title: Enhancement of the pharmacological efficacy of FGF-21 by genetic modification and PEGylation.
abstract: 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 sitespecific manner with 20 kDa 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.
authors.forename: Xianlong
authors.initials: X
authors.lastname: Ye
authors.forename: Jianying
authors.initials: J
authors.lastname: Qi
authors.forename: Guopeng
authors.initials: G
authors.lastname: Sun
authors.forename: Guiping
authors.initials: G
authors.lastname: Ren
authors.forename: Shenglong
authors.initials: S
authors.lastname: Zhu
authors.forename: Yunzhou
authors.initials: Y
authors.lastname: Wu
authors.forename: Dan
authors.initials: D
authors.lastname: Yu
authors.forename: Jingzhuang
authors.initials: J
authors.lastname: Zhao
authors.forename: Mingyao
authors.initials: M
authors.lastname: Liu
authors.affiliation: Biopharmaceutical Lab, College of Life Science, Northeast Agricultural University, No. 59 Mucai Street Xiangfang District, 150030 Harbin, Heilongjiang, China. deshanli@163.com.
authors.forename: Deshan
authors.initials: D
authors.lastname: Li
mesh_terms: D000818:Animals; D000906:Antibodies / Q000097:blood; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy*; D004195:Disease Models, Animal; D005346:Fibroblast Growth Factors / Q000737:chemistry / Q000235:genetics / Q000494:pharmacology / Q000627:therapeutic use*; D005947:Glucose / Q000378:metabolism; D056945:Hep G2 Cells; D006801:Humans; D007004:Hypoglycemic Agents / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D008297:Male; D009154:Mutation; D011092:Polyethylene Glycols / Q000737:chemistry; D017434:Protein Structure, Tertiary; D011817:Rabbits
chemical_list: D000906:Antibodies; D007004:Hypoglycemic Agents; C414620:fibroblast growth factor 21; D011092:Polyethylene Glycols; D005346:Fibroblast Growth Factors; D005947:Glucose