Amyloid β-protein assembly: The effect of molecular tweezers CLR01 and CLR03.
Amyloid β-protein assembly: The effect of molecular tweezers CLR01 and CLR03.
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β-淀粉样蛋白组装：分子镊子 CLR01 和 CLR03 的作用。
DOI：
10.1021/acs.jpcb.5b00692
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发表时间：
2015-04-09
影响因子：
3.3
通讯作者：
Bowers, Michael T.
中科院分区：
文献类型：
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作者：
Zheng, Xueyun;Liu, Deyu;Klaerner, Frank-Gerrit;Schrader, Thomas;Bitan, Gal;Bowers, Michael T.
淀粉样β蛋白（amyloid β-protein，Aβ）的早期寡聚化是阿尔茨海默病（Alzheimer's disease，AD）的重要病理过程。设计靶向Aβ寡聚化的小分子抑制剂是治疗AD的一种有吸引力和前景的策略。本文采用离子迁移谱-质谱联用技术（IMS-MS）研究了分子钳CLR 01和CLR 03对Aβ自组装的不同影响。发现CLR 01直接与Aβ结合并破坏其早期寡聚化。此外，CLR 01通过压缩二聚体和四聚体的结构重塑了Aβ42的早期寡聚化，从而消除了更高级的寡聚体。出乎意料的是，阴性对照衍生物，CLR 03，它缺乏镊子结构的疏水臂，被发现促进早期Aβ寡聚化。我们的研究提供了一个IMS作为研究和更好地理解小分子调节剂与Aβ寡聚化之间相互作用的有力工具的例子，这是其他方法无法实现的，并为AD治疗的分子镊子的治疗开发提供了重要的见解。
The early oligomerization of amyloid β-protein (Aβ) has been shown to be an important event in the pathology of Alzheimer’s disease (AD). Designing small molecule inhibitors targeting Aβ oligomerization is one attractive and promising strategy for AD treatment. Here we used ion mobility spectrometry coupled to mass spectrometry (IMS-MS) to study the different effects of the molecular tweezers CLR01 and CLR03 on Aβ self-assembly. CLR01 was found to bind to Aβ directly and disrupt its early oligomerization. Moreover, CLR01 remodeled the early oligomerization of Aβ42 by compacting the structures of dimers and tetramers and as a consequence eliminated higher-order oligomers. Unexpectedly, the negative-control derivative, CLR03, which lacks the hydrophobic arms of the tweezer structure, was found to facilitate early Aβ oligomerization. Our study provides an example of IMS as a powerful tool to study and better understand the interaction between small molecule modulators and Aβ oligomerization, which is not attainable by other methods, and provides important insights into therapeutic development of molecular tweezers for AD treatment.
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影响因子：
15
作者：
Bernstein, SL;Wyttenbach, T;Bowers, MT
通讯作者：
Bowers, MT
影响因子：
15
作者：
Fokkens, M;Schrader, T;Klärner, FG
通讯作者：
Klärner, FG
影响因子：
21.8
作者：
Bleiholder, Christian;Dupuis, Nicholas F.;Wyttenbach, Thomas;Bowers, Michael T.
通讯作者：
Bowers, Michael T.
影响因子：
2.9
作者：
Gessel, Megan Murray;Wu, Chun;Li, Huiyuan;Bitan, Gal;Shea, Joan-Emma;Bowers, Michael T.
通讯作者：
Bowers, Michael T.
影响因子：
21.8
作者：
通讯作者：
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