Dataset Information

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

ABSTRACT: Islet amyloid polypeptide (IAPP) is a hormone cosecreted with insulin. IAPP proceeds through a series of conformational changes from random coil to ?-sheet via transient ?-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, ?-helical mimetics, oligopyridylamides, was previously shown to target the membrane-bound ?-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.

SUBMITTER: Kumar S

PROVIDER: S-EPMC4384466 | biostudies-literature | 2015 Mar

REPOSITORIES: biostudies-literature

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

Kumar Sunil S Schlamadinger Diana E DE Brown Mark A MA Dunn Joanna M JM Mercado Brandon B Hebda James A JA Saraogi Ishu I Rhoades Elizabeth E Hamilton Andrew D AD Miranker Andrew D AD

Chemistry & biology 20150305 3

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 ...[more]

PMID: 25754474

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Dataset Information

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

Publications

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

Similar Datasets

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