The Catalytically Active Copper‐Amyloid‐Beta State: Coordination Site Responsible for Reactive Oxygen Species Production

Cassagnes, Laure‐Estelle; Hervé, Vincent; Nepveu, Françoise; Hureau, Christelle; Faller, Peter; Collin, Fabrice

doi:10.1002/ange.201305372

Cited by 44 publications

(68 citation statements)

References 39 publications

(23 reference statements)

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“…Therefore, POMds could be outstanding inhibitors of the above peroxidase-like activity, and this hypothesis was confirmed. As described previously, haem-Ab complexes showed remarkably enhanced peroxidase-like activity relative to free haem [28][29][30] . When POM-Dawson was added to the system, the enhanced peroxidase-like activity still existed.…”

supporting

confidence: 77%

“…The inhibition assay was performed as previously described [28][29][30] . Cytotoxicity was measured as follows.…”

Section: Methodsmentioning

confidence: 99%

“…Furthermore, it has been recently reported that haem binds to Ab monomers, which may play another major role in AD (Fig. 7a) [28][29][30] . In native human Ab peptides, simultaneously mutating the His13 and His14 residues can prohibit haem binding and result in the loss of peroxidase-like activity.…”

mentioning

confidence: 93%

“…In the native human Ab peptides, either His13 or His14 can coordinate to haem and His13 probably binds haem specifically. Mutating the His13 and His14 residues simultaneously can prohibit haem binding, inducing loss of peroxidase-like activity [28][29][30] . Therefore, a strong affinity between an inhibitor and His13 and His14 will suppress the peroxidaselike activity, which could potentially be useful in the treatment of AD.…”

mentioning

confidence: 99%

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Transition-metal-substituted polyoxometalate derivatives as functional anti-amyloid agents for Alzheimer’s disease

et al. 2014

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Inhibitions of amyloid b (Ab) aggregation and Ab-haem peroxidase-like activity have received much attention because these two symptoms can be the primary targets of therapeutic strategies for Alzheimer's disease (AD). Recently, our group found that polyoxometalate (POM) with a Wells-Dawson structure can efficiently inhibit Ab aggregation. However, the interaction between POMs and Ab is robust, but still needs to improve Ab binding affinity. More importantly, it is unclear whether POMs can cross the blood-brain barrier and decrease Ab-haem peroxidase-like activity. Here we show that our designed series of transition metal-functionalized POM derivatives with a defined histidine-chelated binding site have much better Ab inhibition and peroxidase-like activity inhibition effects than the parent POM. More intriguingly, we show that these compounds can cross the blood-brain barrier and are metabolized after 48 h. Our work provides insights into the design, synthesis and screening of inorganic metal compounds as multifunctional therapeutic agents against AD.

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supporting

confidence: 77%

“…The inhibition assay was performed as previously described [28][29][30] . Cytotoxicity was measured as follows.…”

Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 93%

mentioning

confidence: 99%

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Transition-metal-substituted polyoxometalate derivatives as functional anti-amyloid agents for Alzheimer’s disease

et al. 2014

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“…1, 2 A significant body of data has indicated that polymerization of amyloid-β peptide (Aβ) into amyloid fibrils is a critical step in the pathogenesis of AD. [3][4][5][6][7] Therefore, inhibition of Aβ aggregation has been considered as attractive therapeutic and preventive strategy for AD treatment. Although considerable progress has been achieved in discovering inhibitors of Aβ aggregation and toxicity [8][9][10] , chiral recognition of Aβ and aggregation morphology can provide more information on Aβ effects involved in AD pathogenesis, and there is no report to show a chiral compound which has enantioselectivity on targeting and inhibiting Aβ aggregation 11 .…”

Section: Introductionmentioning

confidence: 99%

Chiral Metallohelical Complexes Enantioselectively Target Amyloid β for Treating Alzheimer’s Disease

et al. 2014

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Copyright and reuse:The Warwick Research Archive Portal (WRAP) makes this work of researchers of the University of Warwick available open access under the following conditions. Copyright © and all moral rights to the version of the paper presented here belong to the individual author(s) and/or other copyright owners. To the extent reasonable and practicable the material made available in WRAP has been checked for eligibility before being made available.Copies of full items can be used for personal research or study, educational, or not-forprofit purposes without prior permission or charge. Provided that the authors, title and full bibliographic details are credited, a hyperlink and/or URL is given for the original metadata page and the content is not changed in any way. Publisher's statement:This document is the Accepted Manuscript version of a Published Work that appeared in final form in Journal of the American Chemical Society, copyright © American Chemical Society after peer review and technical editing by the publisher. To access the final edited and published work see http://pubs.acs.org/doi/abs/10.1021/ja502789eThe version presented here may differ from the published version or, version of record, if you wish to cite this item you are advised to consult the publisher's version. Please see the 'permanent WRAP url' above for details on accessing the published version and note that access may require a subscription. ABSTRACT: Stereochemistry is a very important issue for pharmaceutical industry and can determine drug efficacy. Design and synthesis of small molecules, especially chiral molecules, which selectively target and inhibit amyloid (Aβ) aggregation represent valid therapeutic strategies for treatment of Alzheimer's disease (AD). Herein we report that two triple-helical dinuclear metallo-supramolecular complexes can act as a novel class of chiral amyloid-β inhibitors. Through targeting α/β-discordant stretches at the early steps of aggregation, these metal complexes can enantioselectively inhibit Aβ aggregation, which are demonstrated using fluorescent living cell-based screening and multiple biophysical and biochemical approaches. To the best of our knowledge, there is no report to show that a chiral compound can enantioselectively inhibit Aβ aggregation. Intriguingly, as a promising candidate for AD treatment, the chiral metal complex can cross the blood-brain barrier (BBB) and have SOD activity. Previous studies have demonstrated that chiral discrimination between enantiomers is extremely important, as stereopure drugs can often reduce the total dose of drug given and minimize any toxicity resulting from the inactive enantiomer. And this is also a critical factor which should be carefully considered in AD treatment. Our work provides new insights into chiral inhibition of Aβ aggregation and opens a new avenue for design and screening of chiral agents as Aβ inhibitors against AD.

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Ehrungen der Société Chimique de France 2013

2013

Angewandte Chemie

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The Catalytically Active Copper‐Amyloid‐Beta State: Coordination Site Responsible for Reactive Oxygen Species Production

Cited by 44 publications

References 39 publications

Transition-metal-substituted polyoxometalate derivatives as functional anti-amyloid agents for Alzheimer’s disease

Transition-metal-substituted polyoxometalate derivatives as functional anti-amyloid agents for Alzheimer’s disease

Chiral Metallohelical Complexes Enantioselectively Target Amyloid β for Treating Alzheimer’s Disease

Ehrungen der Société Chimique de France 2013

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