%0 Journal Article
%A Maity, Debabrata
%A Kumar, Sunil
%A AlHussein, Ruyof
%A Gremer, Lothar
%A Howarth, Madeline
%A Karpauskaite, Laura
%A Hoyer, Wolfgang
%A Magzoub, Mazin
%A Hamilton, Andrew D.
%T Sub-stoichiometric inhibition of IAPP aggregation: a peptidomimetic approach to anti-amyloid agents
%J RSC chemical biology
%V 1
%N 4
%@ 2633-0679
%C Cambridge
%I The Royal Society of Chemistry
%M FZJ-2020-04793
%P 225-232
%D 2020
%X Membrane-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.
%F PUB:(DE-HGF)16
%9 Journal Article
%U <Go to ISI:>//WOS:000616568300007
%R 10.1039/D0CB00086H
%U https://juser.fz-juelich.de/record/888244