title: Folded small molecule manipulation of islet amyloid polypeptide.
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.
authors.affiliation: Department of Molecular Biophysics and Biochemistry, Yale University, 260 Whitney Avenue, New Haven, CT 06520-8114, USA.
authors.forename: Sunil
authors.initials: S
authors.lastname: Kumar
authors.affiliation: Department of Molecular Biophysics and Biochemistry, Yale University, 260 Whitney Avenue, New Haven, CT 06520-8114, USA.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Brown
authors.affiliation: Department of Molecular Biophysics and Biochemistry, Yale University, 260 Whitney Avenue, New Haven, CT 06520-8114, USA.
authors.forename: Abhinav
authors.initials: A
authors.lastname: Nath
authors.affiliation: Department of Molecular Biophysics and Biochemistry, Yale University, 260 Whitney Avenue, New Haven, CT 06520-8114, USA. Electronic address: andrew.miranker@yale.edu.
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Miranker
mesh_terms: D058228:Islet Amyloid Polypeptide / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism*; D007700:Kinetics; D008958:Models, Molecular; D008968:Molecular Conformation; D010316:Particle Size; D011804:Quinolines / Q000737:chemistry* / Q000494:pharmacology*; D013499:Surface Properties
chemical_list: D058228:Islet Amyloid Polypeptide; D011804:Quinolines