title: Interaction of PiB-derivative metal complexes with beta-amyloid peptides: selective recognition of the aggregated forms.
abstract: 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), L(1) and L(2), 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 (15) N-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 GdL(1), at higher concentrations, stabilizes β-sheets, GdL(2) 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.
authors.affiliation: Centre de Biophysique Moléculaire, CNRS, Université d'Orléans, Rue Charles Sadron, 45071 Orléans Cedex 2 (France); Department of Life Sciences, Faculty of Sciences and Technology, University of Coimbra, Calçada Martim de Freitas, 3000-393 Coimbra (Portugal); Coimbra Chemistry Center, University of Coimbra, Rua Larga, 3004-535 Coimbra (Portugal); Present Address: Department of Chemistry, University of Texas at Dallas, Richardson, Texas 75083 (USA).
authors.forename: André F
authors.initials: AF
authors.lastname: Martins
authors.forename: David M
authors.initials: DM
authors.lastname: Dias
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Morfin
authors.forename: Sara
authors.initials: S
authors.lastname: Lacerda
authors.forename: Douglas V
authors.initials: DV
authors.lastname: Laurents
authors.forename: Éva
authors.initials: É
authors.lastname: Tóth
authors.forename: Carlos F G C
authors.initials: CF
authors.lastname: Geraldes
mesh_terms: D000544:Alzheimer Disease / Q000175:diagnosis / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000378:metabolism* / Q000648:ultrastructure*; D000814:Aniline Compounds / Q000737:chemistry / Q000378:metabolism*; D056831:Coordination Complexes / Q000737:chemistry / Q000378:metabolism*; D006573:Heterocyclic Compounds, 1-Ring / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D028581:Lanthanoid Series Elements / Q000737:chemistry / Q000378:metabolism*; D009682:Magnetic Resonance Spectroscopy; D010446:Peptide Fragments / Q000378:metabolism* / Q000648:ultrastructure*; D066329:Protein Aggregates; D020349:Surface Plasmon Resonance; D013844:Thiazoles / Q000737:chemistry / Q000378:metabolism*
chemical_list: C520644:1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid; C475519:2-(4'-(methylamino)phenyl)-6-hydroxybenzothiazole; D016229:Amyloid beta-Peptides; D000814:Aniline Compounds; D056831:Coordination Complexes; D006573:Heterocyclic Compounds, 1-Ring; D028581:Lanthanoid Series Elements; D010446:Peptide Fragments; D066329:Protein Aggregates; D013844:Thiazoles; C078592:amyloid beta-protein (1-40)
keywords: Alzheimer’s disease; amyloid aggregation; amyloid plaques; contrast agent; lanthanides; peptides