Unexpected Trends in Copper Removal from Aβ Peptide: When Less Ligand Is Better and Zn Helps
In: Inorganic chemistry, Jg. 60 (2021-01-06), Heft 2
Online
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Zugriff:
International audience; Cu, Zn, and amyloid-β (Aβ) peptides play an important role in the etiology of Alzheimer’s disease (AD). Their interaction indeed modifies the self-assembly propensity of the peptide that is at the origin of the deposition of insoluble peptide aggregates in the amyloid plaque, a hallmark found in AD brains. Another even more important fallout of the Cu binding to Aβ peptide is the formation of reactive oxygen species (ROS) that contributes to the overall oxidative stress detected in the disease and is due to the redox ability of the Cu ions. Many therapeutic approaches are currently developed to aid fighting against AD, one of them targeting the redox-active Cu ions. Along this research line, we report in the present article the use of a phenanthroline-based peptide-like ligand (L), which is able to withdraw Cu from Aβ and redox-silence it in a very stable 4N Cu(II) binding site even in the presence of Zn(II). In addition and in contrast to what is usually observed, the presence of excess of L lessens the searched effect of ROS production prevention, but it is counterbalanced by the co-presence of Zn(II). To explain such unprecedented trends, we proposed a mechanism that involves the redox reaction between Cu(II)L and Cu(I)L2. We thus illustrated (i) how speciation and redox chemistry can weaken the effect of a ligand that would have appeared perfectly suitable if only tested in a 1:1 ratio and on CuAβ and (ii) how Zn overcomes the undesired lessening of ROS arrest due to excess of ligand. In brief, we have shown how working in biologically relevant conditions is important for the understanding of all of the reactions at play and this must be taken into consideration for the further rational design of ligands aiming to become drug candidates.
Titel: |
Unexpected Trends in Copper Removal from Aβ Peptide: When Less Ligand Is Better and Zn Helps
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Autor/in / Beteiligte Person: | Esmieu, Charlène ; Conte-Daban, Amandine ; Iranzo, Olga ; Balderrama-Martínez-Sotomayor, Raúl ; Hureau, Christelle ; Laboratoire de chimie de coordination (LCC) ; Institut National Polytechnique (Toulouse) (Toulouse INP) ; Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Université Toulouse III - Paul Sabatier (UT3) ; Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie de Toulouse (ICT-FR 2599) ; Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3) ; Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS) ; Institut des Sciences Moléculaires de Marseille (ISM2) ; Aix Marseille Université (AMU)-École Centrale de Marseille (ECM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS) ; CONACYT (grant 439618) ; PRESTIGE Programm (grant n. PCOFUND-GA-2013−609102) ; European Project: 638712,H2020,ERC-2014-STG,aLzINK(2015) ; Institut de Chimie de Toulouse (ICT) ; Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3) ; Université de Toulouse (UT)-Université de Toulouse (UT)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut National Polytechnique (Toulouse) (Toulouse INP) ; Université de Toulouse (UT)-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3) ; Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS) |
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Zeitschrift: | Inorganic chemistry, Jg. 60 (2021-01-06), Heft 2 |
Veröffentlichung: | 2021 |
Medientyp: | unknown |
ISSN: | 1520-510X (print) ; 0020-1669 (print) |
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