Folded small molecule manipulation of islet amyloid polypeptide

Chemistry & Biology
Sunil KumarAndrew D Miranker

Abstract

Islet amyloid polypeptide (IAPP) is a hormone cosecreted with insulin by pancreatic β cells. Upon contact with lipid bilayers, it is stabilized into a heterogeneous ensemble of structural states. These processes are associated with gains of function, including catalysis of β sheet-rich amyloid formation, cell membrane penetration, loss of membrane integrity, and cytotoxicity. These contribute to the dysfunction of β cells, a central component in the pathology and treatment of diabetes. To gain mechanistic insight into these phenomena, a related series of substituted oligoquinolines were designed. These inhibitors are unique in that they have the capacity to affect both solution- and phospholipid bilayer-catalyzed IAPP self-assembly. Importantly, we show that this activity is associated with the oligoquinoline's capacity to irreversibly adopt a noncovalent fold. This suggests that compact foldamer scaffolds, such as oligoquinoline, are an important paradigm for conformational manipulation of disordered protein state.

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Citations

Dec 10, 2015·Journal of Diabetes Research·Amit PithadiaAyyalusamy Ramamoorthy
Aug 22, 2014·The Biochemical Journal·Katelyn M SeitherJames Shorter
Nov 18, 2015·Journal of Diabetes Research·Phuong Trang NguyenSteve Bourgault
Apr 16, 2016·Chemical Communications : Chem Comm·Sunil KumarAndrew D Miranker
Apr 26, 2016·Nature Communications·Sunil KumarAndrew D Miranker
Jul 30, 2016·Chembiochem : a European Journal of Chemical Biology·Pradeep K MandalIvan Huc
Jan 6, 2018·Organic & Biomolecular Chemistry·Sunil KumarAndrew D Hamilton

Related Concepts

Particle Size
Quinolines
Surface Properties
Islet Amyloid Polypeptide Precursor
Amyloid
Plasma Membrane
Diabetes
Hormones
Insulin
Islets of Langerhans

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