Structure based design and characterization of peptides that inhibit IgE binding to its high-affinity receptor.
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.
McDonnell
J M
JM
The Randall Institute, King's College London, UK.
Beavil
A J
AJ
Mackay
G A
GA
Jameson
B A
BA
Korngold
R
R
Gould
H J
HJ
Sutton
B J
BJ
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
D018926:Anti-Allergic Agents; D010456:Peptides, Cyclic; D017455:Receptors, IgE; C099113:cyclo(L-262); C099114:cyclo(retro D-262); D007073:Immunoglobulin E