Therapeutics: Harnessing the Power of Molecular and Pharmacological Chaperones

Gross, David S.; Klein, Ronald L.; Witt, Stephan N.

doi:10.1002/9781118063903.ch12

Protein Chaperones and Protection From Neurodegenerative Diseases 2011

DOI: 10.1002/9781118063903.ch12

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Therapeutics: Harnessing the Power of Molecular and Pharmacological Chaperones

David S. Gross

Ronald L. Klein

Stephan N. Witt

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2014

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“…11 Osmolytes are small organic molecules that protect intracellular macromolecules from denaturation caused by environmental stresses such as perturbing solutes, dehydration, desiccation, extreme temperature, and high hydrostatic pressure. [12][13][14] There are three major categories of stabilizing osmolytes: carbohydrates; amino acids; and methylammonium/methylsulfonium compounds.…”

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‘Click’ assembly of glycoclusters and discovery of a trehalose analogue that retards Aβ40 aggregation and inhibits Aβ40-induced neurotoxicity

Rajaram

Palanivelu

Arumugam

et al. 2014

Bioorganic & Medicinal Chemistry Letters

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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 Alzheimer's disease (AD) is the most common neurodegenerative disorder and the leading cause of dementia.1 Currently, only symptomatic treatments are available and there is an urgent need for a disease-modifying drug.2 According to the modified amyloid cascade hypothesis, 3 AD is caused by small, soluble aggregates of amyloidbeta peptide (Aβ) which are highly neurotoxic. 4 It follows that one strategy to combat AD is to minimize the exposure of neurons to these aggregates and approaches to achieve this include: a) inhibiting the production of Aβ; 5,6 b) inhibiting Aβ aggregation; 7 c) promoting off-pathway aggregation that produces non-toxic Aβ aggregates; 8 and d) improving clearance of Aβ. 9,10 Recently, osmolytes have been proposed as treatments for neurodegenerative proteinopathies including AD. 11 Osmolytes are small organic molecules that protect intracellular macromolecules from denaturation caused by environmental stresses such as perturbing solutes, dehydration, desiccation, extreme temperature, and high hydrostatic pressure.12-14 There are three major categories of stabilizing osmolytes: carbohydrates; amino acids; and methylammonium/methylsulfonium compounds. 12,13 Many carbohydrate osmolytes have been found both to inhibit Aβ aggregation and to attenuate Aβ-induced neurotoxicity. Trehalose inhibits Aβ40/42 aggregation, dissociates pre-formed Aβ40/42 aggregates and decreases the toxicity of Aβ40. 15,16 Similarly, polymers carrying trehalose suppress Aβ40/42 fibril formation and reduce Aβ40/42-induced cytotoxicity.17,18 Myo-, scyllo-, and epi-inositol stabilize a nonfibrillar Aβ42 structure and attenuate Aβ42-induced neurotoxicity.19-21 Fructose inhibits fibrillogenesis of Aβ40/42 22 and attenuates Aβ42-induced neurotoxicity. 23 In many of these cases, the carbohydrate osmolytes were active at millimolar concentrations and for them to become viable treatments for AD their effectiveness must be improved. It is well established that weak interactions between proteins and carbohydrates can be amplified by constructing multivalent carbohydrate ligands and this phenomenon is known as the "cluster glycoside effect". 24,25 However, very few studies have investigated whether this phenomenon applies to carbohydrate osmolyte-Aβ interactions and then only for high MW glycopolymers. 17,18 ...

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mentioning

confidence: 99%

‘Click’ assembly of glycoclusters and discovery of a trehalose analogue that retards Aβ40 aggregation and inhibits Aβ40-induced neurotoxicity

Rajaram

Palanivelu

Arumugam

et al. 2014

Bioorganic & Medicinal Chemistry Letters

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Therapeutics: Harnessing the Power of Molecular and Pharmacological Chaperones

Cited by 1 publication

References 164 publications

‘Click’ assembly of glycoclusters and discovery of a trehalose analogue that retards Aβ40 aggregation and inhibits Aβ40-induced neurotoxicity

‘Click’ assembly of glycoclusters and discovery of a trehalose analogue that retards Aβ40 aggregation and inhibits Aβ40-induced neurotoxicity

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