Cu(II)‐induced Aβ aggregation

“…Ligand H 2 L 2− was therefore probed for its ability to stop Cu(Aβ) ROS production using recently developed in vitro tests [9,10]. As ROS production by Cu species requires the reduction of the air-stable Cu(II) by ascorbate (Asc) (Scheme 1), the rate of Asc consumption is indicative of the Cu species' ability to produce ROS.…”

“…Recently several groups have conceived such new molecules (see Refs. [9][10][11][12][13][14][15][16] and for recent reviews, Refs. [17][18][19]).…”