DataSheet1_Novel Stilbene-Nitroxyl Hybrid Compounds Display Discrete Modulation of Amyloid Beta Toxicity and Structure.pdf

Several neurodegenerative diseases are driven by misfolded proteins that assemble into soluble aggregates. These “toxic oligomers” have been associated with a plethora of cellular dysfunction and dysregulation, however the structural features underlying their toxicity are poorly understood. A major impediment to answering this question relates to the heterogeneous nature of the oligomers, both in terms of structural disorder and oligomer size. This not only complicates elucidating the molecular etiology of these disorders, but also the druggability of these targets as well. We have synthesized a class of bifunctional stilbenes to modulate both the conformational toxicity within amyloid beta oligomers (AβO) and the oxidative stress elicited by AβO. Using a neuronal culture model, we demonstrate this bifunctional approach has the potential to counter the molecular pathogenesis of Alzheimer’s disease in a powerful, synergistic manner. Examination of AβO structure by various biophysical tools shows that each stilbene candidate uniquely alters AβO conformation and toxicity, providing insight towards the future development of structural correctors for AβO. Correlations of AβO structural modulation and bioactivity displayed by each provides insights for future testing in vivo. The multi-target activity of these hybrid molecules represents a highly advantageous feature for disease modification in Alzheimer’s, which displays a complex, multifactorial etiology. Importantly, these novel small molecules intervene with intraneuronal AβO, a necessary feature to counter the cycle of dysregulation, oxidative stress and inflammation triggered during the earliest stages of disease progression.

多种神经退行性疾病由错误折叠蛋白组装形成可溶性聚集体所驱动。这类‘毒性寡聚体（toxic oligomers）’已被发现与诸多细胞功能异常及调控紊乱密切相关，但其毒性背后的核心结构特征仍知之甚少。阻碍该研究问题得以解决的主要瓶颈，在于寡聚体本身的异质性：既体现为结构无序性，也涉及寡聚体的尺寸异质性。这不仅为阐明这类疾病的分子病因学增加了难度，也为相关靶点的成药性研究带来了重重阻碍。本研究合成了一类双功能二苯乙烯类化合物，可同时调控β淀粉样蛋白寡聚体（amyloid beta oligomers, AβO）的构象毒性，以及AβO诱发的氧化应激反应。借助神经元细胞培养模型，我们证实该双功能策略能够以强效且协同的方式，干预阿尔茨海默病的分子发病进程。通过多种生物物理技术对AβO结构进行表征后发现，每一种二苯乙烯候选化合物均可特异性改变AβO的构象与毒性，为未来开发针对AβO的结构矫正剂提供了关键思路。各候选化合物的AβO结构调控效果与其生物活性之间的相关性，也为后续开展体内实验验证提供了研究方向。这类杂合分子所具备的多靶点活性，对于阿尔茨海默病的疾病修饰治疗而言是极具优势的特性——而阿尔茨海默病本身就具有复杂的多因素病因学特征。尤为关键的是，这些新型小分子可靶向作用于神经元内的AβO，而这正是对抗疾病早期进程中引发的功能紊乱、氧化应激与炎症循环的必要手段。