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

ABSTRACT: Alzheimer's disease is a neurodegenerative disorder linked to oligomerization and fibrillization of amyloid ? peptides, with A?1-42 being the most aggregative and neurotoxic one. We report herein the synthesis and conformational analysis of A?1-42-amyloid related ?-hairpin peptidomimetics, built on a piperidine-pyrrolidine semi rigid ?-turn inducer and bearing two small recognition peptide sequences, designed on oligomeric and fibril structures of A?1-42. According to these peptide sequences, a stable ?-hairpin or a dynamic equilibrium between two possible architectures was observed. These original constructs are able to greatly delay the kinetics of A?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? on neuroblastoma cells even at substoichiometric concentrations. This study is the first example of acyclic small ?-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 ?-hairpin targeting other types of amyloid-forming proteins.

SUBMITTER: Pellegrino S

PROVIDER: S-EPMC5359901 | biostudies-literature | 2017 Feb

REPOSITORIES: biostudies-literature

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

Pellegrino S S Tonali N N Erba E E Kaffy J J Taverna M M Contini A A Taylor M M Allsop D D Gelmi M L ML Ongeri S S

Chemical science 20161007 2

Alzheimer's disease is a neurodegenerative disorder linked to oligomerization and fibrillization of amyloid β peptides, with Aβ1-42 being the most aggregative and neurotoxic one. We report herein the synthesis and conformational analysis of Aβ1-42-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 Aβ1-42. Accordi ...[more]

PMID: 28451272

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Project description:Amyloid diseases are degenerative pathologies, highly prevalent today because they are closely related to aging, that have in common the erroneous folding of intrinsically disordered proteins (IDPs) which aggregate and lead to cell death. Type 2 Diabetes involves a peptide called human islet amyloid polypeptide (hIAPP), which undergoes a conformational change, triggering the aggregation process leading to amyloid aggregates and fibers rich in β-sheets mainly found in the pancreas of all diabetic patients. Inhibiting the aggregation of amyloid proteins has emerged as a relevant therapeutic approach and we have recently developed the design of acyclic flexible hairpins based on peptidic recognition sequences of the amyloid β peptide (Aβ1-42) as a successful strategy to inhibit its aggregation involved in Alzheimer's disease. The present work reports the extension of our strategy to hIAPP aggregation inhibitors. The design, synthesis, conformational analyses, and biophysical evaluations of dynamic β-hairpin like structures built on a piperidine-pyrrolidine β-turn inducer are described. By linking to this β-turn inducer three different arms (i) pentapeptide, (ii) tripeptide, and (iii) α/aza/aza/pseudotripeptide, we demonstrate that the careful selection of the peptide-based arms from the sequence of hIAPP allowed to selectively modulate its aggregation, while the peptide character can be decreased. Biophysical assays combining, Thioflavin-T fluorescence, transmission electronic microscopy, capillary electrophoresis, and mass spectrometry showed that the designed compounds inhibit both the oligomerization and the fibrillization of hIAPP. They are also capable to decrease the aggregation process in the presence of membrane models and to strongly delay the membrane-leakage induced by hIAPP. More generally, this work provides the proof of concept that our rational design is a versatile and relevant strategy for developing efficient and selective inhibitors of aggregation of amyloidogenic proteins.

Dataset Information

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

Publications

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

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