Structure-based design of peptides which inhibit IgE binding to its high affinity receptor FceRI

J. M. McDonnell, D. Fushman, A. J. Henry, J. P.D. Cook, G. A. Mackay, H. J. Gould, B. J. Sutton, D. Cowburn

Research output: Contribution to journalArticle

Abstract

Interaction between immunoglobulin E (lgE) and its high afi:inity receptor. FceRI a-chain, is central in the development of allergic disease. One strategy for the design of therapeutics for the treatment of allergic conditions is the production of compounds which inhibit the interaction between lgl and FceRI. In this study we will describe the structure-t)ased design and development of synthetic peptide inhibitors of the IgE-FceRI a-chain interaction. We have undertaken site-directed mutagenesis of the Fc region of IgI and of FceRI a-chain and have characterized the kinetic and thermodynamic effects of these mutations. On the basis of this work we have mapped "hotspots" of binding energy for the lgE-FceRI interaction. Conformationally restricted peptides were designed to mimic one "hotspot" of binding energy comprised of a 3-hairpin loop from FceRI a-chain. Two peptide mimics of this region, one syxlthesized from L-amino acids and another as its retroenantiomer, inhibit the lgE FceRI interaction at low micromolar concentrations. The solution structures of these two peptides minlics have been solved by NMR spectroscopy and demonstrate stable 3-hairpin structure and presentation of similar topochemical surfaces. These compounds have been useful as tools for understanding the interactions between IgI-: and FceRI and may represent first generation therapeutic agents for the treatment of allergic diseases.

Original languageEnglish (US)
Pages (from-to)A1325
JournalFASEB Journal
Volume11
Issue number9
Publication statusPublished - Dec 1 1997
Externally publishedYes

    Fingerprint

ASJC Scopus subject areas

  • Biotechnology
  • Biochemistry
  • Molecular Biology
  • Genetics

Cite this

McDonnell, J. M., Fushman, D., Henry, A. J., Cook, J. P. D., Mackay, G. A., Gould, H. J., ... Cowburn, D. (1997). Structure-based design of peptides which inhibit IgE binding to its high affinity receptor FceRI. FASEB Journal, 11(9), A1325.