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