1. Islet Amyloid-Induced Cell Death and Bilayer Integrity Loss Share a Molecular Origin Targetable with Oligopyridylamide-Based α-Helical Mimetics.
- Author
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Kumar, Sunil, Schlamadinger, Diana E., Brown, Mark A., Dunn, Joanna M., Mercado, Brandon, Hebda, James A., Saraogi, Ishu, Rhoades, Elizabeth, Hamilton, Andrew D., and Miranker, Andrew D.
- Subjects
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CELL death , *LIPIDS , *TOXICITY testing , *LIPOSOMES , *STOICHIOMETRY - Abstract
Summary 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. [ABSTRACT FROM AUTHOR]
- Published
- 2015
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