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@ARTICLE{Maity:888244,
author = {Maity, Debabrata and Kumar, Sunil and AlHussein, Ruyof and
Gremer, Lothar and Howarth, Madeline and Karpauskaite, Laura
and Hoyer, Wolfgang and Magzoub, Mazin and Hamilton, Andrew
D.},
title = {{S}ub-stoichiometric inhibition of {IAPP} aggregation: a
peptidomimetic approach to anti-amyloid agents},
journal = {RSC chemical biology},
volume = {1},
number = {4},
issn = {2633-0679},
address = {Cambridge},
publisher = {The Royal Society of Chemistry},
reportid = {FZJ-2020-04793},
pages = {225-232},
year = {2020},
abstract = {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.},
cin = {IBI-7},
ddc = {540},
cid = {I:(DE-Juel1)IBI-7-20200312},
pnm = {553 - Physical Basis of Diseases (POF3-553)},
pid = {G:(DE-HGF)POF3-553},
typ = {PUB:(DE-HGF)16},
UT = {WOS:000616568300007},
doi = {10.1039/D0CB00086H},
url = {https://juser.fz-juelich.de/record/888244},
}