Small‐Molecule Inhibitors of Islet Amyloid Polypeptide Fibril Formation

Mishra, Rajesh; Bulic, Bruno; Sellin, Daniel; Jha, Suman; Waldmann, Herbert; Winter, Roland

doi:10.1002/anie.200705372

Cited by 104 publications

(55 citation statements)

References 31 publications

(31 reference statements)

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“…Second, the ΛFe enantiomers showed more effective activities than the ΔFe enantiomers. Furthermore, the decreased ThT fluorescence almost reached maximum at the equal concentration of metal complex ( Figure S3), indicating that Aβ1-40 possibly interacted with the metal complexes at 1:1 ratio, which was consistent with previous studies 27 . As indicated by their work 27 , 1:1 binding suggested that the inhibition occurred at a very initial stage of the aggregation process [24][25][26] .…”

Section: Resultssupporting

confidence: 91%

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: Resultssupporting

confidence: 91%

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

et al. 2014

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“…210, 211 Targeting the early helical intermediate states of IAPP aggregation 162–164 , small molecule peptidomimetics 212, 213 have been designed to mimic helixes that complementarily bind to the N-terminal helix of IAPP. Another attractive set of amyloid aggregation inhibitors are small-molecule polyphenols 221 such as epigallocatechin gallate (EGCG), 228 curcumin, 219, 220 and resveratrol, 229 which inhibit aggregation and reduce the related cytotoxicity of IAPP 230 as well as other proteins and peptides such as Aβ. 231 These polyphenols have the advantage of being naturally occurring, and are non-toxic at moderate concentrations.…”

Section: Iapp and Type 2 Diabetesmentioning

confidence: 99%

Implications of peptide assemblies in amyloid diseases

et al. 2017

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Neurodegenerative disorders and type 2 diabetes are global epidemics compromising the quality of life of millions worldwide, with profound social and economic implications. Despite the significant differences in pathology – much of which are poorly understood – these diseases are commonly characterized by the presence of cross-β amyloid fibrils as well as the loss of neuronal or pancreatic β-cells. In this review, we document research progress on the molecular and mesoscopic self-assembly of amyloid-beta, alpha synuclein, human islet amyloid polypeptide and prions, the peptides and proteins associated with Alzheimer’s, Parkinson’s, type 2 diabetes and prions diseases. In addition, we discuss the toxicities of these amyloid proteins based on their self-assembly as well as their interactions with membranes, metal ions, small molecules and engineered nanoparticles. Through this presentation we show the remarkable similarities and differences in the structural transitions of the amyloid proteins through primary and secondary nucleation, the common evolution from disordered monomers to alpha-helices and then to β-sheets when the proteins encounter the cell membrane, and, the consensus (with a few exceptions) that off-pathway oligomers, rather than amyloid fibrils, are the toxic species regardless of the pathogenic protein sequence or physicochemical properties. In addition, we highlight the crucial role of molecular self-assembly in eliciting the biological and pathological consequences of the amyloid proteins within the context of their cellular environments and their spreading between cells and organs. Exploiting such structure-function-toxicity relationship may prove pivotal for the detection and mitigation of amyloid diseases.

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“…The gross features of these data are in good agreement with earlier data. 28 Here, we put forward a more detailed and quantitative analysis of the aggregation reaction by applying resolution enhancement methods and curve fitting to the spectra. During the aggregation process, the peak maximum of the amide-I′ band of hIAPP shifts from 1646 to 1624 cm − 1 .…”

Section: Conformational Changes In Hiapp and Proiapp At Solid Interfamentioning

confidence: 99%

Amyloidogenic Propensities and Conformational Properties of ProIAPP and IAPP in the Presence of Lipid Bilayer Membranes

Jha

Sellin

Seidel

et al. 2009

Journal of Molecular Biology

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Small‐Molecule Inhibitors of Islet Amyloid Polypeptide Fibril Formation

Cited by 104 publications

References 31 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

Implications of peptide assemblies in amyloid diseases

Amyloidogenic Propensities and Conformational Properties of ProIAPP and IAPP in the Presence of Lipid Bilayer Membranes

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