title: 'Click' assembly of glycoclusters and discovery of a trehalose analogue that retards Aβ40 aggregation and inhibits Aβ40-induced neurotoxicity.
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.
authors.affiliation: The University of Queensland, School of Pharmacy, Brisbane, Queensland 4072, Australia.
authors.forename: Hemalatha
authors.initials: H
authors.lastname: Rajaram
authors.affiliation: The University of Queensland, School of Pharmacy, Brisbane, Queensland 4072, Australia.
authors.forename: Manoj Kumar
authors.initials: MK
authors.lastname: Palanivelu
authors.affiliation: Department of Physiology, Yong Loo Lin School Medicine, National University of Singapore, Singapore 117597, Singapore.
authors.forename: Thiruma V
authors.initials: TV
authors.lastname: Arumugam
authors.affiliation: The University of Queensland, School of Pharmacy, Brisbane, Queensland 4072, Australia.
authors.forename: Venkatesan M
authors.initials: VM
authors.lastname: Rao
authors.affiliation: The University of Queensland, School of Pharmacy, Brisbane, Queensland 4072, Australia.
authors.forename: P Nicholas
authors.initials: PN
authors.lastname: Shaw
authors.affiliation: The University of Queensland, School of Chemistry and Molecular Biosciences, Brisbane, Queensland 4072, Australia.
authors.forename: Ross P
authors.initials: RP
authors.lastname: McGeary
authors.affiliation: The University of Queensland, School of Pharmacy, Brisbane, Queensland 4072, Australia. Electronic address: b.ross1@uq.edu.au.
authors.forename: Benjamin P
authors.initials: BP
authors.lastname: Ross
mesh_terms: D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000818:Animals; D057930:Click Chemistry; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D006001:Glycoconjugates / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D015394:Molecular Structure; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D018696:Neuroprotective Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D010446:Peptide Fragments / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship; D014199:Trehalose / Q000031:analogs & derivatives* / Q000737:chemistry
chemical_list: D016229:Amyloid beta-Peptides; D006001:Glycoconjugates; D018696:Neuroprotective Agents; D010446:Peptide Fragments; C078592:amyloid beta-protein (1-40); D014199:Trehalose
keywords: Alzheimer’s disease; Amyloid beta-peptides; Click chemistry; Glycoclusters; Osmolytes