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

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, , for targeting membrane bound IAPP. completely inhibits the aggregation of IAPP at doses of 0.2 equivalents. is also effective at similarly low doses for inhibition of seed-catalyzed secondary nucleation. An NMR based study demonstrates that modulates IAPP self-assembly by stabilizing and/or perturbing the N-terminus helix conformation. at substoichiometric doses rescues rat insulinoma cells from IAPP-mediated cytotoxicity. Most importantly, 0.2 equivalents of disaggregate preformed oligomers and fibrils and can reverse cytotoxicity by modulating toxic preformed oligomers and fibrils of IAPP into non-toxic conformations.