Introduction Amyloid fibrils are self-assembled insoluble aggregates characterized by highly ordered cross-β structures. 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 β-hairpin targeting other types of amyloid-forming proteins. The protective effect is more pronounced than that observed with molecules which have undergone clinical trials. This study is the first example of acyclic small β-hairpin mimics possessing such a highly efficient anti-aggregation activity. Furthermore, compounds protect against toxic effects of Aβ on neuroblastoma cells even at substoichiometric concentrations. Capillary electrophoresis indicates their ability to preserve the monomer species, inhibiting the formation of toxic oligomers. These original constructs are able to greatly delay the kinetics of Aβ 1–42 aggregation process as demonstrated by thioflavin-T fluorescence, and transmission electron microscopy. According to these peptide sequences, a stable β-hairpin or a dynamic equilibrium between two possible architectures was observed. We report herein the synthesis and conformational analysis of Aβ 1–42-amyloid related β-hairpin peptidomimetics, built on a piperidine–pyrrolidine semi rigid β-turn inducer and bearing two small recognition peptide sequences, designed on oligomeric and fibril structures of Aβ 1–42. Paris-Sud, CNRS, Université Paris Saclay, 5 rue Jean-Baptiste Clément, 92296 Châtenay-Malabry Cedex, France d Lancaster University, Division of Biomedical and Life Sciences, Faculty of Health and Medicine, Lancaster LA1 4YQ, UKĪlzheimer's disease is a neurodegenerative disorder linked to oligomerization and fibrillization of amyloid β peptides, with Aβ 1–42 being the most aggregative and neurotoxic one. E-mail: c Protéines et Nanotechnologies en Sciences Séparatives, Institut Galien Paris-Sud, Univ. Paris-Sud, CNRS, Université Paris Saclay, 5 rue Jean-Baptiste Clément, 92296 Châtenay-Malabry Cedex, France. E-mail: b Molécules Fluorées et Chimie Médicinale, BioCIS, Univ. Marchesini”, Universitá degli Studi di Milano, via Venezian 21, 20133 Milano, Italy. Sci., 2017, 8, 1295-1302 β-Hairpin mimics containing a piperidine–pyrrolidine scaffold modulate the β-amyloid aggregation process preserving the monomer species †
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