Curcumin-like compounds designed to modify amyloid beta peptide aggregation patterns
Curcumin-like compounds designed to modify amyloid beta peptide aggregation patterns
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DOI：
10.1039/c7ra05300b
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发表时间：
2017-01-01
期刊：
影响因子：
3.9
通讯作者：
Ortore, Maria Grazia
中科院分区：
文献类型：
--
作者：
Battisti, Antonella;Piccionello, Antonio Palumbo;Ortore, Maria Grazia
姜黄素是一种天然多酚，能够结合与阿尔茨海默病相关的淀粉样β肽，并改变其自组装途径。本文重点关注一项多学科研究，从设计具有抑制β淀粉样蛋白聚集所需的关键化学特征的类姜黄素化合物开始，并报告这些化合物对β淀粉样蛋白肽体外聚集的影响。通过计算能够突出药物样特征的分子描述符进行化学信息学筛选，然后与淀粉样β肽原纤维进行对接研究。计算设计强调了两种不同的支架，它们很容易以良好的产量合成。体外实验，从荧光光谱、共焦显微镜到小角 X 射线散射，提供的证据表明，合成的化合物能够改变淀粉样蛋白 β 肽在二级结构和整体结构尺寸方面的聚集模式。最后用模型神经元细胞系（LAN5）在体外测试了合成化合物的细胞毒性潜力。这项研究的总体观点提出了针对多种淀粉样变性（包括阿尔茨海默病）的新药物设计的新概念和潜在困难。
Curcumin is a natural polyphenol able to bind the amyloid beta peptide, which is related to Alzheimer's disease, and modify its self-assembly pathway. This paper focuses on a multi-disciplinary study that starts from the design of curcumin-like compounds with the key chemical features required for inhibiting amyloid beta aggregation, and reports the effects of these compounds on the in vitro aggregation of amyloid beta peptides. Chemoinformatic screening was performed through the calculation of molecular descriptors that were able to highlight the drug-like profile, followed by docking studies with an amyloid beta peptide fibril. The computational design underlined two different scaffolds that were easily synthesized in good yields. In vitro experiments, ranging from fluorescence spectroscopy and confocal microscopy up to small angle X-ray scattering, provided evidence that the synthesized compounds are able to modify the aggregation pattern of amyloid beta peptides both in the secondary structures, and in terms of the overall structure dimensions. The cytotoxic potential of the synthesized compounds was finally tested in vitro with a model neuronal cell line (LAN5). The overall view of this study suggests new concepts and potential difficulties in the design of novel drugs against diverse amyloidoses, including Alzheimer's disease.