Folded small molecule manipulation of islet amyloid polypeptide.

ABSTRACT: Islet amyloid polypeptide (IAPP) is a hormone cosecreted with insulin by pancreatic ? 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 ? sheet-rich amyloid formation, cell membrane penetration, loss of membrane integrity, and cytotoxicity. These contribute to the dysfunction of ? 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.

SUBMITTER: Kumar S 

PROVIDER: S-EPMC4139143 | biostudies-literature | 2014 Jun

REPOSITORIES: biostudies-literature