title: A foldamer-dendrimer conjugate neutralizes synaptotoxic β-amyloid oligomers.
abstract: OBJECTIVE
  Unnatural 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.
  
  
  RESULTS
  Short 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.
  
  
  CONCLUSIONS
  The 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.
authors.affiliation: Department of Medical Chemistry, University of Szeged, Szeged, Hungary.
authors.forename: Lívia
authors.initials: L
authors.lastname: Fülöp
authors.forename: István M
authors.initials: IM
authors.lastname: Mándity
authors.forename: Gábor
authors.initials: G
authors.lastname: Juhász
authors.forename: Viktor
authors.initials: V
authors.lastname: Szegedi
authors.forename: Anasztázia
authors.initials: A
authors.lastname: Hetényi
authors.forename: Edit
authors.initials: E
authors.lastname: Wéber
authors.forename: Zsolt
authors.initials: Z
authors.lastname: Bozsó
authors.forename: Dóra
authors.initials: D
authors.lastname: Simon
authors.forename: Mária
authors.initials: M
authors.lastname: Benkő
authors.forename: Zoltán
authors.initials: Z
authors.lastname: Király
authors.forename: Tamás A
authors.initials: TA
authors.lastname: Martinek
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism / Q000503:physiopathology; D016229:Amyloid beta-Peptides / Q000737:chemistry* / Q000502:physiology; D000818:Animals; D002151:Calorimetry; D011232:Chemical Precipitation; D050091:Dendrimers / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D006624:Hippocampus / Q000187:drug effects / Q000503:physiopathology; D066298:In Vitro Techniques; D008027:Light; D017774:Long-Term Potentiation / Q000187:drug effects; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D018716:Molecular Mimicry; D010316:Particle Size; D011485:Protein Binding; D017433:Protein Structure, Secondary; D012542:Scattering, Radiation
chemical_list: D016229:Amyloid beta-Peptides; D050091:Dendrimers