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Issue 10, 2021
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Amyloid binding and beyond: a new approach for Alzheimer's disease drug discovery targeting Aβo–PrPC binding and downstream pathways

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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.

Graphical abstract: Amyloid binding and beyond: a new approach for Alzheimer's disease drug discovery targeting Aβo–PrPC binding and downstream pathways

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Supplementary files

Article information


Submitted
03 Sep 2020
Accepted
08 Jan 2021
First published
01 Feb 2021

This article is Open Access
All publication charges for this article have been paid for by the Royal Society of Chemistry

Chem. Sci., 2021,12, 3768-3785
Article type
Edge Article

Amyloid binding and beyond: a new approach for Alzheimer's disease drug discovery targeting Aβo–PrPC binding and downstream pathways

J. D. Grayson, M. P. Baumgartner, C. D. Santos Souza, S. J. Dawes, I. G. El Idrissi, J. C. Louth, S. Stimpson, E. Mead, C. Dunbar, J. Wolak, G. Sharman, D. Evans, A. Zhuravleva, M. S. Roldan, N. A. Colabufo, K. Ning, C. Garwood, J. A. Thomas, B. M. Partridge, A. de la Vega de Leon, V. J. Gillet, A. P. Rauter and B. Chen, Chem. Sci., 2021, 12, 3768
DOI: 10.1039/D0SC04769D

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    [Original citation] - Published by The Royal Society of Chemistry (RSC) on behalf of the Centre National de la Recherche Scientifique (CNRS) and the RSC.
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    [Original citation] - Published by The Royal Society of Chemistry (RSC) on behalf of the European Society for Photobiology, the European Photochemistry Association, and RSC.
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    [Original citation] - Published by The Royal Society of Chemistry.

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