1. The potential of lactulose and melibiose, two novel trehalase-indigestible and autophagy-inducing disaccharides, for polyQ-mediated neurodegenerative disease treatment.
- Author
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Lee GC, Lin CH, Tao YC, Yang JM, Hsu KC, Huang YJ, Huang SH, Kung PJ, Chen WL, Wang CM, Wu YR, Chen CM, Lin JY, Hsieh-Li HM, and Lee-Chen GJ
- Subjects
- Animals, Cell Line, Computer-Aided Design, Disease Models, Animal, Drug Stability, Hydrogen Bonding, Hydrolysis, Lactulose chemistry, Lactulose metabolism, Melibiose chemistry, Melibiose metabolism, Mice, Transgenic, Molecular Docking Simulation, Molecular Structure, Neurodegenerative Diseases genetics, Neurodegenerative Diseases metabolism, Neurodegenerative Diseases pathology, Neuroprotective Agents chemistry, Neuroprotective Agents metabolism, Peptides genetics, Protein Aggregates, Purkinje Cells drug effects, Purkinje Cells metabolism, Purkinje Cells pathology, Structure-Activity Relationship, TATA-Box Binding Protein genetics, TATA-Box Binding Protein metabolism, Time Factors, Transfection, Trehalose chemistry, Trehalose metabolism, Trehalose pharmacology, Autophagy drug effects, Digestion, Drug Design, Lactulose pharmacology, Melibiose pharmacology, Neurodegenerative Diseases prevention & control, Neuroprotective Agents pharmacology, Peptides metabolism, Trehalase metabolism
- Abstract
The unique property of trehalose encourages its pharmaceutical application in aggregation-mediated neurodegenerative disorders, including Alzheimer's, Parkinson's, and many polyglutamine (polyQ)-mediated diseases. However, trehalose is digested into glucose by trehalase and which reduced its efficacy in the disease target tissues. Therefore, searching trehalase-indigestible analogs of trehalose is a potential strategy to enhance therapeutic effect. In this study, two trehalase-indigestible trehalose analogs, lactulose and melibiose, were selected through compound topology and functional group analyses. Hydrogen-bonding network analyses suggest that the elimination of the hydrogen bond between the linker ether and aspartate 321 (D321) of human trehalase is the key for lactulose and melibiose to avoid the hydrolyzation. Using polyQ-mediated spinocerebellar ataxia type 17 (SCA17) cell and slice cultures, we found the aggregation was significantly prohibited by trehalose, lactulose, and melibiose, which may through up-regulating of autophagy. These findings suggest the therapeutic applications of trehalase-indigestible trehalose analogs in aggregation-associated neurodegenerative diseases., (Copyright © 2015 Elsevier Inc. All rights reserved.)
- Published
- 2015
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