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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
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A Foldamer-Dendrimer Conjugate Neutralizes Synaptotoxic Beta-Amyloid Oligomers
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<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>
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<div class="JournalArticle Publication short-list"> <div class="authors"> <span class="author-name" mtid="10000567"> <a href="/gui2/?type=authors&mode=browse&sel=10000567" target="_blank">Fülöp, L</a> </span> <span class="author-type"> </span> ; <span class="author-name" mtid="10022837"> <a href="/gui2/?type=authors&mode=browse&sel=10022837" target="_blank">Mándity, IM</a> </span> <span class="author-type"> </span> ; <span class="author-name" mtid="10063613"> <a href="/gui2/?type=authors&mode=browse&sel=10063613" target="_blank">Juhász, G</a> </span> <span class="author-type"> </span> ; <span class="author-name" mtid="10027696"> <a href="/gui2/?type=authors&mode=browse&sel=10027696" target="_blank">Szegedi, V</a> </span> <span class="author-type"> </span> ; <span class="author-name" mtid="10001147"> <a href="/gui2/?type=authors&mode=browse&sel=10001147" target="_blank">Hetényi, A</a> </span> <span class="author-type"> </span> ; <span class="author-name" mtid="10027663"> <a href="/gui2/?type=authors&mode=browse&sel=10027663" target="_blank">Wéber, E</a> </span> <span class="author-type"> </span> ; <span class="author-name" mtid="10011919"> <a href="/gui2/?type=authors&mode=browse&sel=10011919" target="_blank">Bozsó, Z</a> </span> <span class="author-type"> </span> ; <span class="author-name" mtid="10026778"> <a href="/gui2/?type=authors&mode=browse&sel=10026778" target="_blank">Simon, D</a> </span> <span class="author-type"> </span> ; <span class="author-name" mtid="10031637"> <a href="/gui2/?type=authors&mode=browse&sel=10031637" target="_blank">Benkő, M</a> </span> <span class="author-type"> </span> ; <span class="author-name" mtid="2034559"> <a href="/gui2/?type=authors&mode=browse&sel=2034559" target="_blank">Király, Z</a> </span> <span class="author-type"> </span> et al. </div ><div class="title"><a href="/gui2/?mode=browse¶ms=publication;2034805" mtid="2034805" target="_blank">A Foldamer-Dendrimer Conjugate Neutralizes Synaptotoxic Beta-Amyloid Oligomers</a></div> <div class="pub-info"> <span class="journal-title">PLOS ONE</span> <span class="journal-volume">7</span> : <span class="journal-issue">7</span> <span class="page"> Paper: e39485 , 17 p. </span> <span class="year">(2012)</span> </div> <div class="pub-end"><div class="identifier-list"> <span class="identifiers"> <span class="id identifier oa_GOLD" title=" Gold "> <a style="color:blue" title="10.1371/journal.pone.0039485" target="_blank" href="https://doi.org/10.1371/journal.pone.0039485"> DOI </a> </span> <span class="id identifier oa_GREEN" title=" Green "> <a style="color:black" title="46068" target="_blank" href="http://real.mtak.hu/46068"> REAL </a> </span> <span class="id identifier oa_none" title="none"> <a style="color:blue" title="000306950900007" target="_blank" href="https://www.webofscience.com/wos/woscc/full-record/000306950900007"> WoS </a> </span> <span class="id identifier oa_none" title="none"> <a style="color:blue" title="84864443157" target="_blank" href="http://www.scopus.com/record/display.url?origin=inward&eid=2-s2.0-84864443157"> Scopus </a> </span> <span class="id identifier oa_none" title="none"> <a style="color:blue" title="22859942" target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=22859942&dopt=Abstract"> PubMed </a> </span> <span class="id identifier oa_GREEN" title=" Green "> <a style="color:blue" title="11876" target="_blank" href="http://publicatio.bibl.u-szeged.hu/11876"> SZTE Publicatio </a> </span> </span> </div> <div class="short-pub-prop-list"> <span class="deleted-record">Zárolt</span> <span class="short-pub-mtid"> Közlemény:2034805 </span> <span class="status-holder"><span class="status-data status-VALIDATED"> Egyeztetett </span></span> <span class="pub-core">Forrás Idéző </span> <span class="pub-type">Folyóiratcikk (Szakcikk ) </span> <!-- && !record.category.scientific --> <span class="pub-category">Tudományos</span> <div class="publication-citation" style="margin-left: 0.5cm;"> <span title="Nyilvános idézőközlemények összesen, említések nélkül" class="citingPub-count">Nyilvános idéző összesen: 47</span> | Független: 33 | Függő: 14 | Nem jelölt: 0 | WoS jelölt: 36 | Scopus jelölt: 38 | WoS/Scopus jelölt: 38 | DOI jelölt: 41 </div> </div> </div> </div><div class="JournalArticle Publication long-list">
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<img title="Forrásközlemény" style="float: left" src="/frontend/resources/grid/publication-core-icon.png">
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<div class="autype autype0"> <span class="author-name" mtid="10000567"><a
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<span class="authorAux-mtmt"> Neurodegeneratív betegségekkel kapcsolatos gyóg...</span>)
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<span class="author-affil"><span title="Szegedi Tudományegyetem">SZTE</span>/<span title="Általános Orvostudományi Kar">ÁOK</span>/Orvosi Vegytani Intézet</span>
;
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href="/gui2/?type=authors&mode=browse&sel=10022837" target="_blank">Mándity IM
(<span class="authorship-author-name">Mándity István</span>
<span class="authorAux-mtmt"> Gyógyszerkémia, gyógyszerkutatás</span>)
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<span class="author-affil"><span title="Szegedi Tudományegyetem">SZTE</span>/<span title="Gyógyszerésztudományi Kar">GYTK</span>/Gyógyszerkémiai Intézet</span>
;
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<span class="authorAux-mtmt"> elektofiziológia</span>)
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</span>
<span class="author-affil"><span title="Szegedi Tudományegyetem">SZTE</span>/<span title="Általános Orvostudományi Kar">ÁOK</span>/Orvosi Vegytani Intézet</span>
;
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href="/gui2/?type=authors&mode=browse&sel=10027696" target="_blank">Szegedi V
(<span class="authorship-author-name">Szegedi Viktor</span>
<span class="authorAux-mtmt"> Idegtudomány</span>)
</a>
</span>
;
<span class="author-name" mtid="10001147"><a
href="/gui2/?type=authors&mode=browse&sel=10001147" target="_blank">Hetényi A
(<span class="authorship-author-name">Hetényi Anasztázia</span>
<span class="authorAux-mtmt"> NMR spektroszkópia, molekulamodellezés</span>)
</a>
</span>
<span class="author-affil"><span title="Szegedi Tudományegyetem">SZTE</span>/<span title="Általános Orvostudományi Kar">ÁOK</span>/Orvosi Vegytani Intézet</span>
;
<span class="author-name" mtid="10027663"><a
href="/gui2/?type=authors&mode=browse&sel=10027663" target="_blank">Wéber E
(<span class="authorship-author-name">Wéber Edit</span>
<span class="authorAux-mtmt"> gyógyszerkémia</span>)
</a>
</span>
<span class="author-affil"><span title="Szegedi Tudományegyetem">SZTE</span>/<span title="Gyógyszerésztudományi Kar">GYTK</span>/Gyógyszerkémiai Intézet</span>
;
<span class="author-name" mtid="10011919"><a
href="/gui2/?type=authors&mode=browse&sel=10011919" target="_blank">Bozsó Z
(<span class="authorship-author-name">Bozsó Zsolt</span>
<span class="authorAux-mtmt"> Peptidkémia</span>)
</a>
</span>
<span class="author-affil"><span title="Szegedi Tudományegyetem">SZTE</span>/<span title="Általános Orvostudományi Kar">ÁOK</span>/Orvosi Vegytani Intézet</span>
;
<span class="author-name" mtid="10026778"><a
href="/gui2/?type=authors&mode=browse&sel=10026778" target="_blank">Simon D
(<span class="authorship-author-name">Simon Dóra</span>
<span class="authorAux-mtmt"> Neurobiológia</span>)
</a>
</span>
<span class="author-affil"><span title="Szegedi Tudományegyetem">SZTE</span>/<span title="Általános Orvostudományi Kar">ÁOK</span>/Orvosi Vegytani Intézet</span>
;
<span class="author-name" mtid="10031637"><a
href="/gui2/?type=authors&mode=browse&sel=10031637" target="_blank">Benkő M
(<span class="authorship-author-name">Benkő Mária</span>
<span class="authorAux-mtmt"> Kolloidkémia</span>)
</a>
</span>
<span class="author-affil"><span title="Szegedi Tudományegyetem">SZTE</span>/<span title="Természettudományi és Informatikai Kar">TTIK</span>/<span title="Kémiai Intézet">KI</span>/Fizikai Kémiai és Anyagtudományi Tanszék</span>
;
<span class="author-name" mtid="2034559"><a
href="/gui2/?type=authors&mode=browse&sel=2034559" target="_blank">Király Z
(<span class="authorship-author-name">Király Zoltán</span>
<span class="authorAux-mtmt"> Kolloidkémia</span>)
</a>
</span>
<span class="author-affil"><span title="Szegedi Tudományegyetem">SZTE</span>/<span title="Természettudományi és Informatikai Kar">TTIK</span>/<span title="Kémiai Intézet">KI</span>/Fizikai Kémiai és Anyagtudományi Tanszék</span>
;
<span class="author-name" mtid="10001168"><a
href="/gui2/?type=authors&mode=browse&sel=10001168" target="_blank">Martinek TA ✉
(<span class="authorship-author-name">Martinek Tamás</span>
<span class="authorAux-mtmt"> Gyógyszerkémia</span>)
</a>
</span>
<span class="author-affil"><span title="Szegedi Tudományegyetem">SZTE</span>/<span title="Gyógyszerésztudományi Kar">GYTK</span>/Gyógyszerkémiai Intézet</span>
</div>
</div>
<div class="title"><a href="/gui2/?mode=browse¶ms=publication;2034805" target="_blank">A Foldamer-Dendrimer Conjugate Neutralizes Synaptotoxic Beta-Amyloid Oligomers</a></div> <div> <span class="journal-title">PLOS ONE</span>
<span class="journal-issn">(<a target="_blank" href="https://portal.issn.org/resource/ISSN/1932-6203">1932-6203</a> <a target="_blank" href="https://portal.issn.org/resource/ISSN/1932-6203">1932-6203</a>)</span>:
<span class="journal-volume">7</span> <span class="journal-issue">7</span>
<span class="page">
Paper e39485.
17 p.
</span> <span class="year">(2012)</span>
</div>
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<span title="Nyilvános idézőközlemények összesen, említések nélkül" class="citingPub-count">Nyilvános idéző összesen: 47</span>
| Független: 33
| Függő: 14
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| WoS jelölt: 36
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Idézett közlemények száma: 4
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<div class="mtid"><span class="long-pub-mtid">Közlemény: 2034805</span>
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<span class="oldId">Régi azonosító: 2034805</span> |
Forrás Idéző
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<div class="lastModified">Utolsó módosítás: 2024.02.27. 21:24 Pécsi Éva (MTMT Közp 3, admin)
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<div class="lockedBy">Ideiglenesen zárolva 2024.03.11. 18:47 Pécsi Éva (MTMT Közp 3, admin)
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<pre class="comment" style="margin-top: 0; margin-bottom: 0;"><u>Megjegyzés</u>: 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 Re...</pre>
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