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Publication details

Document type
Journal articles

Document subtype
Full paper

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

Participants in the publication
James D. Grayson (Author)
Matthew P. Baumgartner (Author)
Cleide Dos Santos Souza (Author)
Samuel J. Dawes (Author)
Imane Ghafir El Idrissi (Author)
Jennifer C. Louth (Author)
Sasha Stimpson (Author)
Emma Mead (Author)
Charlotte Dunbar (Author)
Joanna Wolak (Author)
Gary Sharman (Author)
David Evans (Author)
Anastasia Zhuravleva (Author)
Margarita Segovia Roldan (Author)
Nicola Antonio Colabufo (Author)
Ke Ning (Author)
Claire Garwood (Author)
James A. Thomas (Author)
Benjamin M. Partridge (Author)
Antonio de la Vega de Leon (Author)
Valerie J. Gillet (Author)
Amélia P. Rauter (Author)
FACULDADE DE CIÊNCIAS DA UNIVERSIDADE DE LISBOA
 CQE
 Beining Chen (Author)

Summary
Amyloid beta oligomers (Abo) are the main toxic species in Alzheimer's disease, which have been targeted for\\\\\\\\nsingle drug treatment with very little success. In this work we report a new approach for identifying\\\\\\\\nfunctional Abo binding compounds. A tailored library of 971 fluorine containing compounds was\\\\\\\\nselected by a computational method, developed to generate molecular diversity. These compounds\\\\\\\\nwere screened for Abo binding by a combined 19F and STD NMR technique. Six hits were evaluated in\\\\\\\\nthree parallel biochemical and functional assays. Two compounds disrupted Abo binding to its receptor\\\\\\\\nPrPC in HEK293 cells. They reduced the pFyn levels triggered by Abo treatment in neuroprogenitor cells\\\\\\\\nderived from human induced pluripotent stem cells (hiPSC). Inhibitory effects on pTau production in\\\\\\\\ncortical neurons derived from hiPSC were also observed. These drug-like compounds connect three of\\\\\\\\nthe pillars in Alzheimer's disease pathology, i.e. prion, Ab and Tau, affecting three different pathways\\\\\\\\nthrough specific binding to Abo and are, indeed, promising candidates for further development.

Date of Submisson/Request
2020-09-03
Date of Acceptance
2021-01-08
Date of Publication
2021

Institution
FACULDADE DE CIÊNCIAS DA UNIVERSIDADE DE LISBOA

Where published
Chemical Science

Publication Identifiers
ISSN - 2041-6520

Publisher
Royal Society of Chemistry (RSC)

Document Identifiers
DOI - https://doi.org/10.1039/d0sc04769d
URL - http://dx.doi.org/10.1039/d0sc04769d

Awards
Edge article

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APA
James D. Grayson, Matthew P. Baumgartner, Cleide Dos Santos Souza, Samuel J. Dawes, Imane Ghafir El Idrissi, Jennifer C. Louth, Sasha Stimpson, Emma Mead, Charlotte Dunbar, Joanna Wolak, Gary Sharman, David Evans, Anastasia Zhuravleva, Margarita Segovia Roldan, Nicola Antonio Colabufo, Ke Ning, Claire Garwood, James A. Thomas, Benjamin M. Partridge, Antonio de la Vega de Leon, Valerie J. Gillet, Amélia P. Rauter, Beining Chen, (2021). Amyloid binding and beyond: a new approach for Alzheimer's disease drug discovery targeting Aβo–PrPC binding and downstream pathways. Chemical Science, ISSN 2041-6520. eISSN . http://dx.doi.org/10.1039/d0sc04769d

IEEE
James D. Grayson, Matthew P. Baumgartner, Cleide Dos Santos Souza, Samuel J. Dawes, Imane Ghafir El Idrissi, Jennifer C. Louth, Sasha Stimpson, Emma Mead, Charlotte Dunbar, Joanna Wolak, Gary Sharman, David Evans, Anastasia Zhuravleva, Margarita Segovia Roldan, Nicola Antonio Colabufo, Ke Ning, Claire Garwood, James A. Thomas, Benjamin M. Partridge, Antonio de la Vega de Leon, Valerie J. Gillet, Amélia P. Rauter, Beining Chen, "Amyloid binding and beyond: a new approach for Alzheimer's disease drug discovery targeting Aβo–PrPC binding and downstream pathways" in Chemical Science, 2021. 10.1039/d0sc04769d

BIBTEX
@article{48726, author = {James D. Grayson and Matthew P. Baumgartner and Cleide Dos Santos Souza and Samuel J. Dawes and Imane Ghafir El Idrissi and Jennifer C. Louth and Sasha Stimpson and Emma Mead and Charlotte Dunbar and Joanna Wolak and Gary Sharman and David Evans and Anastasia Zhuravleva and Margarita Segovia Roldan and Nicola Antonio Colabufo and Ke Ning and Claire Garwood and James A. Thomas and Benjamin M. Partridge and Antonio de la Vega de Leon and Valerie J. Gillet and Amélia P. Rauter and Beining Chen}, title = {Amyloid binding and beyond: a new approach for Alzheimer's disease drug discovery targeting Aβo–PrPC binding and downstream pathways}, journal = {Chemical Science}, year = 2021, }