Designed Glycopeptidomimetics Disrupt Protein-Protein Interactions Mediating Amyloid β-Peptide Aggregation and Restore Neuroblastoma Cell Viability

Journal of Medicinal Chemistry
Julia KaffySandrine Ongeri

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.

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Citations

Oct 13, 2017·Current Medicinal Chemistry·Anutthaman ParthasarathyKarunakaran A Kalesh
Mar 23, 2018·Beilstein Journal of Organic Chemistry·Yaochun XuSandrine Ongeri
Nov 9, 2019·Chembiochem : a European Journal of Chemical Biology·Nicolo TonaliNorbert Sewald
May 28, 2020·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Lidia CicconeNicolo Tonali
Feb 1, 2017·ChemPlusChem·Serena De SantisAnita Scipioni

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