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    Rights statement: This document is the Accepted Manuscript version of a Published Work that appeared in final form in Journal of Medicinal Chemistry, copyright © 2016 American Chemical Society after peer review and technical editing by the publisher. To access the final edited and published work see http://pubs.acs.org/doi/abs/10.1021/acs.jmedchem.5b01629

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Designed glycopeptidomimetics disrupt protein−protein interactions mediating amyloid β‑peptide aggregation and restore neuroblastoma cell viability

Research output: Contribution to journalJournal article

Published
  • Julia Kaffy
  • Dimitri Brinet
  • Jean-Louis Soulier
  • Nicolo Tonali
  • Katia Fabiana Fera
  • Yasmine Iacone
  • Anais R. F. Hoffmann
  • Lucie Khemtemourian
  • Benoit Crousse
  • Mark Neville Taylor
  • David Allsop
  • Myriam Taverna
  • Olivier Lequin
  • Sandrine Ongeri
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<mark>Journal publication date</mark>10/03/2016
<mark>Journal</mark>Journal of Medicinal Chemistry
Issue number5
Volume59
Number of pages16
Pages (from-to)2025-2040
Publication statusPublished
Early online date20/01/16
Original languageEnglish

Abstract

How anti-Alzheimer’s drug candidates that reduce amyloid 1−42 peptide fibrillization interact with the most neurotoxic species is far from being understood. We report herein the capacity of sugar-based peptidomimetics to
inhibit both Aβ1−42 early oligomerization and fibrillization. A wide range of bio- and physicochemical techniques, such as a new capillary electrophoresis method, nuclear magnetic resonance, and surface plasmon resonance, were used to identify how these new molecules can delay the aggregation of
Aβ1−42. We demonstrate that these molecules interact with soluble oligomers in order to maintain the presence of nontoxic monomers and to prevent fibrillization. These compounds totally suppress the toxicity of Aβ1−42 toward SH-SY5Y neuroblastoma cells, even at substoichiometric concentrations. Furthermore, demonstration that the best molecule combines hydrophobic moieties, hydrogen bond donors and acceptors, ammonium groups, and a hydrophilic β-sheet breaker element provides valuable insight for the future structure-based design of inhibitors of Aβ1−42 aggregation.

Bibliographic note

This document is the Accepted Manuscript version of a Published Work that appeared in final form in Journal of Medicinal Chemistry, copyright © 2016 American Chemical Society after peer review and technical editing by the publisher. To access the final edited and published work see http://pubs.acs.org/doi/abs/10.1021/acs.jmedchem.5b01629