Development of a Platinum Complex as an anti‐Amyloid Agent for the Therapy of Alzheimer’s Disease

Kenche, Vijaya B.; Hung, Lin W.; Perez, Keyla; Volitakes, Irene; Ciccotosto, Guiseppe; Kwok, Jeffrey; Critch, Nicole; Sherratt, Nikki; Cortés, Mikhalina; Lal, Varsha; Masters, Colin L.; Murakami, Kazuma; Cappai, Roberto; Adlard, Paul A.; Barnham, Kevin J.

doi:10.1002/anie.201209885

Cited by 65 publications

(46 citation statements)

References 34 publications

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“…To test this hypothesis, data was acquired for a-syn in the presence of a platinum based agent, VK7. This compound has previously been observed to be non-toxic and to reduce the amyloid plaque burden in human Ab transgenic mice 17 and has recently been observed to inhibit a-syn fibrillisation (Kench, unpublished). The R g and D max distribution induced by the Pt compound shows significant reduction in the proportion of elongated structures, indicating induction of a compact form.…”

Section: Discussionmentioning

confidence: 97%

“…Copper/glycine (CuGly) 10 mM was prepared as described previously 16 and the synthesis and characterisation of the anti-fibril agent ([PtII(N,N-dimethyl-2-[2-(quinolin-8-yl)-1H-benzimidazol-1-yl]ethanamine) Cl2] referred to as VK7) has also been described previously. 17 All buffers and other reagents were of analytical grade or the highest possible purity.…”

Section: Methodsmentioning

confidence: 99%

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Alpha-synuclein oligomers and fibrils originate in two distinct conformer pools: a small angle X-ray scattering and ensemble optimisation modelling study

et al. 2015

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The 140 residue intrinsically disordered protein α-synuclein (α-syn) self-associates to form fibrils that are the major constituent of the Lewy body intracellular protein inclusions, and neurotoxic oligomers. Both of these macromolecular structures are associated with a number of neurodegenerative diseases, including Parkinson's disease and dementia with Lewy bodies. Using ensemble optimisation modelling (EOM) and small angle X-ray scattering (SAXS) on a size-exclusion column equipped beamline, we studied how the distribution of structural conformers in α-syn may be influenced by the presence of the familial early-onset mutations A30P, E45K and A53T, by substituting the four methionine residues with alanines and by reaction with copper (Cu2+) or an anti-fibril organic platinum (Pt) complex. We found that the WT had two major conformer groups, representing ensembles of compact and extended structures. The population of the extended group was increased in the more rapidly fibril-forming E45K and A53T mutants, while the compact group was enlarged in the oligomer-forming A30P mutant. Addition of Cu2+ resulted in the formation of an ensemble of compact conformers, while the anti-fibril agent and alanine substitution substantially reduced the population of extended conformers. Since our observations with the mutants suggest that fibrils may be drawn from the extended conformer ensemble, we propose that the compact and extended ensembles represent the beginning of oligomer and fibril formation pathways respectively, both of which have been reported to lead to a toxic gain of function. Manipulating these pathways and monitoring the results by EOM and SAXS may be useful in the development of anti-Parkinson's disease therapies.

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Section: Discussionmentioning

confidence: 97%

Section: Methodsmentioning

confidence: 99%

Alpha-synuclein oligomers and fibrils originate in two distinct conformer pools: a small angle X-ray scattering and ensemble optimisation modelling study

et al. 2015

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“…Several structure-based designs of aggregation inhibitors have been also recently reported. [129][130][131] Conformation-specific antibodies to target the characteristic structure of Aβ oligomers will shed new light on the accurate diagnosis by ELISA development and vaccination therapy. Eventually, it may be possible to extend the diagnosis and intervention to asymptomatic people.…”

Section: Discussionmentioning

confidence: 99%

Conformation-specific antibodies to target amyloid β oligomers and their application to immunotherapy for Alzheimer’s disease

Murakami

2014

Bioscience, Biotechnology, and Biochemistry

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Amyloid β-protein (Aβ) oligomers, intermediates of Aβ aggregation, cause cognitive impairment and synaptotoxicity in the pathogenesis of Alzheimer's disease (AD). Immunotherapy using anti-Aβ antibody is one of the most promising approaches for AD treatment. However, most clinical trials using conventional sequence-specific antibodies have proceeded with difficulty. This is probably due to the unintended removal of the non-pathological monomer and fibrils of Aβ as well as the pathological oligomers by these antibodies that recognize Aβ sequence, which is not involved in synaptotoxicity. Several efforts have been made recently to develop conformation-specific antibodies that target the tertiary structure of Aβ oligomers. Here, we review the recent findings of Aβ oligomers and anti-Aβ antibodies including our own, and discuss their potential as therapeutic and diagnostic tools.

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“…21). 125 The potential of metal complexes with kinetically inert d 6 complexes to inhibit Ab amyloid has been extended to Ir III , Rh III , and Ru II complexes. Iridium(III) and rhodium(III) complexes with orthometallated phenylpyridine (ppy) ligands, [M(ppy) 2 (OH 2 ) 2 ] + (where M = Rh III or Ir III ) (Fig.…”

Section: The Interaction Of Phosphorescent Ruthenium Polypyridyl Compmentioning

confidence: 99%

Metal complexes designed to bind to amyloid-β for the diagnosis and treatment of Alzheimer's disease

2014

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Alzheimer's disease is the most common form of age-related neurodegenerative dementia. The disease is characterised by the presence of plaques in the cerebral cortex. The major constituent of these plaques is aggregated amyloid-β peptide. This review focuses on the molecular aspects of metal complexes designed to bind to amyloid-β. The development of radioactive metal-based complexes of copper and technetium designed as diagnostic imaging agents to detect amyloid burden in the brain is discussed. Separate sections of the review discuss the use of luminescent metal complexes to act as non-conventional probes of amyloid formation and recent research into the use of metal complexes as inhibitors of amyloid formation and toxicity.

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Development of a Platinum Complex as an anti‐Amyloid Agent for the Therapy of Alzheimer’s Disease

Cited by 65 publications

References 34 publications

Alpha-synuclein oligomers and fibrils originate in two distinct conformer pools: a small angle X-ray scattering and ensemble optimisation modelling study

Alpha-synuclein oligomers and fibrils originate in two distinct conformer pools: a small angle X-ray scattering and ensemble optimisation modelling study

Conformation-specific antibodies to target amyloid β oligomers and their application to immunotherapy for Alzheimer’s disease

Metal complexes designed to bind to amyloid-β for the diagnosis and treatment of Alzheimer's disease

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