期刊
PROTEIN AND PEPTIDE LETTERS
卷 22, 期 5, 页码 470-479出版社
BENTHAM SCIENCE PUBL LTD
DOI: 10.2174/0929866522666150302125218
关键词
Biological activity; hepatocellular carcinoma; human endostatin; liver-targeting peptide; missense mutation; molecular dynamic simulation
资金
- National Science and Technology Key Projects National- a major new drug projects [2013ZX09103003-003]
A missense mutation of Aspartic to Asparagine acid in 113 position of liver-targeting peptide CSP I-plus modified rEndostatin (rES-CSP) happened unexpectedly results in the changes of protein secondary structure and a reduced bioactivity. With the aim to clarify the structure-function relationships featuring the fuse protein rES-CSP, the three-dimensional structural models of wild-type and mutant D113NrES-CSP were constructed by template-based modeling approach. To evaluate the effect of the single mutation on rES-CSP stability, the molecular dynamic simulation was used to reveal the structural and dynamic characteristics. Analysis on the bioactivity were conducted using a number of validated in vitro assays including proliferation, migration, cell cycle and apoptosis in HepG2 cells. Results showed that the mutant rES-CSP reduce the stability and loss of function, and the wild-type rES-CSP could both bind to the normal liver cells Chang's and the hepatoma cells HepG2 but significantly higher than non-targeted rEndostatin. rES-CSP could inhibit the proliferation of hepatoma cells in a dose-dependent manner, and increase the proportion of G1 phase, reduce the proportion of S phase, promote the apoptosis on hepatoma cells. These results make a further complement of the mechanisms by which the fuse protein rES-CSP would provide a feasible and convenient approach to produce liver-targeting drugs for treatment of the liver disease.
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