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Structural Optimization of Foldamer-Dendrimer Conjugates as Multivalent Agents against the Toxic Effects of Amyloid Beta Oligomers

Alzheimer’s disease is one of the most common chronic neurodegenerative disorders. Despite several in vivo and clinical studies, the cause of the disease is poorly understood. Currently, amyloid β (Aβ) peptide and its tendency to assemble into soluble oligomers are known as a main pathogenic event l...

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Autores principales: Bartus, Éva, Olajos, Gábor, Schuster, Ildikó, Bozsó, Zsolt, Deli, Mária A., Veszelka, Szilvia, Walter, Fruzsina R., Datki, Zsolt, Szakonyi, Zsolt, Martinek, Tamás A., Fülöp, Livia
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6222781/
https://www.ncbi.nlm.nih.gov/pubmed/30279351
http://dx.doi.org/10.3390/molecules23102523
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author Bartus, Éva
Olajos, Gábor
Schuster, Ildikó
Bozsó, Zsolt
Deli, Mária A.
Veszelka, Szilvia
Walter, Fruzsina R.
Datki, Zsolt
Szakonyi, Zsolt
Martinek, Tamás A.
Fülöp, Livia
author_facet Bartus, Éva
Olajos, Gábor
Schuster, Ildikó
Bozsó, Zsolt
Deli, Mária A.
Veszelka, Szilvia
Walter, Fruzsina R.
Datki, Zsolt
Szakonyi, Zsolt
Martinek, Tamás A.
Fülöp, Livia
author_sort Bartus, Éva
collection PubMed
description Alzheimer’s disease is one of the most common chronic neurodegenerative disorders. Despite several in vivo and clinical studies, the cause of the disease is poorly understood. Currently, amyloid β (Aβ) peptide and its tendency to assemble into soluble oligomers are known as a main pathogenic event leading to the interruption of synapses and brain degeneration. Targeting neurotoxic Aβ oligomers can help recognize the disease at an early stage or it can be a potential therapeutic approach. Unnatural β-peptidic foldamers are successfully used against many different protein targets due to their favorable structural and pharmacokinetic properties compared to small molecule or protein-like drug candidates. We have previously reported a tetravalent foldamer-dendrimer conjugate which can selectively bind Aβ oligomers. Taking advantage of multivalency and foldamers, we synthesized different multivalent foldamer-based conjugates to optimize the geometry of the ligand. Isothermal titration calorimetry (ITC) was used to measure binding affinity to Aβ, thereafter 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) based tissue viability assay and impedance-based viability assay on SH-SY5Y cells were applied to monitor Aβ toxicity and protective effects of the compounds. Important factors for high binding affinity were determined and a good correlation was found between influencing the valence and the capability of the conjugates for Aβ binding.
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spelling pubmed-62227812018-11-13 Structural Optimization of Foldamer-Dendrimer Conjugates as Multivalent Agents against the Toxic Effects of Amyloid Beta Oligomers Bartus, Éva Olajos, Gábor Schuster, Ildikó Bozsó, Zsolt Deli, Mária A. Veszelka, Szilvia Walter, Fruzsina R. Datki, Zsolt Szakonyi, Zsolt Martinek, Tamás A. Fülöp, Livia Molecules Article Alzheimer’s disease is one of the most common chronic neurodegenerative disorders. Despite several in vivo and clinical studies, the cause of the disease is poorly understood. Currently, amyloid β (Aβ) peptide and its tendency to assemble into soluble oligomers are known as a main pathogenic event leading to the interruption of synapses and brain degeneration. Targeting neurotoxic Aβ oligomers can help recognize the disease at an early stage or it can be a potential therapeutic approach. Unnatural β-peptidic foldamers are successfully used against many different protein targets due to their favorable structural and pharmacokinetic properties compared to small molecule or protein-like drug candidates. We have previously reported a tetravalent foldamer-dendrimer conjugate which can selectively bind Aβ oligomers. Taking advantage of multivalency and foldamers, we synthesized different multivalent foldamer-based conjugates to optimize the geometry of the ligand. Isothermal titration calorimetry (ITC) was used to measure binding affinity to Aβ, thereafter 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) based tissue viability assay and impedance-based viability assay on SH-SY5Y cells were applied to monitor Aβ toxicity and protective effects of the compounds. Important factors for high binding affinity were determined and a good correlation was found between influencing the valence and the capability of the conjugates for Aβ binding. MDPI 2018-10-02 /pmc/articles/PMC6222781/ /pubmed/30279351 http://dx.doi.org/10.3390/molecules23102523 Text en © 2018 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Bartus, Éva
Olajos, Gábor
Schuster, Ildikó
Bozsó, Zsolt
Deli, Mária A.
Veszelka, Szilvia
Walter, Fruzsina R.
Datki, Zsolt
Szakonyi, Zsolt
Martinek, Tamás A.
Fülöp, Livia
Structural Optimization of Foldamer-Dendrimer Conjugates as Multivalent Agents against the Toxic Effects of Amyloid Beta Oligomers
title Structural Optimization of Foldamer-Dendrimer Conjugates as Multivalent Agents against the Toxic Effects of Amyloid Beta Oligomers
title_full Structural Optimization of Foldamer-Dendrimer Conjugates as Multivalent Agents against the Toxic Effects of Amyloid Beta Oligomers
title_fullStr Structural Optimization of Foldamer-Dendrimer Conjugates as Multivalent Agents against the Toxic Effects of Amyloid Beta Oligomers
title_full_unstemmed Structural Optimization of Foldamer-Dendrimer Conjugates as Multivalent Agents against the Toxic Effects of Amyloid Beta Oligomers
title_short Structural Optimization of Foldamer-Dendrimer Conjugates as Multivalent Agents against the Toxic Effects of Amyloid Beta Oligomers
title_sort structural optimization of foldamer-dendrimer conjugates as multivalent agents against the toxic effects of amyloid beta oligomers
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6222781/
https://www.ncbi.nlm.nih.gov/pubmed/30279351
http://dx.doi.org/10.3390/molecules23102523
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