Structural optimization of foldamer-dendrimer conjugates as multivalent agents against the toxic effects of amyloid beta oligomers

Éva Bartus, Gábor Olajos, Ildikó Schuster, Zsolt Bozsó, Mária A. Deli, Szilvia Veszelka, Fruzsina R. Walter, Zsolt Datki, Zsolt Szakonyi, Tamás A. Martinek, Livia Fülöp

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

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 (A β) 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 A β 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 A β 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 A β, 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 A β 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 A β binding.

Original languageEnglish
Article number2523
JournalMolecules
Volume23
Issue number10
DOIs
Publication statusPublished - Oct 2 2018

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Keywords

  • Amyloid β
  • Foldamer
  • Molecular recognition
  • Multivalency
  • Protein aggregation

ASJC Scopus subject areas

  • Analytical Chemistry
  • Chemistry (miscellaneous)
  • Molecular Medicine
  • Pharmaceutical Science
  • Drug Discovery
  • Physical and Theoretical Chemistry
  • Organic Chemistry

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