A foldamer-dendrimer conjugate neutralizes synaptotoxic β-amyloid oligomers.
<h4>Background and aims</h4>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 h...
| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2012-01-01
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| Series: | PLoS ONE |
| Online Access: | https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/22859942/?tool=EBI |
| _version_ | 1818337532179382272 |
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| author | Lívia Fülöp István M Mándity Gábor Juhász Viktor Szegedi Anasztázia Hetényi Edit Wéber Zsolt Bozsó Dóra Simon Mária Benkő Zoltán Király Tamás A Martinek |
| author_facet | Lívia Fülöp István M Mándity Gábor Juhász Viktor Szegedi Anasztázia Hetényi Edit Wéber Zsolt Bozsó Dóra Simon Mária Benkő Zoltán Király Tamás A Martinek |
| author_sort | Lívia Fülöp |
| collection | DOAJ |
| description | <h4>Background and aims</h4>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.<h4>Methods and results</h4>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.<h4>Conclusions</h4>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. |
| first_indexed | 2024-12-13T14:56:42Z |
| format | Article |
| id | doaj.art-c62c21806277426e93cdaa90103e7a4d |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-12-13T14:56:42Z |
| publishDate | 2012-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj.art-c62c21806277426e93cdaa90103e7a4d2022-12-21T23:41:13ZengPublic Library of Science (PLoS)PLoS ONE1932-62032012-01-0177e3948510.1371/journal.pone.0039485A foldamer-dendrimer conjugate neutralizes synaptotoxic β-amyloid oligomers.Lívia FülöpIstván M MándityGábor JuhászViktor SzegediAnasztázia HetényiEdit WéberZsolt BozsóDóra SimonMária BenkőZoltán KirályTamás A Martinek<h4>Background and aims</h4>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.<h4>Methods and results</h4>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.<h4>Conclusions</h4>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.https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/22859942/?tool=EBI |
| spellingShingle | Lívia Fülöp István M Mándity Gábor Juhász Viktor Szegedi Anasztázia Hetényi Edit Wéber Zsolt Bozsó Dóra Simon Mária Benkő Zoltán Király Tamás A Martinek A foldamer-dendrimer conjugate neutralizes synaptotoxic β-amyloid oligomers. PLoS ONE |
| title | A foldamer-dendrimer conjugate neutralizes synaptotoxic β-amyloid oligomers. |
| title_full | A foldamer-dendrimer conjugate neutralizes synaptotoxic β-amyloid oligomers. |
| title_fullStr | A foldamer-dendrimer conjugate neutralizes synaptotoxic β-amyloid oligomers. |
| title_full_unstemmed | A foldamer-dendrimer conjugate neutralizes synaptotoxic β-amyloid oligomers. |
| title_short | A foldamer-dendrimer conjugate neutralizes synaptotoxic β-amyloid oligomers. |
| title_sort | foldamer dendrimer conjugate neutralizes synaptotoxic β amyloid oligomers |
| url | https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/22859942/?tool=EBI |
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