Zheng Xueyun, Liu Deyu, Klärner Frank-Gerrit, Schrader Thomas, Bitan Gal, Bowers Michael T
†Department of Chemistry and Biochemistry, University of California, Santa Barbara, California 93106, United States.
‡Institute of Organic Chemistry, University of Duisburg-Essen, Essen 45117, Germany.
J Phys Chem B. 2015 Apr 9;119(14):4831-41. doi: 10.1021/acs.jpcb.5b00692. Epub 2015 Mar 16.
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.
淀粉样β蛋白（Aβ）的早期寡聚化已被证明是阿尔茨海默病（AD）病理过程中的一个重要事件。设计针对Aβ寡聚化的小分子抑制剂是一种有吸引力且前景广阔的AD治疗策略。在此，我们使用离子淌度光谱联用质谱（IMS-MS）来研究分子钳CLR01和CLR03对Aβ自组装的不同影响。发现CLR01可直接与Aβ结合并破坏其早期寡聚化。此外，CLR01通过压缩二聚体和四聚体的结构重塑了Aβ42的早期寡聚化，从而消除了高阶寡聚体。出乎意料的是，发现缺乏钳状结构疏水臂的阴性对照衍生物CLR03促进了Aβ的早期寡聚化。我们的研究提供了一个例子，说明IMS作为一种强大的工具来研究和更好地理解小分子调节剂与Aβ寡聚化之间的相互作用，这是其他方法无法实现的，并且为用于AD治疗的分子钳的治疗开发提供了重要见解。
