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Int J Endocrinol. 2019 Jan 29;2019:9062032. doi: 10.1155/2019/9062032. eCollection 2019.

A Novel Pentapeptide Inhibitor Reduces Amyloid Deposit Formation by Direct Interaction with hIAPP.

Author information

1
Hepatobiliary Surgery Department and Unit of Organ Transplantation, The First Hospital of China Medical University, Shenyang 110001, China.
2
Department of Geriatric Surgery, The First Hospital of China Medical University, Shenyang 110001, China.
3
Department of General Surgery (VIP Ward), Liaoning Cancer Hospital & Institute, Cancer Hospital of China Medical University, Shenyang 110001, China.

Abstract

Backgrounds:

The presence of amyloid deposits of human islet amyloid polypeptide (hIAPP) in islet β-cells has been associated with type 2 diabetes occurrence and islet graft failure. Self-assembly into oligomers and fibrils during the process of aggregation by hIAPP can lead to failure and depletion of β-cells. Studies have shown that some critical regions of hIAPP might contribute to the aggregation. Thus, many studies focused on finding the effective molecules, especially the short-peptide inhibitors, that bind to these regions and disrupt the aggregation of hIAPP. In the present study, a novel pentapeptide inhibitor Phe-Leu-Pro-Asn-Phe (FLPNF) was designed and its effectiveness on the inhibition of the formation of amyloid deposits was examined.

Methods:

The binding mode between FLPNF and hIAPP was performed using molecular docking. The effectiveness of FLPNF on inhibiting hIAPP amyloid aggregation was tested by Thioflavin T (ThT) staining. Furthermore, negative stain electron microscopy was used to observe hIAPP fibrils. A biolayer interferometry analysis was used to identify the interaction between FLPNF and hIAPP. In addition, the cytotoxicity toward INS-1 cells was tested by a cell proliferation assay.

Results:

FLPNF was predicted to have a compact conformation to bind at the site of hIAPP. FLPNF strongly inhibited the amyloid aggregation of hIAPP at a 10 : 1 molar ratio in vitro. Coincubation of FLPNF with hIAPP decreased the amount of hIAPP fibrils. Furthermore, a direct interaction between FLPNF and hIAPP was confirmed. FLPNF could also decrease the cytotoxic effect of hIAPP.

Conclusions:

The novel pentapeptide inhibitor FLPNF was constructed and inhibited the aggregation through direct binding to hIAPP. It is considered a suitable inhibitor for hIAPP amyloid deposit formation.

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