Resistance of nepetin and its analogs on the fibril formation of human islet amyloid polypeptide.

Abstract The self-aggregation of human islet amyloid polypeptide (hIAPP) into toxic oligomers and fibrils is closely linked to the pathogenesis of type II diabetes mellitus. Inhibitors can resist hIAPP misfolding, and the resistance can be considered an alternative therapeutic strategy for this disease. Flavones have been applied in the field of diabetes research, however, the inhibition mechanism of many compounds on the fibril formation of related pathogenic peptides remains unclear. In this work, four flavones, namely, nepetin (1), genkwanin (2), luteolin (3), and apigenin (4), were used to impede the peptide aggregation of hIAPP and compared with that on Aβ protein, which is correlated with Alzheimer's disease. Results indicated that the four flavones effectively inhibited the aggregation of the two peptides and mostly dispersed the mature fibrils to monomers. The interactions of flavones with the two peptides demonstrated a spontaneous and exothermic reaction through predominant hydrophobic and hydrogen bonding interactions. The binding affinities of 1 and 3 were stronger than those of 2 and 4 possibly because of the difference in the substituent groups of these molecules. These flavones could also decrease membrane leakage and upregulate cell viability by reducing the formation of toxic oligomers. Moreover, the performance of these flavones in terms of binding affinity, cellular viability, and decreased oligomerization was better on hIAPP than on Aβ. This work offered valuable data about these flavones as prospective therapeutic agents against relevant diseases.