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

Debabrata Maity, Sunil Kumar, Ruyof Alhussein, Lothar Gremer, Madeline Howarth, Laura Karpauskaite, Wolfgang Hoyer, Mazin Magzoub, Andrew D. Hamilton

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Pages (from-to)225-232
Number of pages8
JournalRSC Chemical Biology
Volume1
Issue number4
DOIs
StatePublished - Oct 2020

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Biochemistry, Genetics and Molecular Biology (miscellaneous)
  • Chemistry (miscellaneous)

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