Design and synthesis of new trehalose-conjugated pentapeptides as inhibitors of Abeta(1-42) fibrillogenesis and toxicity.
Aggregation of the amyloid Abeta peptide and its accumulation into insoluble deposits (plaques) are believed to be the main cause of neuronal dysfunction associated with Alzheimer's disease (AD); small molecules that can interfere with the Abeta amyloid fibril formation are therefore of interest for a potential therapeutic strategy. Three new trehalose-conjugated peptides of the well known beta-sheet breaker peptide iAbeta5p, were synthesized. The disaccharide was covalently attached to different sites of the LPFFD peptide chain, i.e. at the N-terminus, C-terminus or at the Asp side chain. CD spectroscopy in different solvents was used to assess changes in the peptide conformation of these compounds. The effects of these glycopeptides on the self-assembly and morphology of Abeta aggregates were investigated by ThT fluorescence assay and dynamic Scanning Force Microscopy, respectively. All the synthesized compounds were tested as inhibitors of Abeta toxicity toward pure cultures of rat cortical neurons.
De Bona
Paolo
P
University of Catania, Department of Chemical Sciences, 95125 Catania, Italy.
Giuffrida
Maria Laura
ML
Caraci
Filippo
F
Copani
Agata
A
Pignataro
Bruno
B
Attanasio
Francesco
F
Cataldo
Sebastiano
S
Pappalardo
Giuseppe
G
Rizzarelli
Enrico
E
D000818:Animals; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology* / Q000187:drug effects; D002851:Chromatography, High Pressure Liquid; D013058:Mass Spectrometry; D018625:Microscopy, Atomic Force; D010455:Peptides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D014199:Trehalose / Q000737:chemistry*
D010455:Peptides; D014199:Trehalose