Design and synthesis of new trehalose-conjugated pentapeptides as inhibitors of A?(1-42) fibrillogenesis and toxicity

Aggregation of the amyloid A? 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 A? amyloid fibril formation are therefore of interest for a potential therapeutic strategy. Three new trehalose-conjugated peptides of the well known ?-sheet breaker peptide iA?5p,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 A? aggregates were investigated by ThT fluorescence assay and dynamic Scanning Force Microscopy, respectively. All the synthesized compounds were tested as inhibitors of A? toxicity toward pure cultures of rat cortical neurons. Copyright © 2009 European Peptide Society and John Wiley & Sons, Ltd.