title: Structure based design and characterization of peptides that inhibit IgE binding to its high-affinity receptor.
abstract: We have designed synthetic peptide inhibitors of the interaction between IgE and its high affinity receptor, Fc epsilon RI. The structure of the second domain of CD2 was used as a modelling template for the second alpha-chain domain of Fc epsilon RI, the C-C' loop of which has been implicated in the interaction with IgE. An L-amino acid peptide and a retro-enantiomeric D-amino acid peptide were designed to mimic the conformation of the C-C' region. Both peptides were cyclized by disulphide bond formation between terminal cysteine residues, and show mirror image symmetry by circular dichroism analysis. The C-C' peptide mimics act as competitive inhibitors of IgE binding. The cyclic L- and retro D-peptides exhibited KDs of approximately 3 microM and 11 microM, respectively, for IgE. Further, the peptides inhibit IgE-mediated mast cell degranulation, an in vitro model of an allergic response.
authors.affiliation: The Randall Institute, King's College London, UK.
authors.forename: J M
authors.initials: JM
authors.lastname: McDonnell
authors.forename: A J
authors.initials: AJ
authors.lastname: Beavil
authors.forename: G A
authors.initials: GA
authors.lastname: Mackay
authors.forename: B A
authors.initials: BA
authors.lastname: Jameson
authors.forename: R
authors.initials: R
authors.lastname: Korngold
authors.forename: H J
authors.initials: HJ
authors.lastname: Gould
authors.forename: B J
authors.initials: BJ
authors.lastname: Sutton
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D018926:Anti-Allergic Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D015374:Biosensing Techniques; D015550:Cell Degranulation / Q000187:drug effects; D003198:Computer Simulation; D015195:Drug Design; D006801:Humans; D006967:Hypersensitivity / Q000188:drug therapy; D007073:Immunoglobulin E / Q000378:metabolism*; D008407:Mast Cells / Q000187:drug effects; D008958:Models, Molecular; D018716:Molecular Mimicry; D008969:Molecular Sequence Data; D010456:Peptides, Cyclic / Q000138:chemical synthesis / Q000494:pharmacology*; D011485:Protein Binding; D011487:Protein Conformation; D051381:Rats; D017455:Receptors, IgE / Q000037:antagonists & inhibitors* / Q000737:chemistry
chemical_list: D018926:Anti-Allergic Agents; D010456:Peptides, Cyclic; D017455:Receptors, IgE; C099113:cyclo(L-262); C099114:cyclo(retro D-262); D007073:Immunoglobulin E