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

This title appears in the Scientific Report : 2020

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-base...

Personal Name(s):	Maity, Debabrata (Corresponding author)
	Kumar, Sunil / AlHussein, Ruyof / Gremer, Lothar / Howarth, Madeline / Karpauskaite, Laura / Hoyer, Wolfgang / Magzoub, Mazin / Hamilton, Andrew D. (Corresponding author)
Contributing Institute:	Strukturbiochemie; IBI-7
Published in:	RSC chemical biology, 1 (2020) 4, S. 225-232
Imprint:	Cambridge The Royal Society of Chemistry 2020
DOI:	10.1039/D0CB00086H
Document Type:	Journal Article
Research Program:	Physical Basis of Diseases
Link:	OpenAccess
	Publikationsportal JuSER

Please use the identifier: http://hdl.handle.net/2128/26804 in citations.
Please use the identifier: http://dx.doi.org/10.1039/D0CB00086H in citations.

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.