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Ferrocene-modified peptides as inhibitors against insulin amyloid aggregation based on molecular simulation

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Abstract

Peptide-based inhibitors have gradually been implicated as drugs for treating protein folding diseases because of their favorable biocompatibility and low toxicity. To develop potential therapeutic strategies for amyloid-related disorders, short peptides modified by Fc, ferrocene-L-Phe-L-Phe (Fc-FF) and ferrocene-L-Phe-L-Tyr (Fc-FY), were used as inhibitors for the investigation of the aggregation behavior of insulin. Firstly, molecular docking predicted the interaction between both Fc-peptides and insulin. Then, the experimental data from ThT, DLS, CD and TEM confirmed that Fc-FF and Fc-FY effectively inhibited insulin fibrillation and disaggregated mature insulin fibrils. Based on a dose-dependent manner, both Fc-peptides can strongly inhibit insulin fibrillation, extend lag phase time, reduce final fibril formation (beyond 99% by Fc-peptides of 400 µM), decrease the formation of high-content β-sheet structures and reduce the size of insulin fibrils. Additionally, we found that compared with Fc-FY, the better inhibitory effect of Fc-FF at concentration below 400 µM was mainly resulted from the difference in π–π interaction and hydrogen bonds between Fc-peptides and insulin, according to molecular dynamics analysis. Our results demonstrated Fc-peptides, Fc-FF and Fc-FY, may play effective roles in the development of new therapeutic drugs or strategies for amyloid-related disorders, and the molecular dynamics simulation may be helpful for designing appropriate inhibitors of anti-amyloidosis diseases.

Graphical abstract: Ferrocene-modified peptides as inhibitors against insulin amyloid aggregation based on molecular simulation

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Supplementary files

Article information


Submitted
15 Jan 2020
Accepted
16 Mar 2020
First published
17 Mar 2020

J. Mater. Chem. B, 2020, Advance Article
Article type
Paper

Ferrocene-modified peptides as inhibitors against insulin amyloid aggregation based on molecular simulation

P. Yao, J. Zhang, S. You, W. Qi, R. Su and Z. He, J. Mater. Chem. B, 2020, Advance Article , DOI: 10.1039/D0TB00144A

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