Department of Chemical Engineering, University of South Carolina, Columbia, SC 29208, USA.
Bioorg Med Chem. 2011 Apr 15;19(8):2596-602. doi: 10.1016/j.bmc.2011.03.010. Epub 2011 Mar 12.
Aggregation of the amyloid-β protein (Aβ) plays a pathogenic role in the progression of Alzheimer's disease, and small molecules that attenuate Aβ aggregation have been identified toward a therapeutic strategy that targets the disease's underlying cause. Compounds containing aromatic structures have been repeatedly reported as effective inhibitors of Aβ aggregation, but the functional groups that influence inhibition by these aromatic centers have been less frequently explored. The current study identifies analogs of naturally occurring coumarin as novel inhibitors of Aβ aggregation. Derivatization of the coumarin structure is shown to affect inhibitory capabilities and to influence the point at which an inhibitor intervenes within the nucleation dependent Aβ aggregation pathway. In particular, functional groups found within amyloid binding dyes, such as benzothiazole and triazole, can improve inhibition efficacy. Furthermore, inhibitor intervention at early or late stages within the amyloid aggregation pathway is shown to correlate with the ability of these functional groups to recognize and bind amyloid species that appear either early or late within the aggregation pathway. These results demonstrate that functionalization of small aromatic molecules with recognition elements can be used in the rational design of Aβ aggregation inhibitors to not only enhance inhibition but to also manipulate the inhibition mechanism.
淀粉样蛋白-β（Aβ）的聚集在阿尔茨海默病的进展中起着致病作用，已经确定了一些小分子可以减弱 Aβ的聚集，从而作为针对该疾病根本原因的治疗策略。含有芳香结构的化合物已被反复报道为 Aβ聚集的有效抑制剂，但这些芳香中心影响抑制作用的功能基团却很少被探索。本研究鉴定了天然香豆素的类似物作为 Aβ聚集的新型抑制剂。香豆素结构的衍生化被证明会影响抑制能力，并影响抑制剂在依赖核的 Aβ聚集途径中干预的位置。特别是，在淀粉样蛋白结合染料中发现的功能基团，如苯并噻唑和三唑，可以提高抑制效果。此外，抑制剂在淀粉样蛋白聚集途径的早期或晚期的干预与这些功能基团识别和结合聚集途径中早期或晚期出现的淀粉样蛋白物种的能力相关。这些结果表明，用识别元件对小分子进行功能化可用于合理设计 Aβ聚集抑制剂，不仅可以增强抑制作用，还可以改变抑制机制。
