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

Kaffy, Julia and Brinet, Dimitri and Soulier, Jean-Louis and Tonali, Nicolo and Fera, Katia Fabiana and Iacone, Yasmine and Hoffmann, Anais R. F. and Khemtemourian, Lucie and Crousse, Benoit and Taylor, Mark Neville and Allsop, David and Taverna, Myriam and Lequin, Olivier and Ongeri, Sandrine (2016) Designed glycopeptidomimetics disrupt protein−protein interactions mediating amyloid β‑peptide aggregation and restore neuroblastoma cell viability. Journal of Medicinal Chemistry, 59 (5). pp. 2025-2040. ISSN 0022-2623

[img]
Preview
PDF (JmedChemRevised_submitted)
JmedChemRevised_submitted.pdf - Accepted Version
Available under License Creative Commons Attribution.

Download (1MB)

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.

Item Type:
Journal Article
Journal or Publication Title:
Journal of Medicinal Chemistry
Additional Information:
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
Uncontrolled Keywords:
/dk/atira/pure/subjectarea/asjc/1300/1313
Subjects:
ID Code:
78125
Deposited By:
Deposited On:
05 Feb 2016 13:48
Refereed?:
Yes
Published?:
Published
Last Modified:
20 Sep 2020 03:17