Substituent, Charge, and Size Effects on the Fluorogenic Performance of Amyloid Ligands: A Small-Library Screening Study.
Substituent, Charge, and Size Effects on the Fluorogenic Performance of Amyloid Ligands: A Small-Library Screening Study.
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DOI：
10.1021/acsomega.7b00231
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发表时间：
2017-07-31
期刊：
影响因子：
4.1
通讯作者：
Chi EY
中科院分区：
文献类型：
--
作者：
Donabedian PL;Evanoff M;Monge FA;Whitten DG;Chi EY
开发用于直接检测和跟踪淀粉样蛋白聚集体的新分子配体是理解和击败无数神经退行性疾病和其他疾病（包括阿尔茨海默病和帕金森病）的关键。淀粉样蛋白染料性能的关键因素是其独立于淀粉样蛋白形成原聚体的序列检测淀粉样蛋白结构基序的能力。目前的研究调查一类新的苯乙炔（PPE）为基础的染料和荧光聚合物使用淀粉样蛋白纤维形成的两个模型蛋白质：溶菌酶和胰岛素的结构-功能关系。测试了分子量、电荷密度、水溶解度以及官能团的类型和几何形状不同的18种PPE化合物的小文库。一种化合物，小阴离子低聚（对亚苯基乙炔基）电解质OPE 1，被确定为溶菌酶和胰岛素的淀粉样蛋白构象的选择性传感器。基于在来自这组PPE化合物的染料中观察到的蛋白质结合和生物物理变化，选择性检测淀粉样蛋白构象的关键包括中等大小、负电荷和对荧光产率提供高微环境灵敏度的取代基。这些原则可以作为指导进一步完善有效的淀粉样蛋白传感分子。
Developing new molecular ligands for the direct detection and tracking of amyloid protein aggregates is key to understanding and defeating myriad neurodegenerative and other disorders including Alzheimer’s and Parkinson’s diseases. A crucial factor in the performance of an amyloid dye is its ability to detect the amyloid structural motif independent of the sequence of the amyloid-forming protomer. The current study investigates structure–function relationships of a class of novel phenyleneethynylene (PPE)-based dyes and fluorescent polymers using amyloid fibrils formed by two model proteins: lysozyme and insulin. A small library of 18 PPE compounds that vary in molecular weights, charge densities, water solubilities, and types and geometries of functional groups was tested. One compound, the small anionic oligo(p-phenylene ethynylene) electrolyte OPE1, was identified as a selective sensor for the amyloid conformation of both lysozyme and insulin. On the basis of protein binding and photophysical changes observed in the dye from this set of PPE compounds, keys to the selective detection of the amyloid protein conformation include moderate size, negative charge, and substituents that provide high microenvironment sensitivity to the fluorescence yield. These principles can serve as a guide for the further refinement of the effective amyloid-sensing molecules.