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摘要
The misfolding of alpha-synuclein is a critical event in the death of dopaminergic neurons and the progression of Parkinson's disease. Previously, it was suggested that drugs, which bind to alpha-synuclein and form a loop structure between the N- and C-termini, tend to be neuroprotective, whereas others, which cause a more compact structure, tend to be neurotoxic. To improve the binding to alpha-synuclein, eight novel compounds were synthesized from a caffeine scaffold attached to (R,S)-1-aminoindan, (R,S)-nicotine, and metformin, and their binding to alpha-synuclein determined through nanopore analysis and isothermal titration calorimetry. The ability of the dimers to interact with alpha-synuclein in a cell system was assayed in a yeast model of PD which expresses an AS-GFP (alpha-synuclein-Green Fluorescent Protein) construct under the control of a galactose promoter. In 5 mM galactose this yeast strain will not grow and large cytoplasmic foci are observed by fluorescent microscopy. Two of the dimers, C-8-6-I and C-8-6-N, at a concentration of 0.1 mu M allowed the yeast to grow normally in 5 mM galactose and the AS-GFP became localized to the periphery of the cell. Both dimers were superior when compared to the monomeric compounds. The presence of the dimers also caused the disappearance of preformed cytoplasmic foci. Nanopore analysis of C-8-6-I and C-8-6-N were consistent with simultaneous binding to both the N- and C-terminus of alpha-synuclein but the binding constants were only 10(5) M-1.
- 出版日期2016-12
- 单位Saskatchewan; Saskatoon
