β-Hairpin mimics containing a piperidine-pyrrolidine scaffold modulate the β-amyloid aggregation process preserving the monomer species

Alzheimer's disease is a neurodegenerative disorder linked to oligomerization and fibrillization of amyloid beta peptides, with A beta(1-42) being the most aggregative and neurotoxic one. We report herein the synthesis and conformational analysis of A beta(1-42)-amyloid related beta-hairpin peptidomimetics, built on a piperidine-pyrrolidine semi rigid beta-turn inducer and bearing two small recognition peptide sequences, designed on oligomeric and fibril structures of A beta(1-42). According to these peptide sequences, a stable b-hairpin or a dynamic equilibrium between two possible architectures was observed. These original constructs are able to greatly delay the kinetics of A beta(1-42) aggregation process as demonstrated by thioflavin-T fluorescence, and transmission electron microscopy. Capillary electrophoresis indicates their ability to preserve the monomer species, inhibiting the formation of toxic oligomers. Furthermore, compounds protect against toxic effects of A beta on neuroblastoma cells even at substoichiometric concentrations. This study is the first example of acyclic small beta-hairpin mimics possessing such a highly efficient anti-aggregation activity. The protective effect is more pronounced than that observed with molecules which have undergone clinical trials. The structural elements made in this study provide valuable insights in the understanding of the aggregation process and insights to explore the design of novel acyclic beta-hairpin targeting other types of amyloid-forming proteins.