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 (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.
Highlights
Alzheimer’s disease (AD) is one of the most common forms of senile dementia and it belongs to the aggregation-associated disorders [1,2]
We have reported a tetravalent β-peptidic dendrimer conjugate which can selectively recognize the low molecular weight (LMW) fraction of amyloid β (Aβ) (1–42) and binds to peptide assemblies without remodeling its conformation or disaggregating oligomers into monomers with random coil structures
To study the role of certain structure elements in the binding affinity, a set of new foldamer sequences were designed (Figure 2) and ligated to lysine-dendron scaffolds having a focal symmetry. This template with biotin affinity tag can be synthesized by solid phase peptide synthesis and immobilized on a streptavidin coated support such as the surface of the ELISA plate [36]
Summary
Alzheimer’s disease (AD) is one of the most common forms of senile dementia and it belongs to the aggregation-associated disorders [1,2]. The pathology of AD is not yet fully understood and simultaneous effects of several different factors may be responsible for the onset of the disease Several potential disease-modifying therapeutic strategies are at preclinical or clinical stages of development, aiming either to prevent the formation of the protein aggregates and/or to eliminate them. These attempts involve the inhibition of the biosynthesis of Aβ peptides by β- and γ-secretase modulators [8,9], the removal of the produced
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
