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Updated: Mar 14, 2026
Screening and Identification of Small Peptides Targeting Fibroblast Growth Factor Receptor2 using a Phage Display Peptide Library
Published on: September 30, 2019
Discovery of an artificial peptide agonist to the fibroblast growth factor receptor 1c/βKlotho complex from random
Kotaro Sakamoto1, Yayoi Kawata1, Yasushi Masuda1
1Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, 26-1, Muraoka-Higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan.
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.
Insights
Researchers developed a novel artificial peptide that selectively targets the Fibroblast Growth Factor Receptor-1c (FGFR1c)/βKlotho (KLB) complex. This peptide demonstrates potent agonist activity, offering potential for new anti-obesity and anti-diabetic therapies.
Area of Science:
- Biochemistry
- Molecular Biology
- Pharmacology
Background:
- Fibroblast growth factor 21 (FGF21) exhibits therapeutic potential for metabolic disorders like obesity and diabetes.
- FGF21 exerts its effects by binding to the Fibroblast Growth Factor Receptor-1c (FGFR1c)/βKlotho (KLB) complex.
- Developing selective agonists for the FGFR1c/KLB complex is crucial for targeted metabolic therapies.
Purpose of the Study:
- To design and characterize a novel artificial peptide agonist targeting the FGFR1c/KLB heterodimer complex.
- To evaluate the binding selectivity and functional activity of the developed peptide compared to native FGF21.
- To investigate the in vivo efficacy of the artificial peptide agonist.
Main Methods:
- Peptide discovery using T7 phage display against the FGFR1c/KLB complex.
- Synthesis and dimerization of the lead peptide (F91-8A07) using a polyethylene glycol (PEG) linker.
- In vitro assessment of receptor binding selectivity and agonist activity in human adipocytes.
- In vivo analysis of target gene expression (Egr-1 mRNA) following peptide administration.
Main Results:
- A novel peptide, F91-8A07, was identified that selectively binds to the FGFR1c/KLB complex.
- Dimerized F91-8A07 peptide exhibited superior agonist activity compared to native FGF21 in human adipocytes.
- In vivo administration of the dimeric peptide induced expression of Egr-1 mRNA, a known FGFR1c target gene.
Conclusions:
- This study reports the first artificial peptide agonist specifically targeting the FGFR1c/KLB complex.
- The developed dimeric peptide demonstrates potent metabolic signaling capabilities, exceeding native FGF21 in vitro.
- This artificial peptide represents a promising new therapeutic candidate for metabolic diseases.
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