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A Foldamer-Dendrimer Conjugate Neutralizes Synaptotoxic β-Amyloid Oligomers

BACKGROUND AND AIMS: Unnatural self-organizing biomimetic polymers (foldamers) emerged as promising materials for biomolecule recognition and inhibition. Our goal was to construct multivalent foldamer-dendrimer conjugates which wrap the synaptotoxic β-amyloid (Aβ) oligomers with high affinity throug...

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Autores principales: Fülöp, Lívia, Mándity, István M., Juhász, Gábor, Szegedi, Viktor, Hetényi, Anasztázia, Wéber, Edit, Bozsó, Zsolt, Simon, Dóra, Benkő, Mária, Király, Zoltán, Martinek, Tamás A.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2012
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3408453/
https://www.ncbi.nlm.nih.gov/pubmed/22859942
http://dx.doi.org/10.1371/journal.pone.0039485
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author Fülöp, Lívia
Mándity, István M.
Juhász, Gábor
Szegedi, Viktor
Hetényi, Anasztázia
Wéber, Edit
Bozsó, Zsolt
Simon, Dóra
Benkő, Mária
Király, Zoltán
Martinek, Tamás A.
author_facet Fülöp, Lívia
Mándity, István M.
Juhász, Gábor
Szegedi, Viktor
Hetényi, Anasztázia
Wéber, Edit
Bozsó, Zsolt
Simon, Dóra
Benkő, Mária
Király, Zoltán
Martinek, Tamás A.
author_sort Fülöp, Lívia
collection PubMed
description BACKGROUND AND AIMS: Unnatural self-organizing biomimetic polymers (foldamers) emerged as promising materials for biomolecule recognition and inhibition. Our goal was to construct multivalent foldamer-dendrimer conjugates which wrap the synaptotoxic β-amyloid (Aβ) oligomers with high affinity through their helical foldamer tentacles. Oligomeric Aβ species play pivotal role in Alzheimer's disease, therefore recognition and direct inhibition of this undruggable target is a great current challenge. METHODS AND RESULTS: Short helical β-peptide foldamers with designed secondary structures and side chain chemistry patterns were applied as potential recognition segments and their binding to the target was tested with NMR methods (saturation transfer difference and transferred-nuclear Overhauser effect). Helices exhibiting binding in the µM region were coupled to a tetravalent G0-PAMAM dendrimer. In vitro biophysical (isothermal titration calorimetry, dynamic light scattering, transmission electron microscopy and size-exclusion chromatography) and biochemical tests (ELISA and dot blot) indicated the tight binding between the foldamer conjugates and the Aβ oligomers. Moreover, a selective low nM interaction with the low molecular weight fraction of the Aβ oligomers was found. Ex vivo electrophysiological experiments revealed that the new material rescues the long-term potentiation from the toxic Aβ oligomers in mouse hippocampal slices at submicromolar concentration. CONCLUSIONS: The combination of the foldamer methodology, the fragment-based approach and the multivalent design offers a pathway to unnatural protein mimetics that are capable of specific molecular recognition, and has already resulted in an inhibitor for an extremely difficult target.
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spelling pubmed-34084532012-08-02 A Foldamer-Dendrimer Conjugate Neutralizes Synaptotoxic β-Amyloid Oligomers Fülöp, Lívia Mándity, István M. Juhász, Gábor Szegedi, Viktor Hetényi, Anasztázia Wéber, Edit Bozsó, Zsolt Simon, Dóra Benkő, Mária Király, Zoltán Martinek, Tamás A. PLoS One Research Article BACKGROUND AND AIMS: Unnatural self-organizing biomimetic polymers (foldamers) emerged as promising materials for biomolecule recognition and inhibition. Our goal was to construct multivalent foldamer-dendrimer conjugates which wrap the synaptotoxic β-amyloid (Aβ) oligomers with high affinity through their helical foldamer tentacles. Oligomeric Aβ species play pivotal role in Alzheimer's disease, therefore recognition and direct inhibition of this undruggable target is a great current challenge. METHODS AND RESULTS: Short helical β-peptide foldamers with designed secondary structures and side chain chemistry patterns were applied as potential recognition segments and their binding to the target was tested with NMR methods (saturation transfer difference and transferred-nuclear Overhauser effect). Helices exhibiting binding in the µM region were coupled to a tetravalent G0-PAMAM dendrimer. In vitro biophysical (isothermal titration calorimetry, dynamic light scattering, transmission electron microscopy and size-exclusion chromatography) and biochemical tests (ELISA and dot blot) indicated the tight binding between the foldamer conjugates and the Aβ oligomers. Moreover, a selective low nM interaction with the low molecular weight fraction of the Aβ oligomers was found. Ex vivo electrophysiological experiments revealed that the new material rescues the long-term potentiation from the toxic Aβ oligomers in mouse hippocampal slices at submicromolar concentration. CONCLUSIONS: The combination of the foldamer methodology, the fragment-based approach and the multivalent design offers a pathway to unnatural protein mimetics that are capable of specific molecular recognition, and has already resulted in an inhibitor for an extremely difficult target. Public Library of Science 2012-07-30 /pmc/articles/PMC3408453/ /pubmed/22859942 http://dx.doi.org/10.1371/journal.pone.0039485 Text en © 2012 Fülöp et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Fülöp, Lívia
Mándity, István M.
Juhász, Gábor
Szegedi, Viktor
Hetényi, Anasztázia
Wéber, Edit
Bozsó, Zsolt
Simon, Dóra
Benkő, Mária
Király, Zoltán
Martinek, Tamás A.
A Foldamer-Dendrimer Conjugate Neutralizes Synaptotoxic β-Amyloid Oligomers
title A Foldamer-Dendrimer Conjugate Neutralizes Synaptotoxic β-Amyloid Oligomers
title_full A Foldamer-Dendrimer Conjugate Neutralizes Synaptotoxic β-Amyloid Oligomers
title_fullStr A Foldamer-Dendrimer Conjugate Neutralizes Synaptotoxic β-Amyloid Oligomers
title_full_unstemmed A Foldamer-Dendrimer Conjugate Neutralizes Synaptotoxic β-Amyloid Oligomers
title_short A Foldamer-Dendrimer Conjugate Neutralizes Synaptotoxic β-Amyloid Oligomers
title_sort foldamer-dendrimer conjugate neutralizes synaptotoxic β-amyloid oligomers
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3408453/
https://www.ncbi.nlm.nih.gov/pubmed/22859942
http://dx.doi.org/10.1371/journal.pone.0039485
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