Modeling the Interface between Islet Amyloid Polypeptide and Insulin-Based Aggregation Inhibitors: Correlation to Aggregation Kinetics and Membrane Damage

• Published in: Journal of chemical information and modeling Vol. 52; no. 5; pp. 1298 - 1307
• Main Authors: Figueroa, Hector, Peddi, Durgaprasad, Osborne, Joshua M., Wilson, Brenan M., Pesaru, Ranadheer Reddy, Kurva, Balakrishna, Ramaraju, Swathi, Milletti, Maria C., Heyl, Deborah L.
• Format: Journal Article
• Language: English
• Published: Washington, DC American Chemical Society 25.05.2012
• Subjects: Amino Acid Sequence; Biological and medical sciences; Cell Membrane - drug effects; Chemical compounds; Chemical, physic and infectious diseases; Chemistry; Classical and quantum physics: mechanics and fields; Colloidal state and disperse state; Cytotoxicity; Diabetes; Exact sciences and technology; Functional analytical methods; General and physical chemistry; Humans; Insulin; Insulin - chemistry; Insulin - pharmacology; Islet Amyloid Polypeptide - antagonists & inhibitors; Kinetics; Medical sciences; Membranes; Models, Molecular; Molecular Sequence Data; Occupational medicine; Physics; Polypeptides; Protein Structure, Secondary; Proteins - chemical synthesis; Proteins - chemistry; Proteins - pharmacology; Public health. Hygiene-occupational medicine; Quantum mechanics; Quantum Theory; Aggregation; Interfaces; Membranes; Density functional; Polypeptides; Toxicity; Cytotoxicity; Amyloid; Modelling; Kinetics; Man; Damage
• ISSN: 1549-9596; 1549-960X
• DOI: 10.1021/ci300119c

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.