A Trishistidine Pseudopeptide with Ability to Remove Both Cu^Ι and Cu^ΙΙ from the Amyloid‐β Peptide and to Stop the Associated ROS Formation

Abstract

The pseudopeptide L, derived from a nitrilotriacetic acid scaffold and functionalized with three histidine moieties, is reminiscent of the amino acid side chains encountered in the Alzheimer's peptide (Aβ). Its synthesis and coordination properties for Cu and Cu are described. L efficiently complex Cu in a square-planar geometry involving three imidazole nitrogen atoms and an amidate-Cu bond. By contrast, Cu is coordinated in a tetrahedral environment. The redox behavior is irreversible and follows an ECEC mechanism in accordance with the very different environments of the two redox states of the Cu center. This is in line with the observed resistance of the Cu complex to oxidation by oxygen and the Cu complex reduction by ascorbate. The affinities of L for Cu and Cu at physiological pH are larger than that reported for the Aβ peptide. Therefore, due to its peculiar Cu coordination properties, the ligand L is able to target both redox states of Cu, redox silence them and prevent reactive oxygen species production by the CuAβ complex. Because reactive oxygen species contribute to the oxidative stress, a key issue in Alzheimer's disease, this ligand thus represents a new strategy in the long route of finding molecular concepts for fighting Alzheimer's disease.

Kinetics Are Crucial When Targeting Copper Ions to Fight Alzheimer's Disease: An Illustration with Azamacrocyclic Ligands

“…As ag eneral trend,a ddition of methylpicolinate arm(s) makes the reduction easier,t hat is, the reduction occurs at higher potential (Table 1). [10] In line with the electrochemical measurements, once the Cu 2 + complexes are formed with any of the six ligands, they cannotb er educed by Asc as probed by the absence of Asc consumption monitored by UV/Vis ( Figure S6, panelsAand B in the Supporting Information). [10] In line with the electrochemical measurements, once the Cu 2 + complexes are formed with any of the six ligands, they cannotb er educed by Asc as probed by the absence of Asc consumption monitored by UV/Vis ( Figure S6, panelsAand B in the Supporting Information).…”

“…Thisi si nl ine with the higherC u 2 + affinity values of the ligands compared with Ab (Table1)a nd the resistance to Asc reduction of the resulting Cu 2 + -L complexes. [10,22] Here, we also directly monitor the formation of HOC by using af luorescent assay ( Figure S7 in the Supporting Information) and the results perfectly match those of the Asc consumption experiment. [20] Under such conditions,t he arrest of Asc consumption dependso nt he ligand:t he arrest is total with do1pa, te1pa, and te2pa,q uasi-total with do2pa, anda bsent for both cyclam and cyclen.I ti sw orth noting that the Asc consumption experimentsm irror the formation of ROS, in particular H 2 O 2 and HOC, [21] and is ar obust way to documentt he ability of the ligand in the removal and redox-silencing of Cu-Ab species.…”

“…Such ligands can remove Cu 2 + from Ab (chelator) and optionally redistribute it intracellularly( metallophore) and many of them have been reported in the last few years. [10] As econdo ne is to design Cu 2 + drug candidates that are able to remove Cu 2 + "fast enough"f rom the Ab peptide. [7] However,b ecause the synaptic cleft where the Cu-Ab interactiono ccurs is proposed to be aq uite reducing environment, [8] Cu 2 + might not be the most appropriate redox state of copper to target.T hus, af irst possible strategy is to targetC u + [9] or both redox states.…”

A Metallo Pro‐Drug to Target CuII in the Context of Alzheimer's Disease

“…Either Cu(Aβ) and 1 + (or Cu(Aβ) and LH as control) were first pre-mixed and then Asc was added (Figure S10) or Cu(Aβ) was reacted with Asc and then 1 + (or LH as control) was added (Figure 3), according to a previously published procedure. [24–25] The absence of Asc consumption or its preclusion was observed, respectively. This indicates that 1 + is able to remove Cu(II) from Aβ leading to 2 + , which is not competent for Asc oxidation.…”

Crystal structure of catena-poly[[[dichloridocopper(II)]-{μ-tert-butyl N-methyl-N-[4-(6-{[4-(pyridin-2-yl-κN)-1H-1,2,3-triazol-1-yl-κN 3]methyl}-1,3-benzothiazol-2-yl)phenyl]carbamato}] acetonitrile monosolvate]

“…More specifically, Cu II has been found to form a complex with the amyloid peptide for which aggregation is one of the major hallmarks of AD (Eury et al, 2011;Faller et al, 2014). This has triggered significant ongoing interest in the development of chelators able to interact with metals in the context of AD (Santos et al, 2016;Conte-Daban et al, 2017).…”