TY - JOUR AU - Fülöp, Lívia AU - Mándity, István AU - Juhász, Gábor AU - Szegedi, Viktor AU - Hetényi, Anasztázia AU - Wéber, Edit AU - Bozsó, Zsolt AU - Simon, Dóra AU - Benkő, Mária AU - Király, Zoltán AU - Martinek, Tamás TI - A Foldamer-Dendrimer Conjugate Neutralizes Synaptotoxic Beta-Amyloid Oligomers JF - PLOS ONE J2 - PLOS ONE VL - 7 PY - 2012 IS - 7 PG - 17 SN - 1932-6203 DO - 10.1371/journal.pone.0039485 UR - https://m2.mtmt.hu/api/publication/2034805 ID - 2034805 N1 - Funding Agency and Grant Number: EU FP7 [HEALTH-F2-2007-201159, HEALTH-F2-2007-211696]; COST [CM0803]; Hungarian Research Foundation [NK81371, PD83581, PD83600, K68152]; Hungarian Academy of Sciences, Lendulet programme\n Funding text: This work was supported by the EU FP7 (HEALTH-F2-2007-201159, HEALTH-F2-2007-211696 and COST CM0803) (http://cordis.europa.eu/fp7/home_en.html); the Hungarian Research Foundation (NK81371, PD83581, PD83600 and K68152) (http://www.otka.hu/); and the Hungarian Academy of Sciences, Lendulet programme (http://mta.hu/). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.\n Department of Medical Chemistry, University of Szeged, Szeged, Hungary Institute of Pharmaceutical Chemistry, University of Szeged, Szeged, Hungary Bay Zoltán Foundation for Applied Research - BAYGEN, Szeged, Hungary Department of Physical Chemistry and Materials Science, University of Szeged, Szeged, Hungary Cited By :31 Export Date: 24 April 2020 Correspondence Address: Martinek, T. A.; Institute of Pharmaceutical Chemistry, University of Szeged, Szeged, Hungary; email: martinek@pharm.u-szeged.hu Chemicals/CAS: amyloid beta protein, 109770-29-8; Amyloid beta-Peptides; Dendrimers CAplus AN 2012:1144372; MEDLINE PMID: 22859942 (Journal; Article; Research Support, Non-U.S. Gov't); AB - Background and Aims

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.

Methods and 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.

LA - English DB - MTMT ER -