Issue 4, 2020

Sub-stoichiometric inhibition of IAPP aggregation: a peptidomimetic approach to anti-amyloid agents

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.

Graphical abstract: Sub-stoichiometric inhibition of IAPP aggregation: a peptidomimetic approach to anti-amyloid agents

Supplementary files

Article information

Article type
Paper
Submitted
04 6月 2020
Accepted
03 8月 2020
First published
19 8月 2020
This article is Open Access
Creative Commons BY-NC license

RSC Chem. Biol., 2020,1, 225-232

Sub-stoichiometric inhibition of IAPP aggregation: a peptidomimetic approach to anti-amyloid agents

D. Maity, S. Kumar, R. AlHussein, L. Gremer, M. Howarth, L. Karpauskaite, W. Hoyer, M. Magzoub and A. D. Hamilton, RSC Chem. Biol., 2020, 1, 225 DOI: 10.1039/D0CB00086H

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