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000888244 1001_ $$00000-0002-4301-3106$$aMaity, Debabrata$$b0$$eCorresponding author
000888244 245__ $$aSub-stoichiometric inhibition of IAPP aggregation: a peptidomimetic approach to anti-amyloid agents
000888244 260__ $$aCambridge$$bThe Royal Society of Chemistry$$c2020
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000888244 520__ $$aMembrane-catalysed misfolding of islet amyloid polypeptide is associated with the death of β-cells in type II diabetes (T2D). Most active compounds so far reported require high doses for inhibition of membrane bound IAPP fibrillation. Here, we describe a naphthalimide-appended oligopyridylamide-based α-helical mimetic, DM 1, for targeting membrane bound IAPP. DM 1 completely inhibits the aggregation of IAPP at doses of 0.2 equivalents. DM 1 is also effective at similarly low doses for inhibition of seed-catalyzed secondary nucleation. An NMR based study demonstrates that DM 1 modulates IAPP self-assembly by stabilizing and/or perturbing the N-terminus helix conformation. DM 1 at substoichiometric doses rescues rat insulinoma cells from IAPP-mediated cytotoxicity. Most importantly, 0.2 equivalents of DM 1 disaggregate preformed oligomers and fibrils and can reverse cytotoxicity by modulating toxic preformed oligomers and fibrils of IAPP into non-toxic conformations.
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000888244 7001_ $$00000-0001-5472-4619$$aKumar, Sunil$$b1
000888244 7001_ $$0P:(DE-HGF)0$$aAlHussein, Ruyof$$b2
000888244 7001_ $$0P:(DE-Juel1)145165$$aGremer, Lothar$$b3
000888244 7001_ $$0P:(DE-HGF)0$$aHowarth, Madeline$$b4
000888244 7001_ $$0P:(DE-HGF)0$$aKarpauskaite, Laura$$b5
000888244 7001_ $$0P:(DE-Juel1)166306$$aHoyer, Wolfgang$$b6
000888244 7001_ $$0P:(DE-HGF)0$$aMagzoub, Mazin$$b7
000888244 7001_ $$00000-0002-0538-175X$$aHamilton, Andrew D.$$b8$$eCorresponding author
000888244 773__ $$0PERI:(DE-600)3037398-0$$a10.1039/D0CB00086H$$n4$$p225-232$$tRSC chemical biology$$v1$$x2633-0679$$y2020
000888244 8564_ $$uhttps://juser.fz-juelich.de/record/888244/files/Sub-stoichiometric%20inhibition%20of%20IAPP%20aggregation%3A%20a%20peptidomimetic%20approach%20to%20anti-amyloid%20agents.pdf$$yOpenAccess
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