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

dc.rights.licenseopenen_US
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
hal.structure.identifierChimie et Biologie des Membranes et des Nanoobjets [CBMN]
dc.contributor.authorKHEMTEMOURIAN, Lucie
dc.contributor.authorGRIESINGER, Christian
dc.contributor.authorKILLIAN, J. Antoinette
dc.date.accessioned2020-05-06T13:04:05Z
dc.date.available2020-05-06T13:04:05Z
dc.date.issued2019
dc.identifier.issn2045-2322en_US
dc.identifier.urihttps://oskar-bordeaux.fr/handle/20.500.12278/7486
dc.description.abstractEnType 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 similar to 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 substoichiometric 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 nontoxic oligomers. Together, these results indicate that anle145c is a promising candidate for inhibition of amyloid formation in T2DM.
dc.language.isoENen_US
dc.title.enThe small molecule inhibitor anle145c thermodynamically traps human islet amyloid peptide in the form of non-cytotoxic oligomers
dc.title.alternativeSci Repen_US
dc.typeArticle de revueen_US
dc.identifier.doi10.1038/s41598-019-54919-z
dc.subject.halChimie/Matériauxen_US
bordeaux.journalScientific Reportsen_US
bordeaux.volume9en_US
bordeaux.hal.laboratoriesInstitut de Chimie & de Biologie des Membranes & des Nano-objets (CBMN) - UMR 5248en_US
bordeaux.institutionBordeaux INPen_US
bordeaux.institutionUniversité de Bordeauxen_US
bordeaux.peerReviewedouien_US
bordeaux.inpressnonen_US
hal.identifierhal-03182127
hal.version1
hal.date.transferred2021-03-26T09:42:55Z
hal.exporttrue
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