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Fashioning FGFs from phage?

Nature Biotechnology volume 17, pages 1157–1158 (1999)Cite this article

The development of orally active, small-molecule mimetics of therapeutically relevant cytokines and growth factors, such as insulin, erythropoetin, and granulocyte colony-stimulating factor, is of tremendous pharmaceutical interest. The stability of small-molecule mimetics should make them highly desirable as replacements for more labile therapeutic proteins, whose applications are limited by the need for frequent injections. Fibroblast growth factors (FGF) are currently being investigated in a variety of therapeutic settings and thus are prime candidates for mimicry by small molecules. In this issue, Kavanaugh and colleagues1 at Chiron report the potent mimicry of an FGF by a novel "semi-rationally designed" small protein. Their study has important implications for the development of small-molecule agonists for this class of thereuputic targets.

The Chiron group began their search for an FGF mimetic by screening a phage display library for peptides that bound to the extracellular domain of the FGF receptor (FGFR). They isolated a novel peptide (C19) that bound to but did not activate the receptor. Guided by a body of work showing that agonist activity is conferred by the ability to cause receptor dimerization, they expressed the C19 peptide as a fusion protein coupled to domains that undergo spontaneous dimer formation (immunoglobulin Fc and c-jun leucine zipper), which enhanced binding affinity to isolated receptors. Interestingly, only this C19–jun fusion protein possessed agonist activity on cellular FGFRs, and this required the presence of heparin. The c-jun region previously had been known to bind heparin, and this was confirmed when mutation of the heparin-binding site abolished FGFR activation by the fusion protein.

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Figure 1: Schematic representation of the FGF-FGFR complex (after reference 10, figure 6).

References

  1. Ballinger, M.D. et al. Nat. Biotechnol. 17, 1199– 1204 (1999).

    Article  CAS  Google Scholar 

  2. Clackson, T. & Wells J.A. Science 267, 383–386 (1995).

    Article  CAS  Google Scholar 

  3. Wrighton, N.C. et al. Science 273, 458–464 (1996).

    Article  CAS  Google Scholar 

  4. Livnah, O. et al. Science 273, 464–471 ( 1996).

    Article  CAS  Google Scholar 

  5. Wrighton, N.C. et al. Nat. Biotechnol. 15, 1261– 1265 (1997).

    Article  CAS  Google Scholar 

  6. Cwirla, S.E. et al. Science 276, 1696–1699 (1997).

    Article  CAS  Google Scholar 

  7. Tian, S. et al. Science 281, 257–259 ( 1998).

    Article  CAS  Google Scholar 

  8. Qureshi, S.A. et al. Proc. Natl. Acad. Sci. USA 96, 12156– 12161 (1999).

    Article  CAS  Google Scholar 

  9. Vainikka, S., Mustonen, T. & Alitalo, K. in Guidebook to cytokines and their receptors (ed. Nicola, N.A.) 214–217 (Oxford University Press, Oxford, New York, Tokyo; 1994).

    Google Scholar 

  10. Plotnikov, A.N. et al. Cell 98, 641–650 (1999).

    Article  CAS  Google Scholar 

  11. Grötzinger, J., Kernebeck, T., Kallen, K.J., & Rose-John, S. Biol. Chem. 380, 803–813 (1999).

    Article  Google Scholar 

  12. Roberts, R. et al. Nature 332, 376–378 (1998).

    Article  Google Scholar 

Download references

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  1. Millennium Pharmaceuticals, Cambridge, MA 02139

    Nick Wrighton & David Gearing

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  1. Nick Wrighton
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  2. David Gearing
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Wrighton, N., Gearing, D. Fashioning FGFs from phage?. Nat Biotechnol 17, 1157–1158 (1999). https://doi.org/10.1038/70696

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