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Interaction of PiB-derivative metal complexes with beta-amyloid peptides: selective recognition of the aggregated forms.
- Source :
-
Chemistry (Weinheim an der Bergstrasse, Germany) [Chemistry] 2015 Mar 27; Vol. 21 (14), pp. 5413-22. Date of Electronic Publication: 2015 Feb 25. - Publication Year :
- 2015
-
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.<br /> (© 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)
- Subjects :
- Alzheimer Disease diagnosis
Alzheimer Disease metabolism
Aniline Compounds chemistry
Coordination Complexes chemistry
Heterocyclic Compounds, 1-Ring chemistry
Heterocyclic Compounds, 1-Ring metabolism
Humans
Lanthanoid Series Elements chemistry
Magnetic Resonance Spectroscopy
Surface Plasmon Resonance
Thiazoles chemistry
Amyloid beta-Peptides metabolism
Amyloid beta-Peptides ultrastructure
Aniline Compounds metabolism
Coordination Complexes metabolism
Lanthanoid Series Elements metabolism
Peptide Fragments metabolism
Peptide Fragments ultrastructure
Protein Aggregates
Thiazoles metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1521-3765
- Volume :
- 21
- Issue :
- 14
- Database :
- MEDLINE
- Journal :
- Chemistry (Weinheim an der Bergstrasse, Germany)
- Publication Type :
- Academic Journal
- Accession number :
- 25712142
- Full Text :
- https://doi.org/10.1002/chem.201406152