Journal Article

FZJ-2020-04793

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Sub-stoichiometric inhibition of IAPP aggregation: a peptidomimetic approach to anti-amyloid agents

Maity, D. (Corresponding author) ; Kumar, S. ; AlHussein, R. ; Gremer, L.FZJ* ; Howarth, M. ; Karpauskaite, L. ; Hoyer, W.FZJ* ; Magzoub, M. ; Hamilton, A. D. (Corresponding author)

2020
The Royal Society of Chemistry Cambridge

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Please use a persistent id in citations: http://hdl.handle.net/2128/26804  doi:10.1039/D0CB00086H

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.

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Contributing Institute(s):

1. Strukturbiochemie (IBI-7)

Research Program(s):

1. 553 - Physical Basis of Diseases (POF3-553) (POF3-553)

Appears in the scientific report 2020

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