Supramolecular Inhibition of Neurodegeneration by a Synthetic Receptor

Shengke Li (1) , Huanxian Chen (1) , Xue Yang (1) , David Bardelang (2) , Ian W. Wyman (3) , Jianbo Wan (1) , Simon M. Y. Lee (1) , Ruibing Wang (1)

1 State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Taipa, Macau, China
2 ICR - Institut de Chimie Radicalaire
3 Chemistry Department, Queen's University

Cucurbit[7]uril (CB[7]) was found in vitro to sequester the neurotoxins MPTP (N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) and MPP+ (N-methyl-4-phenylpyridine). The CB[7]/neurotoxin host–guest complexes were studied in detail with 1H NMR, electrospray ionization mass spectrometry, UV–visible spectroscopic titration, and molecular modeling by density functional theory. The results supported the macrocyclic encapsulation of MPTP and MPP+, respectively, by CB[7] in aqueous solutions with relatively strong affinities and 1:1 host–guest binding stoichiometries in both cases. More importantly, the progression of MPTP/MPP+ induced neurodegeneration (often referred to as a Parkinson’s disease model) was observed to be strongly inhibited in vivo by the synthetic CB[7] receptor, as shown in zebrafish models. These results show that a supramolecular approach could lead to a new preventive and/or therapeutic strategy for counteracting the deleterious effects of some neurotoxins leading to neurodegeneration.

Mots clés: cucurbituril; inhibition; Neurodegeneration; neurotoxin; supramolecular complexation

Domaines: Chimie

Shengke Li, Huanxian Chen, Xue Yang, David Bardelang, Ian W. Wyman, et al.. Supramolecular Inhibition of Neurodegeneration by a Synthetic Receptor. ACS Medicinal Chemistry Letters, 2015, 6 (12), pp.1174 - 1178. ⟨10.1021/acsmedchemlett.5b00372⟩. ⟨hal-01414666⟩