Inhibiting Human Calcitonin Fibril Formation with Its Most Relevant Aggregation-Resistant Analog

Yi Ting Chen, Kai Wei Hu, Bo Jie Huang, Chian Hui Lai, Ling Hsien Tu*

*此作品的通信作者

研究成果: 雜誌貢獻期刊論文同行評審

5 引文 斯高帕斯(Scopus)

摘要

The most common obstacles to the development of therapeutic polypeptides are peptide stability and aggregation. Human calcitonin (hCT) is a 32-residue hormone polypeptide secreted from the C-cells of the thyroid gland and is responsible for calcium and phosphate regulation in the blood. hCT reduces calcium levels by inhibiting the activity of osteoclasts, which are bone cells that are mainly responsible for breaking down the bone tissue or decreasing the resorption of calcium from the kidneys. Thus, calcitonin injection has been used to treat osteoporosis and Paget's disease of bone. hCT is an aggregation-prone peptide with a high tendency to form amyloid fibrils. As a result, salmon calcitonin (sCT), which is different from hCT at 16-residue positions and has a lower propensity to aggregate, has been chosen as a clinical substitute for hCT. However, significant side effects, including immune reactions, have been shown with the use of sCT injection. In this study, we found that two residues, Tyr-12 and Asn-17, play key roles in inducing the fibrillization of hCT. Double mutation of hCT at these two crucial sites could greatly enhance its resistance to aggregation and provide a peptide-based inhibitor to prevent amyloid formation by hCT. Double-mutated hCT retains its ability to interact with its receptor in vivo. These findings suggest that this variant of hCT would serve as a valuable therapeutic alternative to sCT.

原文英語
頁(從 - 到)10171-10180
頁數10
期刊Journal of Physical Chemistry B
123
發行號48
DOIs
出版狀態已發佈 - 2019 十二月 5

ASJC Scopus subject areas

  • 物理與理論化學
  • 表面、塗料和薄膜
  • 材料化學

指紋

深入研究「Inhibiting Human Calcitonin Fibril Formation with Its Most Relevant Aggregation-Resistant Analog」主題。共同形成了獨特的指紋。

引用此