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

Gao, Nan; Sun, Hanjun; Dong, Kai; Ren, Jinsong; Duan, Taicheng; Xu, Can; Qu, Xiaogang

doi:10.1038/ncomms4422

Cited by 228 publications

(189 citation statements)

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“…By using a high-throughput screening method based on the fluorescence of an Aβ-enhanced cyan fluorescent protein (ECFP) fusion expression system constructed in our laboratory 16,21,23 which was originally developed by Hecht and co-workers 22 , we have identified the two pairs of metal complexes capable of inhibiting Aβ aggregation ( Figure 1A). ECFP folds into its native state slowly and the fluorescence of the Aβ-ECFP fusion depends on Aβ folding and solubility.…”

Section: Resultsmentioning

confidence: 99%

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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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Section: Resultsmentioning

confidence: 99%

“…23,54,55 Although multiple structures of Aβ (PDB 2LFM, 1IYT, 1BA4, 1ZE9, etc.) 54 have been demonstrated, we employed the structure obtained in an aqueous environment to carry out our study.…”

Section: Esi-msmentioning

confidence: 99%

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

et al. 2014

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“…Alongside with applications of POMs in catalysis (Wang and Yang, 2015), nanotechnology (Yamase and Pope, 2006), electrochemistry (Sadakane and Steckhan, 1998), material sciences (Proust et al, 2008), and molecular magnetism (Clemente-Juan et al, 2012), POMs have also been proven to exhibit remarkable biological activity. Due to the highly negative charge, strong acidity, geometry, their use in macromolecular crystallography (Bijelic and Rompel, 2015, 2017; Molitor et al, 2017) and as antimicrobial, (Yamase, 2005; Li et al, 2016; Bijelic et al, 2018), antiviral (Judd et al, 2001), antitumor (Fu et al, 2015), antidiabetes (Nomiya et al, 2001), and antiamyloid-fibril agents (related to Alzheimer's disease) (Gao et al, 2014) has been reported so far and more attention should be given to the biological and therapeutic effect of POMs.…”

Section: Introductionmentioning

confidence: 99%

Antibacterial Activity of Polyoxometalates Against Moraxella catarrhalis

et al. 2018

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The antibacterial activity of 29 different polyoxometalates (POMs) against Moraxella catarrhalis was investigated by determination of the minimum inhibitory concentration (MIC). The Preyssler type polyoxotungstate (POT) [NaP5W30O110]14− demonstrates the highest activity against M. catarrhalis (MIC = 1 μg/ml) among all tested POMs. Moreover, we show that the Dawson type based anions, [P2W18O62]6−, [(P2O7)Mo18O54]4−, [As2Mo18O62]6−, [H3P2W15V3O62]6−, and [AsW18O60]7− are selective on M. catarrhalis (MIC range of 2-8 μg/ml). Among the six tested Keggin type based POTs ([PW12O40]3−, [H2PCoW11O40]5−, [H2CoTiW11O40]6−, [SiW10O36]8−, [SbW9O33]9−, [AsW9O33]9−), only the mono-substituted [H2CoTiW11O40]6− showed MIC value comparable to those of the Dawson type group. Polyoxovanadates (POVs) and Anderson type POMs were inactive against M. catarrhalis within the tested concentration range (1-256 μg/ml). Four Dawson type POMs [P2W18O62]6−, [(P2O7)Mo18O54]4−, [As2Mo18O62]6−, [H3P2W15V3O62]6− and the Preyssler POT [NaP5W30O110]14− showed promising antibacterial activity against M. catarrhalis (MICs < 8 μg/ml) and were therefore tested against three additional bacteria, namely S. aureus, E. faecalis, and E. coli. The most potent antibacterial agent was [NaP5W30O110]14−, exhibiting the lowest MIC values of 16 μg/ml against S. aureus and 8 μg/ml against E. faecalis. The three most active compounds ([NaP5W30O110]14−, [P2W18O62]6−, and [H3P2W15V3O62]6−) show bacteriostatic effects in killing kinetics study against M. catarrhalis. We demonstrate, that POM activity is mainly depending on composition, shape, and size, but in the case of medium-size POTs (charge is more than −12 and number of addenda atoms is not being higher than 22) its activity correlates with the total net charge.

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“…Hala ere, bereziki aipatzekoa da Wells-Dawson erako anioiek Alzheimer gaitzaren eragiletzat jotzen den β-amiloideen agregazioa eta berauen peroxidasa aktibitatea inhibitzeko erakutsi duten ahalmena. In vivo egindako ikerketek erakusten dute farmakoa muga hematoentzefalikoa zeharkatzeko gai dela eta 48 orduren ostean metabolizatzeko aukera dagoela [22].…”

Section: Biomedikuntza: Alzheimerraren Eta Minbiziaren Aurkako Erremeunclassified

Polioxometalatoak: Elhuyar anaien ametsak bizirik dirau!

Artetxe

Reinoso

Gutiérrez‐Zorrilla

2017

EKAIA

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Laburpena: Polioxometalatoak (POMak) kimika ez-organikoaren munduan ezagunak diren metalez eta oxigenoz osatutako kluster anionikoak dira. Azaldu ohi duten forma, konposizio eta propietate aniztasunaren ondorioz, POMek aplikazio ugari dituzte teknologiari, ekonomiari edo ingurugiroari lotutako arlo ezberdinetan. Nahiz eta aspaldidanik aplikazio katalitikoetan erabili, gaur egun etorkizunerako garrantzitsuak izango diren esparru oso ezberdinetarako ikertzen ari dira, besteak beste, hondakin-uren tratamenduan, medikuntzan, konputazio kuantikoan, energia-iturri berriztagarrietan edota sentsore kimiko lumineszenteetan. Horrengatik guztiagatik, polioxometalatoen kimika, etorkizun handiko kimika ezorganikoaren alorreko esparru dinamikoenetariko bat dela baiezta genezake.Hitz gakoak: polioxometalatoak, materialen zientzia, katalisia, nanozientzia, sentsore lumineszenteak, medikuntza.Abstract: Polyoxometalates (POMs) are a well known class of anionic metal-oxygen clusters within the area of inorganic chemistry, with a large variety of shapes, compositions and structures. These features make POMs unique compounds with a wide range of applications in current fields of interest related to technology, economy and environment. In spite of their traditional use as catalysts, they are nowadays being explored for very different issues such as wastewater treatment, medicine, quantum computing, renewable energies or luminescent sensors. Therefore, POM chemistry can be considered as one of the most dynamic fields of the inorganic chemistry, as well as one of the fields with the greatest future.

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

Cited by 228 publications

References 53 publications

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

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

Antibacterial Activity of Polyoxometalates Against Moraxella catarrhalis

Polioxometalatoak: Elhuyar anaien ametsak bizirik dirau!

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