Islet amyloid-induced cell death and bilayer integrity loss share a molecular origin targetable with oligopyridylamide-based α-helical mimetics

Chemistry & Biology
Sunil KumarAndrew D Miranker

Abstract

Islet amyloid polypeptide (IAPP) is a hormone cosecreted with insulin. IAPP proceeds through a series of conformational changes from random coil to β-sheet via transient α-helical intermediates. An unknown subset of these events are associated with seemingly disparate gains of function, including catalysis of self-assembly, membrane penetration, loss of membrane integrity, mitochondrial localization, and finally, cytotoxicity, a central component of diabetic pathology. A series of small molecule, α-helical mimetics, oligopyridylamides, was previously shown to target the membrane-bound α-helical oligomeric intermediates of IAPP. In this study, we develop an improved, microwave-assisted synthesis of oligopyridylamides. A series of designed tripyridylamides demonstrate that lipid-catalyzed self-assembly of IAPP can be deliberately targeted. In addition, these molecules affect IAPP-induced leakage of synthetic liposomes and cellular toxicity in insulin-secreting cells. The tripyridylamides inhibit these processes with identical rank orders of effectiveness. This indicates a common molecular basis for the disparate set of observed effects of IAPP.

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Citations

Jul 1, 2016·Journal of Medicinal Chemistry·Ranganath GopalakrishnanEric Valeur
Mar 9, 2017·Journal of the American Chemical Society·Sunil Kumar, Andrew D Hamilton
Apr 16, 2016·Chemical Communications : Chem Comm·Sunil KumarAndrew D Miranker
Aug 16, 2017·Journal of Molecular Endocrinology·Daniel RaleighAnne Clark
Apr 26, 2016·Nature Communications·Sunil KumarAndrew D Miranker
Mar 3, 2019·Chemistry : a European Journal·Debabrata MaityAndrew D Hamilton
Jan 26, 2016·Chembiochem : a European Journal of Chemical Biology·Michal JewginskiCameron David Mackereth
Jan 6, 2018·Organic & Biomolecular Chemistry·Sunil KumarAndrew D Hamilton
Oct 21, 2016·Chembiochem : a European Journal of Chemical Biology·Pradeep K MandalIvan Huc
Jan 12, 2021·European Journal of Medicinal Chemistry·Sergio AlgarRosario González-Muñiz
Jan 23, 2021·Chemistry : a European Journal·Tim SeedorfDanny Solga
Apr 13, 2018·Journal of the American Chemical Society·Sunil KumarAndrew D Hamilton
Jul 7, 2020·Langmuir : the ACS Journal of Surfaces and Colloids·Qiuchen ZhengNoel D Lazo
Oct 24, 2017·Journal of the American Chemical Society·Sunil KumarAndrew D Hamilton
Aug 29, 2019·Journal of the American Chemical Society·Zachary A LevineJoan-Emma Shea
Aug 31, 2021·RSC Chemical Biology·Debabrata MaityAndrew D Hamilton
Oct 13, 2021·Journal of Cellular Physiology·Carine MarmentiniMirian A Kurauti

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