Amyloid β-protein assembly: The effect of molecular tweezers CLR01 and CLR03.
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.
†Department of Chemistry and Biochemistry, University of California, Santa Barbara, California 93106, United States.
Xueyun
X
Zheng
†Department of Chemistry and Biochemistry, University of California, Santa Barbara, California 93106, United States.
Deyu
D
Liu
‡Institute of Organic Chemistry, University of Duisburg-Essen, Essen 45117, Germany.
Frank-Gerrit
FG
Klärner
‡Institute of Organic Chemistry, University of Duisburg-Essen, Essen 45117, Germany.
Thomas
T
Schrader
§Department of Neurology, David Geffen School of Medicine, Brain Research Institute, and Molecular Biology Institute, University of California at Los Angeles, Los Angeles, California 90095, United States.
Gal
G
Bitan
†Department of Chemistry and Biochemistry, University of California, Santa Barbara, California 93106, United States.
Michael T
MT
Bowers
D016229:Amyloid beta-Peptides / Q000737:chemistry* / Q000378:metabolism; D001952:Bridged-Ring Compounds / Q000378:metabolism / Q000494:pharmacology*; D008958:Models, Molecular; D010755:Organophosphates / Q000378:metabolism / Q000494:pharmacology*; D009943:Organophosphorus Compounds / Q000378:metabolism / Q000494:pharmacology*; D010446:Peptide Fragments / Q000737:chemistry* / Q000378:metabolism; D055503:Protein Multimerization / Q000187:drug effects*; D017433:Protein Structure, Secondary
D016229:Amyloid beta-Peptides; D001952:Bridged-Ring Compounds; C583031:CLR01 compound; C000603750:CLR03 compound; D010755:Organophosphates; D009943:Organophosphorus Compounds; D010446:Peptide Fragments; C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42)