title: Selection of a novel FGF23-binding peptide antagonizing the inhibitory effect of FGF23 on phosphate uptake.
abstract: Fibroblast growth factor 23 (FGF23) is a bone-derived endocrine regulator of phosphate homeostasis and has been considered as a potential therapeutic target for hypophosphatemic disorders. Herein, we isolated a novel FGF23-binding peptide by screening a phage display library with FGF23180-205, the minimal epitope of FGF23 binding to the binary fibroblast growth factor receptor (FGFR)-Klotho complex. The corresponding peptide (referred to as 23-b6) showed high homology to the immunoglobulin-like (Ig-like) domain III (D3) of FGFR1c, the predominant receptor mediating the phosphaturic activity of FGF23. The 23-b6 peptide and panning target FGF23180-205 carried opposite charges and shared similar hydrophilic profiles. Functional analysis indicated that synthetic 23-b6 peptide exhibited antagonistic effect on the inhibition of phosphate uptake by FGF23 in opossum kidney cells (OK cells). The mechanisms of 23-b6 peptide impairing the bioactivity of FGF23 involved blockade of the activation of Erk cascade and up-regulation of NaPi-2a and NaPi-2c expression in OK cells. Our results demonstrate that the 23-b6 peptide is a potent FGF23 antagonist with increased effect on phosphate uptake in kidney cells and might have therapeutic potentials in hypophosphatemic disorders characterized by an abnormally high level of FGF23.
authors.affiliation: Institute of Tissue Transplantation and Immunology, Jinan University, Guangzhou, 510632, China.
authors.forename: Tao
authors.initials: T
authors.lastname: Huang
authors.forename: Xiaomian
authors.initials: X
authors.lastname: Lin
authors.forename: Quchou
authors.initials: Q
authors.lastname: Li
authors.forename: Wu
authors.initials: W
authors.lastname: Luo
authors.forename: Li
authors.initials: L
authors.lastname: Song
authors.forename: Xiangpeng
authors.initials: X
authors.lastname: Tan
authors.forename: Wenhui
authors.initials: W
authors.lastname: Wang
authors.forename: Xiaokun
authors.initials: X
authors.lastname: Li
authors.forename: Xiaoping
authors.initials: X
authors.lastname: Wu
mesh_terms: D000818:Animals; D002478:Cells, Cultured / Q000187:drug effects; D000939:Epitopes; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D000089703:Fibroblast Growth Factor-23; D005346:Fibroblast Growth Factors / Q000037:antagonists & inhibitors / Q000378:metabolism* / Q000494:pharmacology; D005966:Glucuronidase / Q000378:metabolism; D007668:Kidney / Q000166:cytology; D000090265:Klotho Proteins; D009893:Opossums; D019151:Peptide Library; D010455:Peptides / Q000378:metabolism / Q000494:pharmacology*; D010710:Phosphates / Q000378:metabolism / Q000493:pharmacokinetics*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D050610:Sodium-Phosphate Cotransporter Proteins, Type II / Q000235:genetics / Q000378:metabolism
chemical_list: D000939:Epitopes; D019151:Peptide Library; D010455:Peptides; D010710:Phosphates; D050610:Sodium-Phosphate Cotransporter Proteins, Type II; D005346:Fibroblast Growth Factors; D000089703:Fibroblast Growth Factor-23; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases; D005966:Glucuronidase; D000090265:Klotho Proteins