Dihydroxybenzoic acid isomers differentially dissociate soluble biotinyl-Aβ(1-42) oligomers.
Dihydroxybenzoic acid isomers differentially dissociate soluble biotinyl-Aβ(1-42) oligomers.
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DOI：
10.1021/bi201288x
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发表时间：
2012-01-10
期刊：
影响因子：
2.9
通讯作者：
Augelli-Szafran CE
中科院分区：
文献类型：
--
作者：
LeVine H 3rd;Lampe L;Abdelmoti L;Augelli-Szafran CE
多酚类化合物包括许多天然产物，如白藜芦醇、姜黄素、儿茶素衍生物和去甲二氢愈创木酸，它们对Aβ纤维和低聚物的组装以及纤维形态都有影响。基于从小分子多样性文库筛选得到的铅结构，根据芳环上羟基的数量和位置区分的简单苯甲酸衍生物显示出不同的解离预先形成的生物素-Aβ(1-42)低聚物的能力。2，3-，2，5-和3，4-二羟基苯甲酸(DHBA)异构体是活性低聚物解离剂。其余的DHBA异构体以及单羟基和未取代的苯甲酸是无效的，不会与活性化合物竞争来阻止齐聚物的解离。所有化合物都没有阻止低聚物组装，表明它们不与单体Aβ相互作用来改变低聚物-单体的平衡。解离活性与化合物的苯醌氧化还原循环能力无关。没食子酸(3，4，5-三羟基苯甲酸)稳定生物素基-Aβ(1-42)低聚物以对抗本征解离，并阻断活性解离剂的作用，而不依赖解离剂的浓度。DHBA解离剂作用机理的模型认为，这些化合物破坏了低聚物结构的稳定，促进了单体的渐进解离，而不是将低聚物裂变成更小但仍然是大分子的物种。没食子酸通过稳定低聚物来阻止这一过程。
Polyphenolic compounds including a number of natural products such as resveratrol, curcumin, catechin derivatives, and nordihydroguaiaretic acid have effects on the assembly of Aβ fibrils and oligomers as well as on fibril morphology. Based on a lead structure obtained from a screen of a small molecule diversity library, simple benzoic acid derivatives distinguished by the number and position of hydroxyls on the aromatic ring displayed different abilities to dissociate pre-formed biotinyl-Aβ(1–42) oligomers. The 2, 3-, 2, 5-, and 3, 4- dihydroxybenzoic acid (DHBA) isomers were active oligomer dissociators. The remaining DHBA isomers and the monohydroxy and unsubstituted benzoic acids were inactive and did not compete with the active compounds to block oligomer dissociation. None of the compounds blocked oligomer assembly, indicating that they do not interact with monomeric Aβ to shift the oligomer-monomer equilibrium. Dissociating activity was not associated with quinone redox cycling capacity of the compounds. Gallic acid (3, 4, 5-trihydroxybenzoic acid) stabilized biotinyl-Aβ(1–42) oligomers against intrinsic dissociation and blocked the effects of the active dissociators, independent of the concentration of dissociator. A model for the mechanism of action of the DHBA dissociators proposes that these compounds destabilize oligomer structure promoting progressive monomer dissociation rather than fissioning oligomers into smaller, but still macromolecular species. Gallic acid blocks dissociation by stabilizing oligomers against this process.
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影响因子：
2.9
作者：
LeVine, H
通讯作者：
LeVine, H
影响因子：
64.8
作者：
Walsh, DM;Klyubin, I;Selkoe, DJ
通讯作者：
Selkoe, DJ
影响因子：
2.9
作者：
LeVine, Harry, III
通讯作者：
LeVine, Harry, III
DOI：
10.1073/pnas.95.11.6448
发表时间：
1998-05-26
影响因子：
11.1
作者：
Lambert, MP;Barlow, AK;Klein, WL
通讯作者：
Klein, WL
影响因子：
2.9
作者：
Hong, Hyun-Seok;Maezawa, Izumi;Jin, Lee-Way
通讯作者：
Jin, Lee-Way