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Article Dans Une Revue Chemistry - A European Journal Année : 2015

Interaction of PiB-Derivative Metal Complexes with Beta-Amyloid Peptides: Selective Recognition of the Aggregated Forms

Résumé

Metal complexes are increasingly explored as imaging probes in amyloid peptide related pathologies. We report the first detailed study on the mechanism of interaction between a metal complex and both the monomer and the aggregated form of Aβ1–40 peptide. We have studied lanthanide(III) chelates of two PiB-derivative ligands (PiB=Pittsburgh compound B), L1 and L2, differing in the length of the spacer between the metal-complexing DO3A macrocycle (DO3A= 1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid) and the peptide-recognition PiB moiety. Surface plasmon resonance (SPR) and saturation transfer difference (STD) NMR spectroscopy revealed that they both bind to aggregated Aβ1–40 (KD=67–160 μM), primarily through the benzothiazole unit. HSQC NMR spectroscopy on the 15N-labeled, monomer Aβ1–40 peptide indicates nonsignificant interaction with monomeric Aβ. Time-dependent circular dichroism (CD), dynamic light scattering (DLS), and TEM investigations of the secondary structure and of the aggregation of Aβ1–40 in the presence of increasing amounts of the metal complexes provide coherent data showing that, despite their structural similarity, the two complexes affect Aβ fibril formation distinctly. Whereas GdL1, at higher concentrations, stabilizes β-sheets, GdL2 prevents aggregation by promoting α-helical structures. These results give insight into the behavior of amyloid-targeted metal complexes in general and contribute to a more rational design of metal-based diagnostic and therapeutic agents for amyloid- associated pathologies.

Dates et versions

hal-01171718 , version 1 (06-07-2015)

Identifiants

Citer

André F. Martins, David M. Dias, Jean-François Morfin, Sara Lacerda, Douglas V. Laurents, et al.. Interaction of PiB-Derivative Metal Complexes with Beta-Amyloid Peptides: Selective Recognition of the Aggregated Forms. Chemistry - A European Journal, 2015, 21 (14), pp.5413-5422. ⟨10.1002/chem.201406152⟩. ⟨hal-01171718⟩
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