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The small molecule inhibitor anle145c thermodynamically traps human islet amyloid peptide in the form of non-cytotoxic oligomers

dc.contributor.authorSaravanan, Manikam S.
dc.contributor.authorRyazanov, Sergey
dc.contributor.authorLeonov, Andrei
dc.contributor.authorNicolai, Janine
dc.contributor.authorPraest, Patrique
dc.contributor.authorGiese, Armin
dc.contributor.authorWinter, Roland
dc.contributor.authorKhemtemourian, Lucie
dc.contributor.authorGriesinger, Christian
dc.contributor.authorKillian, J. Antoinette
dc.date.accessioned2020-01-14T09:55:36Z
dc.date.available2020-01-14T09:55:36Z
dc.date.issued2019de
dc.relation.ISSN2045-2322de
dc.identifier.urihttp://resolver.sub.uni-goettingen.de/purl?gs-1/17084
dc.description.abstractType 2 diabetes (T2DM) is associated with aggregation of the human islet amyloid polypeptide (hIAPP) into cytotoxic amyloid species. Here we tested the effect of a diphenylpyrazole (DPP)-derived small molecule inhibitor, anle145c, on cytotoxicity and on aggregation properties of hIAPP. We demonstrate that incubation of hIAPP with the inhibitor yields ~10 nm-sized non-toxic oligomers, independent of the initial aggregation state of hIAPP. This suggests that anle145c has a special mode of action in which anle145c-stabilized oligomers act as a thermodynamic sink for the preferred aggregation state of hIAPP and anle145c. We also demonstrate that the inhibitor acts in a very efficient manner, with sub-stoichiometric concentrations of anle145c being sufficient to (i) inhibit hIAPP-induced death of INS-1E cells, (ii) prevent hIAPP fibril formation in solution, and (iii) convert preformed hIAPP fibrils into non-toxic oligomers. Together, these results indicate that anle145c is a promising candidate for inhibition of amyloid formation in T2DM.de
dc.language.isoengde
dc.relationinfo:eu-repo/grantAgreement/EC/FP7/317371/EU//MANIFOLDde
dc.rightsopenAccess
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/
dc.subjectoligomers; anle145c;de
dc.subject.ddc573
dc.subject.ddc612
dc.titleThe small molecule inhibitor anle145c thermodynamically traps human islet amyloid peptide in the form of non-cytotoxic oligomersde
dc.typejournalArticlede
dc.identifier.doi10.1038/s41598-019-54919-z
dc.type.versionpublishedVersionde
dc.relation.eISSN2045-2322
dc.bibliographicCitation.volume9de
dc.bibliographicCitation.issue1de
dc.type.subtypejournalArticle
dc.identifier.pmid31836748
dc.bibliographicCitation.articlenumber19023de
dc.description.statuspeerReviewedde
dc.bibliographicCitation.journalScientific Reportsde


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