Drew, S.C. Chelator PBT2 Forms a Ternary Cu2+ Complex with β-Amyloid That Has High Stability but Low Specificity. Int. J. Mol. Sci.2023, 24, 9267.
Drew, S.C. Chelator PBT2 Forms a Ternary Cu2+ Complex with β-Amyloid That Has High Stability but Low Specificity. Int. J. Mol. Sci. 2023, 24, 9267.
Drew, S.C. Chelator PBT2 Forms a Ternary Cu2+ Complex with β-Amyloid That Has High Stability but Low Specificity. Int. J. Mol. Sci.2023, 24, 9267.
Drew, S.C. Chelator PBT2 Forms a Ternary Cu2+ Complex with β-Amyloid That Has High Stability but Low Specificity. Int. J. Mol. Sci. 2023, 24, 9267.
Abstract
The metal chelator PBT2 (5,7-dichloro-2-[(dimethylamino)methyl]-8-hydroxyquinoline) acts as a terdentate ligand capable of forming binary and ternary Cu2+ complexes. It was clinically trialed as an Alzheimer’s disease (AD) therapeutic but failed to progress beyond phase II. The β-amyloid (Aβ) peptide associated with AD was recently concluded to form a unique Cu(Aβ) complex that is inaccessible to PBT2. Herein, it is shown that the species ascribed to this binary Cu(Aβ) complex in fact corresponds to ternary Cu(PBT2)NIm[Aβ] complexes formed by anchoring of Cu(PBT2) on imine nitrogen (NIm) donors of His side chains. The primary site of ternary complex formation is His6, having a conditional stepwise formation constant at pH 7.4 (K [M−1] ) of log K = 6.4 ± 0.1, and a second site is supplied by His13 or His14 (log K = 4.4 ± 0.1). The stability of Cu(PBT2)NIm[H13/14] is comparable with that of the simplest ternary complexes involving free imidazole (log K = 4.22 ± 0.09) and histamine (log K = 4.00 ± 0.05). The 100-fold larger formation constant for Cu(PBT2)NIm[H6] indicates that outer-sphere ligand–peptide interactions strongly stabilize its structure. Despite the relatively high stability of Cu(PBT2)NImH6, PBT2 is a promiscuous Cu2+-binding ligand capable of forming a ternary Cu(PBT2)NIm complex with any ligand containing NIm donor. These ligands include histamine, L-His, and ubiquitous His side chains of peptides and proteins in the extracellular milieu, whose combined effect should outweigh that of a single Cu(PBT2)NIm[H6] complex regardless of its stability. We therefore conclude that PBT2 is capable of accessing Cu(Aβ) complexes with high stability but not specificity. The results have implications for future AD therapeutic strategies and understanding the role of PBT2 in the bulk transport of transition metal ions. Given the repurposing of PBT2 as a drug for breaking antibiotic resistance, ternary Cu(PBT2)NIm and analogous Zn(PBT2)NIm complexes may be relevant to its antimicrobial properties.
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