1. Discovery of an artificial peptide agonist to the fibroblast growth factor receptor 1c/βKlotho complex from random peptide T7 phage display
- Author
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Taiji Asami, Tetsuya Ohtaki, Shiro Takekawa, Yayoi Kawata, Kotaro Sakamoto, Yasushi Masuda, Tadashi Umemoto, Takashi Ito, and Hiroshi Inooka
- Subjects
Male ,0301 basic medicine ,Agonist ,animal structures ,Phage display ,medicine.drug_class ,T7 phage ,Biophysics ,Peptide ,Biology ,βKlotho ,Fibroblast growth factor ,Biochemistry ,03 medical and health sciences ,FGF21 ,Peptide Library ,Bacteriophage T7 ,Drug Discovery ,Adipocytes ,medicine ,Animals ,Humans ,Receptor, Fibroblast Growth Factor, Type 1 ,Receptor ,Peptide library ,Klotho Proteins ,Molecular Biology ,chemistry.chemical_classification ,Mice, Inbred BALB C ,FGFR ,Membrane Proteins ,Cell Biology ,biology.organism_classification ,Molecular biology ,Fibroblast Growth Factors ,030104 developmental biology ,chemistry ,Fibroblast growth factor receptor ,Multiprotein Complexes ,Cell Surface Display Techniques ,Peptides ,Dimerization - Abstract
Fibroblast growth factor receptor-1c (FGFR1c)/βKlotho (KLB) complex is a receptor of fibroblast growth factor 21 (FGF21). Pharmacologically, FGF21 shows anti-obesity and anti-diabetic effects upon peripheral administration. Here, we report the development of an artificial peptide agonist to the FGFR1c/KLB heterodimer complex. The peptide, F91-8A07 (LPGRTCREYPDLWWVRCY), was discovered from random peptide T7 phage display and selectively bound to the FGFR1c/KLB complex, but not to FGFR1c and KLB individually. After subsequent peptide dimerization using a short polyethyleneglycol (PEG) linker, the dimeric F91-8A07 peptide showed higher potent agonist activity than that of FGF21 in cultured primary human adipocytes. Moreover, the dimeric peptide led to an expression of the early growth response protein-1 (Egr-1) mRNA in vivo, which is a target gene of FGFR1c. To the best of our knowledge, this is the first report of a FGFR1c/KLB complex-selective artificial peptide agonist.
- Published
- 2016
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