Triterpenoids impede the fibrillation and cytotoxicity of human islet amyloid polypeptide

The inhibition of human islet amyloid polypeptide (hIAPP) deposition to block its toxicity is an important strategy for the prevention and treatment of type II diabetes mellitus (T2DM). Natural compounds with pharmacological properties and low toxicity can serve as a good point to discover potential inhibitors of protein misfolding, which may be useful for the treatment of various amyloidosis-related diseases. Previous studies have reported that triterpenoids, such as maslinic acid (MA) and momordicin I (MI), can modulate glucose metabolism partially by reducing insulin resistance. However, the internal antidiabetic mechanism of these triterpenoids remains unclear. In this study, we examined the inhibition and disaggregation of MA and its isomer MI on the fibrillation of hIAPP using various experimental and computational approaches. The assembly behaviors and peptide-induced cytotoxicity of hIAPP could be effectively resisted by MA and MI. Moreover, the interaction of the two triterpenoids with hIAPP displayed a spontaneous and exothermic process. Moreover, molecular dynamics simulation results of different peptides revealed that MA and MI could bind to Asn and other non-polar residues near the core C-terminal region and reduce the oligomerization of hIAPP. The binding affinity was predominantly contributed by hydrophobic, electrostatic and hydrogen bonding interactions. The present work provides valuable data for MA and MI to treat T2DM and amyloidosis-related diseases.