Discovery of an artificial peptide agonist to the fibroblast growth factor receptor 1c/βKlotho complex from random peptide T7 phage display

• Published in: Biochemical and biophysical research communications 2016-11, Vol.480 (1), p.55-60
• Main Authors: Sakamoto, Kotaro, Kawata, Yayoi, Masuda, Yasushi, Umemoto, Tadashi, Ito, Takashi, Asami, Taiji, Takekawa, Shiro, Ohtaki, Tetsuya, Inooka, Hiroshi
• Format: Article
• Language: English
• Subjects: Adipocytes - drug effects; Agonist; Animals; Bacteriophage T7; Cell Surface Display Techniques; Dimerization; Drug Discovery; FGF21; FGFR; Fibroblast Growth Factors - chemistry; Humans; Male; Membrane Proteins - agonists; Membrane Proteins - metabolism; Mice, Inbred BALB C; Multiprotein Complexes - metabolism; Peptide; Peptide Library; Peptides - chemistry; Peptides - pharmacology; Phage display; Receptor, Fibroblast Growth Factor, Type 1 - agonists; Receptor, Fibroblast Growth Factor, Type 1 - metabolism; βKlotho
• ISSN: 0006-291X; 1090-2104
• DOI: 10.1016/j.bbrc.2016.10.009

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. [Display omitted] •Artificial peptide agonist to FGFR1c/KLB complex is generated.•The peptide has no sequence similarity with FGF21.•The peptide selectively recognizes the complex interface of FGFR1c/βKlotho and activates the it both in vitro and in vivo.