文献类型：期刊文献

英文题名：Enhancement of the Pharmacological Efficacy of FGF-21 by Genetic Modification and PEGylation

作者：Ye, Xianlong[1];Qi, Jianying[1];Sun, Guopeng[2];Ren, Guiping[1];Zhu, Shenglong[1];Wu, Yunzhou[1];Yu, Dan[1];Zhao, Jingzhuang[3];Liu, Mingyao[1];Li, Deshan[1,4]

第一作者：Ye, Xianlong

通讯作者：Ren, GP[1]

机构：[1]Northeast Agr Univ, Coll Life Sci, Biopharmaceut Lab, Harbin 150030, Heilongjiang, Peoples R China;[2]Xinxiang Univ, Coll Life Sci & Biotechnol, Biotechnol Res Ctr, Xinxiang 453003, Peoples R China;[3]Chinese Acad Fishery Sci, Heilongjiang River Fishery Res Inst, Harbin 150070, Peoples R China;[4]Northeast Agr Univ, Key Lab Agr Biol Funct Gene, Harbin 150030, Heilongjiang, Peoples R China

第一机构：Northeast Agr Univ, Coll Life Sci, Biopharmaceut Lab, Harbin 150030, Heilongjiang, Peoples R China

通讯机构：[1]corresponding author), Northeast Agr Univ, Coll Life Sci, Biopharmaceut Lab, 59 Mucai St, Harbin 150030, Heilongjiang, Peoples R China.

年份：2013

卷号：14

期号：15

起止页码：1287-1298

外文期刊名：CURRENT PHARMACEUTICAL BIOTECHNOLOGY

收录：;WOS:【SCI-EXPANDED(收录号:WOS:000209409000008)】；

语种：英文

外文关键词：Diabetes; FGF-21; genetic modification; immunogenicity; PEGylation; stability

摘要：FGF-21 is a potential candidate for the treatment of type 2 diabetes mellitus. However, the clinical application of wild-type human FGF-21 is challenging due to some limitations, such as its poor hypoglycemic potency and short in vivo half-life. In this paper, we have produced an FGF-21 mutant (ahmFGF-21) by exchanging the functional domain of hFGF-21 with that of mFGF-21 to improve the potency of FGF-21. Results showed that the ahmFGF-21 protein was more potent than wild-type hFGF-21 in stimulating glucose uptake in vitro and lowering blood glucose levels of diabetic animals. To decrease its immunogenicity and increase its biostability, the N-terminus of ahmFGF-21 was modified in a site-specific manner with 20kDa mPEG-propionaldehyde (mPEG-ALD). We found that the preservation time of ahmFGF-21 in vitro was significantly prolonged after PEGylation. The serum antibody levels against ahmFGF-21 in immunized rabbits with the PEGylated ahmFGF-21 were significantly reduced than those with the unmodified ahmFGF-21, and the target protein concentration in the rabbits administrated with the PEGylated ahmFGF-21 increased 9.5-fold higher than that of the unmodified ahmFGF-21. The animal experimental results showed that PEGylation of ahmFGF-21 enhanced the hypoglycemic effect in diabetic mice. These results suggest that the in vitro and in vivo hypoglycemic effects of FGF-21 are significantly enhanced by genetic modification and the metabolic pharmacology of FGF-21 in type 2 diabetic mice is improved by PEGylation at a specific site.