[Optimization and characterization of a novel FGF21 mutant]

Area of Science:

• Biochemistry
• Molecular Biology
• Endocrinology

Background:

• Fibroblast Growth Factor 21 (FGF21) is a key regulator of glucose metabolism.
• FGF21 has shown potential as a safe and effective therapeutic for managing blood glucose levels.
• Enhancing FGF21's activity is crucial for developing more potent anti-diabetic agents.

Purpose of the Study:

• To engineer a novel FGF21 variant with improved biological activity.
• To enhance the soluble expression and glucose-regulatory function of human FGF21.
• To evaluate the in vitro and in vivo efficacy of the engineered FGF21.

Main Methods:

• Constructed a chimeric FGF21 gene (hmFGF21) by domain exchange between human and mouse FGF21.
• Expressed the hmFGF21 gene as a SUMO-fusion protein (SUMO-hmFGF21) in E. coli.
• Assessed glucose uptake in HepG2 cells and anti-diabetic effects in db/db mice.

Main Results:

• Soluble expression of hmFGF21 increased approximately twofold compared to wild-type hFGF21.
• hmFGF21 exhibited enhanced stimulation of glucose uptake in HepG2 cells.
• hmFGF21 demonstrated superior blood glucose-lowering efficacy in db/db diabetic mice.

Conclusions:

• Domain optimization significantly improves the biological properties of FGF21.
• The engineered hmFGF21 represents a promising candidate for enhanced diabetes therapy.
• This strategy offers a viable approach to optimize protein therapeutics.