Jump to main content
Jump to site search

Issue 4, 2020
Previous Article Next Article

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

Author affiliations

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

Back to tab navigation

Supplementary files

Article information


Submitted
04 Jun 2020
Accepted
03 Aug 2020
First published
19 Aug 2020

This article is Open Access

RSC Chem. Biol., 2020,1, 225-232
Article type
Paper

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

This article is licensed under a Creative Commons Attribution-NonCommercial 3.0 Unported Licence. Material from this article can be used in other publications provided that the correct acknowledgement is given with the reproduced material and it is not used for commercial purposes.

Reproduced material should be attributed as follows:

  • For reproduction of material from NJC:
    [Original citation] - Published by The Royal Society of Chemistry (RSC) on behalf of the Centre National de la Recherche Scientifique (CNRS) and the RSC.
  • For reproduction of material from PCCP:
    [Original citation] - Published by the PCCP Owner Societies.
  • For reproduction of material from PPS:
    [Original citation] - Published by The Royal Society of Chemistry (RSC) on behalf of the European Society for Photobiology, the European Photochemistry Association, and RSC.
  • For reproduction of material from all other RSC journals:
    [Original citation] - Published by The Royal Society of Chemistry.

Information about reproducing material from RSC articles with different licences is available on our Permission Requests page.


Social activity

Search articles by author

Spotlight

Advertisements