A Novel Pentapeptide Inhibitor Reduces Amyloid Deposit Formation by Direct Interaction with hIAPP
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...
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| Main Authors: | , , , , |
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| Format: | Article |
| Language: | English |
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Wiley
2019-01-01
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| Series: | International Journal of Endocrinology |
| Online Access: | http://dx.doi.org/10.1155/2019/9062032 |
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| author | Yue Shi Wu Lv Ao Jiao Chengshuo Zhang Jialin Zhang |
| author_facet | Yue Shi Wu Lv Ao Jiao Chengshuo Zhang Jialin Zhang |
| author_sort | Yue Shi |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-0142fc7a311649b79acefc2d2badaa17 |
| institution | OA Journals |
| issn | 1687-8337 1687-8345 |
| language | English |
| publishDate | 2019-01-01 |
| publisher | Wiley |
| record_format | Article |
| series | International Journal of Endocrinology |
| spelling | doaj-art-0142fc7a311649b79acefc2d2badaa172025-08-20T02:01:34ZengWileyInternational Journal of Endocrinology1687-83371687-83452019-01-01201910.1155/2019/90620329062032A Novel Pentapeptide Inhibitor Reduces Amyloid Deposit Formation by Direct Interaction with hIAPPYue Shi0Wu Lv1Ao Jiao2Chengshuo Zhang3Jialin Zhang4Hepatobiliary Surgery Department and Unit of Organ Transplantation, The First Hospital of China Medical University, Shenyang 110001, ChinaHepatobiliary Surgery Department and Unit of Organ Transplantation, The First Hospital of China Medical University, Shenyang 110001, ChinaHepatobiliary Surgery Department and Unit of Organ Transplantation, The First Hospital of China Medical University, Shenyang 110001, ChinaHepatobiliary Surgery Department and Unit of Organ Transplantation, The First Hospital of China Medical University, Shenyang 110001, ChinaHepatobiliary Surgery Department and Unit of Organ Transplantation, The First Hospital of China Medical University, Shenyang 110001, ChinaBackgrounds. 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.http://dx.doi.org/10.1155/2019/9062032 |
| spellingShingle | Yue Shi Wu Lv Ao Jiao Chengshuo Zhang Jialin Zhang A Novel Pentapeptide Inhibitor Reduces Amyloid Deposit Formation by Direct Interaction with hIAPP International Journal of Endocrinology |
| title | A Novel Pentapeptide Inhibitor Reduces Amyloid Deposit Formation by Direct Interaction with hIAPP |
| title_full | A Novel Pentapeptide Inhibitor Reduces Amyloid Deposit Formation by Direct Interaction with hIAPP |
| title_fullStr | A Novel Pentapeptide Inhibitor Reduces Amyloid Deposit Formation by Direct Interaction with hIAPP |
| title_full_unstemmed | A Novel Pentapeptide Inhibitor Reduces Amyloid Deposit Formation by Direct Interaction with hIAPP |
| title_short | A Novel Pentapeptide Inhibitor Reduces Amyloid Deposit Formation by Direct Interaction with hIAPP |
| title_sort | novel pentapeptide inhibitor reduces amyloid deposit formation by direct interaction with hiapp |
| url | http://dx.doi.org/10.1155/2019/9062032 |
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