2 research outputs found
Modeling the Interface between Islet Amyloid Polypeptide and Insulin-Based Aggregation Inhibitors: Correlation to Aggregation Kinetics and Membrane Damage
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
(10Ă— 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