title: Islet amyloid-induced cell death and bilayer integrity loss share a molecular origin targetable with oligopyridylamide-based α-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 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.
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: Diana E
authors.initials: DE
authors.lastname: Schlamadinger
authors.affiliation: Department of Chemistry, Yale University, 225 Prospect Street, New Haven, CT 06520-8107, 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: Joanna M
authors.initials: JM
authors.lastname: Dunn
authors.affiliation: Department of Chemistry, Yale University, 225 Prospect Street, New Haven, CT 06520-8107, USA.
authors.forename: Brandon
authors.initials: B
authors.lastname: Mercado
authors.affiliation: Department of Chemistry, Amherst College, Amherst, MA 01002-5000, USA.
authors.forename: James A
authors.initials: JA
authors.lastname: Hebda
authors.affiliation: Department of Chemistry, Indian Institute of Science Education and Research, Bhopal, MP 462066, India.
authors.forename: Ishu
authors.initials: I
authors.lastname: Saraogi
authors.affiliation: Department of Molecular Biophysics and Biochemistry, Yale University, 260 Whitney Avenue, New Haven, CT 06520-8114, USA.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Rhoades
authors.affiliation: Chemistry Research Laboratory, University of Oxford, 12 Mansfield Road, Oxford OX1 3TA, UK.
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Hamilton
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: D000577:Amides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000595:Amino Acid Sequence; D000818:Animals; D017209:Apoptosis / Q000502:physiology; D040761:Biomimetic Materials / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D015195:Drug Design; D006801:Humans; D007340:Insulinoma; D058228:Islet Amyloid Polypeptide / Q000737:chemistry* / Q000378:metabolism*; D008051:Lipid Bilayers / Q000737:chemistry / Q000378:metabolism; D008081:Liposomes / Q000737:chemistry / Q000378:metabolism; D008560:Membrane Fluidity / Q000502:physiology; D008872:Microwaves; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010190:Pancreatic Neoplasms; D017433:Protein Structure, Secondary; D011725:Pyridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D013329:Structure-Activity Relationship
chemical_list: D000577:Amides; D058228:Islet Amyloid Polypeptide; D008051:Lipid Bilayers; D008081:Liposomes; D011725:Pyridines