A foldamer-dendrimer conjugate neutralizes synaptotoxic β-amyloid oligomers.

<h4>Background and aims</h4>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 h...

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Autores principales:	Lívia Fülöp, István M Mándity, Gábor Juhász, Viktor Szegedi, Anasztázia Hetényi, Edit Wéber, Zsolt Bozsó, Dóra Simon, Mária Benkő, Zoltán Király, Tamás A Martinek
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2012
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/c62c21806277426e93cdaa90103e7a4d
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spelling	oai:doaj.org-article:c62c21806277426e93cdaa90103e7a4d2021-11-18T07:10:29ZA foldamer-dendrimer conjugate neutralizes synaptotoxic β-amyloid oligomers.1932-620310.1371/journal.pone.0039485https://doaj.org/article/c62c21806277426e93cdaa90103e7a4d2012-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/22859942/?tool=EBIhttps://doaj.org/toc/1932-6203<h4>Background and aims</h4>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.<h4>Methods and results</h4>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.<h4>Conclusions</h4>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.Lívia FülöpIstván M MándityGábor JuhászViktor SzegediAnasztázia HetényiEdit WéberZsolt BozsóDóra SimonMária BenkőZoltán KirályTamás A MartinekPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 7, Iss 7, p e39485 (2012)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Lívia Fülöp István M Mándity Gábor Juhász Viktor Szegedi Anasztázia Hetényi Edit Wéber Zsolt Bozsó Dóra Simon Mária Benkő Zoltán Király Tamás A Martinek A foldamer-dendrimer conjugate neutralizes synaptotoxic β-amyloid oligomers.
description	<h4>Background and aims</h4>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.<h4>Methods and results</h4>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.<h4>Conclusions</h4>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.
format	article
author	Lívia Fülöp István M Mándity Gábor Juhász Viktor Szegedi Anasztázia Hetényi Edit Wéber Zsolt Bozsó Dóra Simon Mária Benkő Zoltán Király Tamás A Martinek
author_facet	Lívia Fülöp István M Mándity Gábor Juhász Viktor Szegedi Anasztázia Hetényi Edit Wéber Zsolt Bozsó Dóra Simon Mária Benkő Zoltán Király Tamás A Martinek
author_sort	Lívia Fülöp
title	A foldamer-dendrimer conjugate neutralizes synaptotoxic β-amyloid oligomers.
title_short	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_sort	foldamer-dendrimer conjugate neutralizes synaptotoxic β-amyloid oligomers.
publisher	Public Library of Science (PLoS)
publishDate	2012
url	https://doaj.org/article/c62c21806277426e93cdaa90103e7a4d
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A foldamer-dendrimer conjugate neutralizes synaptotoxic β-amyloid oligomers.

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