Abstract
Osmolytes have been proposed as treatments for neurodegenerative proteinopathies including Alzheimer's disease. However, for osmolytes to reach the clinic their efficacy must be improved. In this work, copper(I)-catalyzed azide-alkyne cycloaddition chemistry was used to synthesize glycoclusters bearing six copies of trehalose, lactose, galactose or glucose, with the aim of improving the potency of these osmolytes via multivalency. A trehalose glycocluster was found to be superior to monomeric trehalose in its ability to retard the formation of amyloid-beta peptide 40 (Aβ40) fibrils and protect neurons from Aβ40-induced cell death.
Keywords:
Alzheimer’s disease; Amyloid beta-peptides; Click chemistry; Glycoclusters; Osmolytes.
Copyright © 2014 Elsevier Ltd. All rights reserved.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Amyloid beta-Peptides / antagonists & inhibitors*
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Amyloid beta-Peptides / metabolism
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Animals
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Click Chemistry*
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Dose-Response Relationship, Drug
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Drug Discovery*
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Glycoconjugates / chemical synthesis
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Glycoconjugates / chemistry
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Glycoconjugates / pharmacology*
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Mice
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Mice, Inbred C57BL
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Molecular Structure
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Neurons / drug effects*
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Neurons / metabolism
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Neurons / pathology
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Neuroprotective Agents / chemical synthesis
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Neuroprotective Agents / chemistry
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Neuroprotective Agents / pharmacology*
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Peptide Fragments / antagonists & inhibitors*
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Peptide Fragments / metabolism
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Structure-Activity Relationship
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Trehalose / analogs & derivatives*
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Trehalose / chemistry
Substances
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Amyloid beta-Peptides
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Glycoconjugates
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Neuroprotective Agents
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Peptide Fragments
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amyloid beta-protein (1-40)
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Trehalose