title: Modeling the interface between islet amyloid polypeptide and insulin-based aggregation inhibitors: correlation to aggregation kinetics and membrane damage.
abstract: Human islet amyloid polypeptide (hIAPP) forms cytotoxic fibrils in type-2 diabetes and insulin is known to inhibit formation of these aggregates. In this study, a series of insulin-based inhibitors were synthesized and assessed for their ability to slow aggregation and impact hIAPP-induced membrane damage. Computational studies were employed to examine the underlying mechanism of inhibition. Overall, all compounds were able to slow aggregation at sufficiently high concentrations (10× molar excess); however, only two peptides showed any inhibitory capability at the 1:1 molar ratio (EALYLV and VEALYLV). The results of density functional calculations suggest this is due to the strength of a salt bridge formed with the Arg11 side chain of hIAPP and the inhibitors' ability to span from the Arg11 to past the Phe15 residue of hIAPP, blocking one of the principal amyloidogenic regions of the molecule. Unexpectedly, slowing fibrillogenesis actually increased damage to lipid membranes, suggesting that the aggregation process itself, rather than the fibrilized peptide, may be the cause of cytotoxicity in vivo.
authors.affiliation: Chemistry Department, Eastern Michigan University, Ypsilanti, Michigan 48197, USA.
authors.forename: Hector
authors.initials: H
authors.lastname: Figueroa
authors.forename: Durgaprasad
authors.initials: D
authors.lastname: Peddi
authors.forename: Joshua M
authors.initials: JM
authors.lastname: Osborne
authors.forename: Brenan M
authors.initials: BM
authors.lastname: Wilson
authors.forename: Ranadheer Reddy
authors.initials: RR
authors.lastname: Pesaru
authors.forename: Balakrishna
authors.initials: B
authors.lastname: Kurva
authors.forename: Swathi
authors.initials: S
authors.lastname: Ramaraju
authors.forename: Maria C
authors.initials: MC
authors.lastname: Milletti
authors.forename: Deborah L
authors.initials: DL
authors.lastname: Heyl
mesh_terms: D000595:Amino Acid Sequence; D002462:Cell Membrane / Q000187:drug effects*; D006801:Humans; D007328:Insulin / Q000737:chemistry / Q000494:pharmacology; D058228:Islet Amyloid Polypeptide / Q000037:antagonists & inhibitors*; D007700:Kinetics; D008958:Models, Molecular; D008969:Molecular Sequence Data; D017433:Protein Structure, Secondary; D011506:Proteins / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011789:Quantum Theory
chemical_list: D007328:Insulin; D058228:Islet Amyloid Polypeptide; D011506:Proteins