Modeling the interface between islet amyloid polypeptide and insulin-based aggregation inhibitors: correlation to...

Area of Science:

• Biochemistry
• Molecular Biology
• Computational Chemistry

Background:

• Human islet amyloid polypeptide (hIAPP) aggregation into cytotoxic fibrils is implicated in type-2 diabetes.
• Insulin is known to inhibit hIAPP aggregation, but the mechanisms and effectiveness of insulin-based inhibitors require further investigation.

Purpose of the Study:

• To synthesize and evaluate insulin-based inhibitors for their efficacy in slowing hIAPP aggregation.
• To assess the impact of these inhibitors on hIAPP-induced membrane damage.
• To elucidate the mechanism of inhibition using computational studies.

Main Methods:

• Synthesis of insulin-based peptide inhibitors.
• Assessment of aggregation inhibition and membrane damage assays.
• Density functional theory calculations for mechanistic insights.

Main Results:

• All tested compounds slowed hIAPP aggregation at a 10× molar excess.
• Two peptides, EALYLV and VEALYLV, demonstrated inhibitory capability at a 1:1 molar ratio.
• Computational studies indicated inhibition is mediated by salt bridge formation and blocking key amyloidogenic regions.
• Slowing fibrillogenesis unexpectedly enhanced lipid membrane damage.

Conclusions:

• Specific insulin-based peptides can inhibit hIAPP aggregation, offering potential therapeutic avenues for type-2 diabetes.
• The mechanism involves specific interactions with hIAPP residues, blocking aggregation.
• The aggregation process, not just the fibrils, may be the primary cause of hIAPP cytotoxicity in vivo.