Study of the kinetics and mechanism of ferrocene-tripeptide inhibiting insulin aggregation

Peptides are gaining popularity as neurodegenerative disease-targeting drugs due to their medicinal value and simplicity in the biomedical and pharmaceutical industry fields. Herein, based on previously studied ferrocene-modified dipeptide (Fc-dipeptide) ferrocene-L-Phe-L-Phe (Fc-FF), we developed four Fc-tripeptides, i.e., Fc-FFY, Fc-FFF, Fc-FFD, and Fc-FFK, to further study the anti-amyloid effects of peptide-based inhibitors. The results showed that all Fc-tripeptides inhibited the formation of insulin fibrils in a dose-dependent manner more responsive than Fc-FF. Meanwhile, Fc-FFY and Fc-FFF had a more significant inhibitory effect on insulin amyloid fibrillation than Fc-FFD and Fc-FFK. In addition, molecular dynamics simulations indicated that Fc-FFY and Fc-FFF were contacted mainly with the hydrophobic core residues of insulin chain A and chain B, respectively. The research indicated that Fc-tripeptides have potential effects in preventing protein misfolding diseases and could be further used to design effective anti-amyloidosis compounds.