Designed Glycopeptidomimetics Disrupt Protein–Protein Interactions Mediating Amyloid β-Peptide Aggregation and Restore Neuroblastoma Cell Viability
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- 作者：Julia Kaffy ; Dimitri Brinet ; Jean-Louis Soulier ; Isabelle Correia ; Nicolo Tonali ; Katia Fabiana Fera ; Yasmine Iacone ; Anaïs R. F. Hoffmann ; Lucie Khemtémourian ; Benoit Crousse ; Mark Taylor ; David Allsop ; Myriam Taverna ; Olivier Lequin ; Sandrine Ongeri
- 刊名：Journal of Medicinal Chemistry
- 出版年：2016
- 出版时间：March 10, 2016
- 年：2016
- 卷：59
- 期：5
- 页码：2025-2040
- 全文大小：726K
- ISSN：1520-4804
文摘
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 Aβ<sub>1–42sub> 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 Aβ<sub>1–42sub>. 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 Aβ<sub>1–42sub> 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 Aβ<sub>1–42sub> aggregation.