(R)-alpha-Trifluoromethylalanine Containing Short Peptide in the Inhibition of Amyloid Peptide Fibrillation

Autor: Botz, Alexandra, Gasparik, Vincent, Devillers, Emmanuelle, Hoffmann, Anais R. F., Caillon, Lucie, Chelain, Evelyne, Lequin, Olivier, Brigaud, Thierry, Khemtemourian, Lucie
Přispěvatelé: Département de Chimie - ENS Paris, École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL), Université Pierre et Marie Curie - Paris 6 (UPMC), Laboratoire de Chimie Biologique (LCB), Université de Cergy Pontoise (UCP), Université Paris-Seine-Université Paris-Seine, Chimie et Biologie des Membranes et des Nanoobjets (CBMN), Université de Bordeaux (UB)-École Nationale d'Ingénieurs des Travaux Agricoles - Bordeaux (ENITAB)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), École normale supérieure - Paris (ENS-PSL)
Jazyk: angličtina
Rok vydání: 2015
Předmět:
Zdroj: Biopolymers
Biopolymers, Wiley, 2015, 104 (5, SI), pp.601-610. ⟨10.1002/bip.22670⟩
Biopolymers, 2015, 104 (5, SI), pp.601-610. ⟨10.1002/bip.22670⟩
ISSN: 0006-3525
1097-0282
DOI: 10.1002/bip.22670⟩
Popis: International audience; The extracellular deposition of insoluble amyloid fibrils resulting from the aggregation of the amyloid-beta (A beta) is a pathological feature of neuronal loss in Alzheimer's disease (AD). Numerous small molecules have been reported to interfere with the process of A beta aggregation. Compounds containing aromatic structures, hydrophobic amino acids and/or the alpha-aminoisobutyric acid (Aib) as beta-sheet breaker elements have been reported to be effective inhibitors of A beta aggregation. We synthesized two peptides, one containing the Aib amino acid and the other including its trifluoromethylated analog (R)-alpha-Trifluoromethylalanine ((R)-Tfm-Alanine) and we evaluated the impact of these peptides on A beta amyloid formation. The compounds were tested by standard methods such as thioflavin-T fluorescence spectroscopy and transmission electron microscopy but also by circular dichroism, liquid state nuclear magnetic resonance (NMR) and NMR saturation transfer difference (STD) experiments to further characterize the effect of the two molecules on A beta structure and on the kinetics of depletion of monomeric, soluble A beta. Our results demonstrate that the peptide containing Aib reduces the quantity of aggregates containing beta-sheet structure but slightly inhibits A beta fibril formation, while the molecule including the trifluoromethyl (Tfm) group slows down the kinetics of A beta fibril formation, delays the random coil to beta-sheet structure transition and induces a change in the oligomerization pathway. These results suggest that the hydrophobic Tfm group has a better affinity with A beta than the methyl groups of the Aib and that this Tfm group is effective and important in preventing the A beta aggregation.
Databáze: OpenAIRE
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