Structure–activity relationships of sugar-based peptidomimetics as modulators of amyloid β-peptide early oligomerization and fibrillization

• Structure–activity relationships of Sugar-based pentapeptide analogs.
• Two hydrophobic dipeptides are linked to a d-glucopyranosyl scaffold.
• The molecules delay or accelerate the kinetics of β-amyloid early oligomerization.
• The early oligomerization is monitored by capillary electrophoresis.

Alzheimer's disease is a neurodegenerative disorder linked to oligomerization and fibrillization of amyloid β peptides. Aβ1–42 being the most aggregative and neurotoxic amyloid peptide, we report herein the capacity of sugar-based pentapeptide analogs to modulate the Aβ1–42 aggregation process using thioflavin fluorescence and transmission electron microscopy assays. The importance of the free hydroxyl groups of the sugar moiety, used as a β-breaker element, is confirmed since hydroxylated compounds inhibit the aggregation process while benzylated ones enhance it. Furthermore, the most effective molecules were also evaluated by a recently developed capillary electrophoresis method, providing in vitro monitoring of the crucial, very early stages of the self-assembly process. This technique allowed us to investigate the effect of these compounds on the small non-fibrillar Aβ1–42 oligomers suspected by several groups worldwide as highly neurotoxic. We clearly demonstrated that molecules delaying the aggregation can stabilize the monomeric peptide or promote the formation of soluble oligomeric species. In contrast, molecules that accelerate the aggregation can prevent the presence of small toxic oligomers.

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