A foldamer-dendrimer conjugate neutralizes synaptotoxic beta-amyloid oligomers

<sec><title>Background and Aims</title><p>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-amy...

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Main Authors: Fülöp Lívia
Mándity István M.
Juhász Gábor Dénes
Szegedi Viktor
Hetényi Anasztázia
Wéber Edit
Bozsó Zsolt
Simon Dóra
Benkő Mária
Király Zoltán
Martinek Tamás A.
Format: Article
Published: Public Library of Science (PLoS) 2012
Series:PLOS ONE 7 No. 7
doi:10.1371/journal.pone.0039485

mtmt:2034805
Online Access:http://publicatio.bibl.u-szeged.hu/11876
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520 3 |a <sec><title>Background and Aims</title><p>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.</p></sec><sec><title>Methods and Results</title><p>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. <italic>In vitro</italic> 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. <italic>Ex vivo</italic> electrophysiological experiments revealed that the new material rescues the long-term potentiation from the toxic Aβ oligomers in mouse hippocampal slices at submicromolar concentration.</p></sec><sec><title>Conclusions</title><p>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.</p></sec> 
700 0 1 |a Mándity István M.  |e aut 
700 0 1 |a Juhász Gábor Dénes  |e aut 
700 0 1 |a Szegedi Viktor  |e aut 
700 0 1 |a Hetényi Anasztázia  |e aut 
700 0 1 |a Wéber Edit  |e aut 
700 0 1 |a Bozsó Zsolt  |e aut 
700 0 1 |a Simon Dóra  |e aut 
700 0 1 |a Benkő Mária  |e aut 
700 0 1 |a Király Zoltán  |e aut 
700 0 1 |a Martinek Tamás A.  |e aut 
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