A Novel Approach to Improve the Function of FGF21
| Autor: | Amy N. Duguay, Yang Li, Richard Smith, Ed Belouski, Junming Yie, Shanaka Stanislaus, Jing Xu, Ling Cai, Xinle Wu, Jamila Gupte, Jennifer Weiszmann |
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| Rok vydání: | 2013 |
| Předmět: |
Blood Glucose
Male Domain of a function FGF21 Recombinant Fusion Proteins Molecular Sequence Data Mice Inbred Strains Computational biology Protein Engineering Energy homeostasis Mice Animals Humans Hypoglycemic Agents Potency Pharmacology (medical) Amino Acid Sequence Obesity Pharmacology Chemistry Wild type General Medicine Avimer Fibroblast Growth Factors Biochemistry Anti-Obesity Agents Interaction domain Function (biology) Biotechnology |
| Zdroj: | BioDrugs. 27:159-166 |
| ISSN: | 1179-190X 1173-8804 |
| Popis: | Fibroblast growth factor 21 (FGF21) has potent effects on normalizing glucose, lipid, and energy homeostasis, and represents an attractive novel therapy for type 2 diabetes mellitus and obesity. Approaches to improve the pharmacokinetic properties of FGF21, such as conjugation with polyethylene glycol, have been explored for therapeutic development. However, not only is there room for further pharmacokinetic improvements, additional re-engineering approaches to improve the potency and stability of FGF21 have not been reported. Here, we describe a novel approach to modify and improve the function of FGF21 by altering its C-terminal βKlotho interaction domain. We first identified Avimer proteins that are capable of binding βKlotho. Then we explored replacing the C-terminal βKlotho interaction domain of FGF21 with a βKlotho-binding Avimer protein. Such a βKlotho-binding Avimer protein was able to fully complement the C-terminal domain function of FGF21. The resulting FGF21-Avimer fusion is functionally indistinguishable from wild type FGF21, and more tolerant of C-terminal modification. These results demonstrate a viable strategy to modulate the affinity, potency, and engineering of FGF21, paving the way for further improvements of FGF21 as a therapeutic. |
| Databáze: | OpenAIRE |
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