Grayson, J.D., Baumgartner, M.P., Santos Souza, C.D. et al. (20 more authors) (2021) Amyloid binding and beyond: a new approach for Alzheimer's disease drug discovery targeting Aβo–PrPC binding and downstream pathways. Chemical Science, 12 (10). pp. 3768-3785. ISSN 2041-6520
Abstract
Amyloid β oligomers (Aβo) are the main toxic species in Alzheimer's disease, which have been targeted for single drug treatment with very little success. In this work we report a new approach for identifying functional Aβo binding compounds. A tailored library of 971 fluorine containing compounds was selected by a computational method, developed to generate molecular diversity. These compounds were screened for Aβo binding by a combined 19F and STD NMR technique. Six hits were evaluated in three parallel biochemical and functional assays. Two compounds disrupted Aβo binding to its receptor PrPC in HEK293 cells. They reduced the pFyn levels triggered by Aβo treatment in neuroprogenitor cells derived from human induced pluripotent stem cells (hiPSC). Inhibitory effects on pTau production in cortical neurons derived from hiPSC were also observed. These drug-like compounds connect three of the pillars in Alzheimer's disease pathology, i.e. prion, Aβ and Tau, affecting three different pathways through specific binding to Aβo and are, indeed, promising candidates for further development.
Metadata
Item Type: | Article |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | © 2021 The Author(s). Published by the Royal Society of Chemistry. This Open Access Article is licensed under a Creative Commons Attribution-Non Commercial 3.0 Unported Licence (http://creativecommons.org/licenses/by-nc/3.0/) |
Dates: |
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Institution: | The University of Sheffield |
Academic Units: | The University of Sheffield > Faculty of Science (Sheffield) > Department of Chemistry (Sheffield) The University of Sheffield > Faculty of Social Sciences (Sheffield) > Information School (Sheffield) The University of Sheffield > Sheffield Teaching Hospitals |
Funding Information: | Funder Grant number EUROPEAN COMMISSION - FP6/FP7 612347 |
Depositing User: | Symplectic Sheffield |
Date Deposited: | 02 Mar 2021 14:47 |
Last Modified: | 15 Feb 2022 17:10 |
Status: | Published |
Publisher: | Royal Society of Chemistry (RSC) |
Refereed: | Yes |
Identification Number: | 10.1039/d0sc04769d |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:170690 |