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

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.

目前，能够减少淀粉样蛋白1–42（amyloid 1–42）肽纤维形成的抗阿尔茨海默病候选药物，其与最具神经毒性的聚集物种之间的相互作用机制仍未得到充分阐明。本文报道了糖类拟肽（sugar-based peptidomimetics）同时抑制Aβ1–42早期寡聚化与纤维形成的能力。研究采用了包括新型毛细管电泳（capillary electrophoresis）法、核磁共振（nuclear magnetic resonance）及表面等离子体共振（surface plasmon resonance）在内的多种生物及物理化学技术，以阐明此类新型分子延缓Aβ1–42聚集的具体机制。研究证实，这些分子可通过结合可溶性寡聚体，维持无毒单体的稳态并阻断纤维形成过程。即便在亚化学计量浓度下，此类化合物仍可完全抵消Aβ1–42对SH-SY5Y神经母细胞瘤细胞的毒性。此外，最优分子同时兼具疏水基团、氢键供体与受体、铵基以及亲水性β折叠阻断元件，这一发现为未来基于结构的Aβ1–42聚集抑制剂设计提供了极具价值的理论参考。