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

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.

Neurodegeneration-related beta-amyloid as autocatabolism-attenuator in a micro-in vivo system

“…To explore the possible sequence specificity of this molecule, we applied their scrambled version as control. The molecular content and weight of S-Aβ42 were the same as that in wild-type human form, with different order of amino acids Bartus et al, 2018).…”

The Clustering of mApoE Anti-Amyloidogenic Peptide on Nanoparticle Surface Does Not Alter Its Performance in Controlling Beta-Amyloid Aggregation

“…Thus far, there have been many efforts to develop various monovalent Aβ ligands such as curcumin, but multivalent ligands may enhance the binding affinity towards Aβ [40]. Recently, foldamer-dendrimer conjugates have been optimized to selectively recognize and bind Aβ1-42 and its assemblies, fine tuning the topology of the multivalent interaction, without affecting the aggregation/disaggregation process of Aβ [41]. Thus, our results show that it is possible to cluster a single Aβ-binding ligand on NP surface, without decreasing its Aβ-binding affinity and its anti-amyloidogenic activity.…”

Binding Profile Mapping of the S100 Protein Family Using a High-throughput Local Surface Mimetic Holdup Assay

“…Synthesis and purification of the foldamer libraries. The foldamer libraries were synthetized and purified as described previously [28]. Briefly, the 256-memberd library was divided to four sublibraries (aromatic, charged, apolar, non-charged polar) containing 64 members.…”

“…Holdup assay. Screening the interaction between the foldamer libraries and the S100ome was performed by holdup assays as described previously [28]. Briefly, S100 proteins were immobilized in a buffer containing 20 mM HEPES pH 7.5, 150 mM NaCl, 2 mM CaCl 2 , 1 mM TCEP on Co 2+ -affinity resin (~2 mg protein / ml resin concentration) via the N-terminal His 6 -tag followed by the addition of the foldamer libraries.…”