TY  - JOUR
AU  - Maity, Debabrata
AU  - Kumar, Sunil
AU  - AlHussein, Ruyof
AU  - Gremer, Lothar
AU  - Howarth, Madeline
AU  - Karpauskaite, Laura
AU  - Hoyer, Wolfgang
AU  - Magzoub, Mazin
AU  - Hamilton, Andrew D.
TI  - Sub-stoichiometric inhibition of IAPP aggregation: a peptidomimetic approach to anti-amyloid agents
JO  - RSC chemical biology
VL  - 1
IS  - 4
SN  - 2633-0679
CY  - Cambridge
PB  - The Royal Society of Chemistry
M1  - FZJ-2020-04793
SP  - 225-232
PY  - 2020
AB  - 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.
LB  - PUB:(DE-HGF)16
UR  - <Go to ISI:>//WOS:000616568300007
DO  - DOI:10.1039/D0CB00086H
UR  - https://juser.fz-juelich.de/record/888244
ER  -