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Eur J Med Chem. 2014 Dec 17;88:42-54. doi: 10.1016/j.ejmech.2014.07.090. Epub 2014 Jul 25.

The use of nanopore analysis for discovering drugs which bind to α-synuclein for treatment of Parkinson's disease.

Author information

1
Department of Biochemistry, 107 Wiggins Road, University of Saskatchewan, Saskatoon, Canada S7N 0W0.
2
Department of Biochemistry, 107 Wiggins Road, University of Saskatchewan, Saskatoon, Canada S7N 0W0. Electronic address: jeremy.lee@usask.ca.

Abstract

A major feature of Parkinson's disease is the formation of Lewy bodies in dopaminergic neurons which consist of misfolded α-synuclein. The binding of natural products to α-synuclein was evaluated by nanopore analysis and caffeine, curcumin, and nicotine all caused large conformational changes which may be related to their known neuroprotective effect in Parkinson's disease. The binding of the stereoisomers of nicotine were also studied by ITC, CD and NMR. It is proposed that (-)-nicotine causes the folding of α-synuclein into a loop with interaction between the N- and C-termini. For (+)-nicotine the binding is weaker and mainly involves residues in the N-terminus. Caffeine and nicotine can bind to α-synuclein simultaneously and may provide lead structures for the development of other compounds for the treatment of PD.

KEYWORDS:

Caffeine; Curcumin; Induced folding; Intrinsically disordered protein; Nanopore analysis; Nicotine; Parkinson's disease; α-Synuclein

PMID:
25081642
DOI:
10.1016/j.ejmech.2014.07.090
[Indexed for MEDLINE]
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