A Foldamer-Dendrimer Conjugate Neutralizes Synaptotoxic β-Amyloid Oligomers

Abstract

Background and AimsUnnatural self-organizing biomimetic polymers (foldamers) emerged as promising materials for biomolecule recognition and inhibition. Our goal was to construct multivalent foldamer-dendrimer conjugates which wrap the synaptotoxic β-amyloid (Aβ) oligomers with high affinity through their helical foldamer tentacles. Oligomeric Aβ species play pivotal role in Alzheimer's disease, therefore recognition and direct inhibition of this undruggable target is a great current challenge.Methods and ResultsShort helical β-peptide foldamers with designed secondary structures and side chain chemistry patterns were applied as potential recognition segments and their binding to the target was tested with NMR methods (saturation transfer difference and transferred-nuclear Overhauser effect). Helices exhibiting binding in the µM region were coupled to a tetravalent G0-PAMAM dendrimer. In vitro biophysical (isothermal titration calorimetry, dynamic light scattering, transmission electron microscopy and size-exclusion chromatography) and biochemical tests (ELISA and dot blot) indicated the tight binding between the foldamer conjugates and the Aβ oligomers. Moreover, a selective low nM interaction with the low molecular weight fraction of the Aβ oligomers was found. Ex vivo electrophysiological experiments revealed that the new material rescues the long-term potentiation from the toxic Aβ oligomers in mouse hippocampal slices at submicromolar concentration.ConclusionsThe combination of the foldamer methodology, the fragment-based approach and the multivalent design offers a pathway to unnatural protein mimetics that are capable of specific molecular recognition, and has already resulted in an inhibitor for an extremely difficult target.

Multivalent foldamer-based affinity assay for selective recognition of Aβ oligomers

“…It has been previously shown that the divalent PAMAM-foldamer conjugate does not display low nanomolar affinity [36] and spurred on by the good performance of biot-8, the effects of increasing the number of arms on M A N U S C R I P T…”

“…The Aβ solutions with different aggregation state were prepared according to literature protocols. [36,39] …”

Multivalent helix mimetics for PPI-inhibition

“…42 Moreover, a recent study by the Roche group revealed that hDM2 and hDMX could be induced to form dimers, by a small molecule that spans the p53 binding site of two hDM2(X) monomers (Fig. 51 Similarly, palindromic ligands have been utilised to inhibit amyloid assembly e.g. 43 This inspired the current studywe hypothesized that the use of multivalent 44 helix mimetics might lead to co-operative binding properties either through the avidity resulting from chemically induced dimerisation of the target protein or the higher effective ligand concentration afforded by the proximity of additional covalently tethered copies of the protein-binding ligand (Fig.…”

Controlling the Helix Handedness of ααβ‐Peptide Foldamers through Sequence Shifting

“…[3] Then on-typical conformational arrangements of b-peptides, as well as their other unique properties (e.g., high resistance against enzymatic hydrolysis), has led to the discovery of numerous molecules with valuable properties. [9] Moreover,o ther distinctive properties such as gelation, [10] catalysis, [11] self-organization, [12] and molecular recognition [13] have been shown for peptides containing b-amino acids. [9] Moreover,o ther distinctive properties such as gelation, [10] catalysis, [11] self-organization, [12] and molecular recognition [13] have been shown for peptides containing b-amino acids.…”