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

Aggregation of the amyloid Aβ 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 Aβ amyloid fibril formation are therefore of interest for a potential therapeutic strategy. Three new trehalose-conjugated peptides of the well known β-sheet breaker peptide iAβ5p,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 Aβ aggregates were investigated by ThT fluorescence assay and dynamic Scanning Force Microscopy, respectively. All the synthesized compounds were tested as inhibitors of Aβ toxicity toward pure cultures of rat cortical neurons.