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Interaction of PiB‐Derivative Metal Complexes with Beta‐Amyloid Peptides: Selective Recognition of the Aggregated Forms
Author(s) -
Martins André F.,
Dias David M.,
Morfin JeanFrançois,
Lacerda Sara,
Laurents Douglas V.,
Tóth Éva,
Geraldes Carlos F. G. C.
Publication year - 2015
Publication title -
chemistry – a european journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.687
H-Index - 242
eISSN - 1521-3765
pISSN - 0947-6539
DOI - 10.1002/chem.201406152
Subject(s) - chemistry , peptide , circular dichroism , monomer , nuclear magnetic resonance spectroscopy , heteronuclear single quantum coherence spectroscopy , amyloid (mycology) , stereochemistry , metal , dynamic light scattering , crystallography , biochemistry , materials science , organic chemistry , nanotechnology , nanoparticle , inorganic chemistry , polymer
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 Aβ 1–40 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 Aβ 1–40 ( K D =67–160 μ M ), primarily through the benzothiazole unit. HSQC NMR spectroscopy on the 15 N‐labeled, monomer Aβ 1–40 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 Aβ 1–40 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.