Synthesis and Characterization of Hairpin Mimics that Modulate the Early Oligomerization and Fibrillization of Amyloid β-Peptide

Alzheimer's disease is a neurodegenerative disorder that is linked to oligomerization and fibrillization of different amyloid beta-peptide isoforms. Among these amyloid peptides, A beta(1-42) is considered the most aggregative and neurotoxic species. We report herein the synthesis of four beta-sheet mimics composed of a peptidomimetic arm based on a 5-amino-2-methoxy benzhydrazide derivative, a 2,5-diketopiperazine scaffold (either cis-DKP or trans-DKP) and a tetrapeptide sequence (either Gly-Val-Val-Ile, GVVI, or Lys-Leu-Val-Phe, KLVF). The derivatives containing the cis-DKP were shown by NMR and computational studies to adopt a stable beta-hairpin conformation in solution, whereas the trans-DKP scaffold promoted the formation of extended structures. The activity of these compounds in modulating the aggregation of A beta(1-42) peptide was investigated by conducting Thioflavin T fluorescence assays to measure the kinetics of aggregation. Capillary electrophoresis (CE) and transmission electron microscopy (TEM) were then used to monitor the formation of small soluble A beta oligomers and higher molecular weight and insoluble A beta aggregates, respectively. As a result, small hairpin mimics containing the cis-DKP scaffold were found to prevent the formation of small A beta(1-42) oligomeric and neurotoxic species.