Semirational design of a potent, artificial agonist of fibroblast growth factor receptors

Fibroblast growth factors (FGFs) are being investigated in human clinical t rials as treatments for angina, claudication, and stroke. We designed a mol ecule structurally unrelated to all FGFs, which potently mimicked basic FGF activity, by combining domains that (1) bind FGF receptors (2) bind hepari n, and (3) mediate dimerization. A 26-residue peptide identified by phage d isplay specifically bound FGF receptor (FGFR) Ic extracellular domain but h ad no homology with FGFs. When fused with the c-jun leucine zipper domain, which binds heparin and forms homodimers, the polypeptide specifically repr oduced the mitogenic and morphogenic activities of basic FGF with similar p otency (EC50= 240 pM). The polypeptide required interaction with heparin fo r activity, demonstrating the importance of heparin for FGFR activation eve n with designed ligands structurally unrelated to FGF. Our results demonstr ate the feasibility of engineering potent artificial agonists for the recep tor tyrosine kinases, and have important implications for the design of non peptidic ligands for FGF receptors. Furthermore, artificial FGFR agonists m ay be useful alternatives to FGF in the treatment of ischemic vascular dise ase.