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

Abstract

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.

Sialic acid (SA)-modified selenium nanoparticles coated with a high blood–brain barrier permeability peptide-B6 peptide for potential use in Alzheimer’s disease

“…Here, we tested NPs inhibitory potentials using the ThT binding assay to provide quantitative information on amyloid fibril growth [38,39].…”

Folic acid inhibits the amyloid fibrils formation of β-lactoglobulin

“…One of the most attractive therapeutics options is to search small molecules which can prevent the accumulation-prone species by inhibiting the amyloid formation. Thus, studying the effect of small molecule inhibitors on the amyloid formation is of significance for understanding the mechanism of aggregation and preventing the amyloid-disease (35)(36)(37)(38).…”

Supramolecular Chirality in Dynamic Coordination Chemistry

“…The corresponding triple helicate exhibited high, stereodependent toxicity to human colon cancer cell lines, but no significant toxicity to Gram-positive and Gram-negative bacteria [67]. The dinuclear helicates also exhibited enantioselective inhibition of amyloid-β aggregation [68]. Thus, these dinuclear helicates are strong candidates for new enantioselective pharmaceuticals.…”