Amyloid β-Protein Assembly: The Effect of Molecular Tweezers CLR01 and CLR03

The early oligomerization of amyloid beta-protein (A beta) has been shown to be an important event in the pathology of Alzheimer's disease (AD). Designing small molecule inhibitors targeting A beta 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 CLRO3 on A beta self assembly CLR01 was found to bind to A beta directly and disrupt its early oligornerization. Moreover, CLR01 remodeled the early oligomerization of A beta 42 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 A beta oligomerization. Our study provides an example of IMS as a powerful tool to study and better understand the interaction between small molecule modulators and A beta oligomerization, which is not attainable by other methods, and provides important insights into therapeutic development of molecular tweezers for AD treatment.