NDA@SZTAKI

A Foldamer-Dendrimer Conjugate Neutralizes Synaptotoxic β-Amyloid Oligomers

Fülöp, Lívia

Mándity, István

Juhász, Gábor

Szegedi, Viktor

Hetényi, Anasztázia

WĂ©ber, Edit

BozsĂł, Zsolt

Simon, DĂłra

Benkő, Mária

Király, Zoltán

Martinek, Tamás

Public Library of Science (PLoS)

2012

QD Chemistry / kémia

<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>

angol

Article

PeerReviewed

info:eu-repo/semantics/article

text

http://real.mtak.hu/46068/1/journal.pone.0039485.PDF

Fülöp, Lívia and Mándity, István and Juhász, Gábor and Szegedi, Viktor and Hetényi, Anasztázia and Wéber, Edit and Bozsó, Zsolt and Simon, Dóra and Benkő, Mária and Király, Zoltán and Martinek, Tamás (2012) A Foldamer-Dendrimer Conjugate Neutralizes Synaptotoxic β-Amyloid Oligomers. PLOS ONE, 7 (7). e39485. ISSN 1932-6203

http://real.mtak.hu/46068/

MTMT:2034805; doi:10.1371/journal.pone.0039485