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

Sunil Kumar, Diana E. Schlamadinger, Mark A. Brown, Joanna M. Dunn, Brandon Mercado, James A. Hebda, Ishu Saraogi, Elizabeth Rhoades, Andrew D. Hamilton, Andrew D. Miranker

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Article number3006
Pages (from-to)369-378
Number of pages10
JournalChemistry and Biology
Volume22
Issue number3
DOIs
StatePublished - Mar 19 2015

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmacology
  • Drug Discovery
  • Clinical Biochemistry

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    Kumar, S., Schlamadinger, D. E., Brown, M. A., Dunn, J. M., Mercado, B., Hebda, J. A., Saraogi, I., Rhoades, E., Hamilton, A. D., & Miranker, A. D. (2015). Islet amyloid-induced cell death and bilayer integrity loss share a molecular origin targetable with oligopyridylamide-based α-helical mimetics. Chemistry and Biology, 22(3), 369-378. [3006]. https://doi.org/10.1016/j.chembiol.2015.01.006