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

Nature Biotechnology volume 17, pages 1199–1204 (1999)Cite this article

Abstract

Fibroblast growth factors (FGFs) are being investigated in human clinical trials as treatments for angina, claudication, and stroke. We designed a molecule structurally unrelated to all FGFs, which potently mimicked basic FGF activity, by combining domains that (1) bind FGF receptors (2) bind heparin, and (3) mediate dimerization. A 26-residue peptide identified by phage display specifically bound FGF receptor (FGFR) 1c extracellular domain but had no homology with FGFs. When fused with the c-jun leucine zipper domain, which binds heparin and forms homodimers, the polypeptide specifically reproduced the mitogenic and morphogenic activities of basic FGF with similar potency (EC50 = 240 pM). The polypeptide required interaction with heparin for activity, demonstrating the importance of heparin for FGFR activation even with designed ligands structurally unrelated to FGF. Our results demonstrate the feasibility of engineering potent artificial agonists for the receptor tyrosine kinases, and have important implications for the design of nonpeptidic ligands for FGF receptors. Furthermore, artificial FGFR agonists may be useful alternatives to FGF in the treatment of ischemic vascular disease.

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Figure 1: Structure of C19jun.
Figure 2: C19jun is a potent FGFR agonist.
Figure 3: Specificity of C19jun for FGFR.
Figure 4: Competition of C19jun and bFGF for 125I-bFGF binding to FGFR1.
Figure 5: Activities of C19jun variants.

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Acknowledgements

The authors thank Jaime Escobedo, Anke Klippel, and Lewis T. Williams for helpful discussions and provision of reagents; Hermel Manalo and Hamid Khoja for expert technical assistance; and Leah Conroy, Gwynn Pardee, and Stephania Widger for baculovirus-expressed proteins.

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  1. Chiron Corporation, 4560 Horton St., Room 4.4144, Emeryville, 94608, CA

    Marcus D. Ballinger, Venkatakrishna Shyamala, Louise D. Forrest, Maja Deuter-Reinhard, Laura V. Doyle, Jian-xin Wang, Lootsee Panganiban-Lustan, Jennifer R. Stratton, Gerald Apell, Jill A. Winter, Michael V. Doyle, Steven Rosenberg & W. Michael Kavanaugh

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Correspondence to W. Michael Kavanaugh.

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Ballinger, M., Shyamala, V., Forrest, L. et al. Semirational design of a potent, artificial agonist of fibroblast growth factor receptors. Nat Biotechnol 17, 1199–1204 (1999). https://doi.org/10.1038/70746

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