title: Effective mast cell degranulating peptide inhibitors of the IgE/Fc epsilonRI receptor interaction.
abstract: Previous studies with mast cell degranulating (MCD) peptide have shown that peptide [Ala(12)]MCD 8 was an inhibitor of IgE binding to mast cell receptors. In an attempt to produce increased inhibition, analogs were synthesized that maintained the alanine residue in position 12 in the MCD peptide sequence and were further modified at both termini. Analogs modified at the C-terminus were [Ala(12),desLys(21)]MCD 2 and [Ala(12),D-Lys(21)]MCD 4. N-terminus modifications were [desLys(6)-Arg(7)-His(8),Ala(12)]MCD 1, [Ala(6), Ala(12)]MCD 6, and [Val(6),Ala(12)]MCD 7. To assess the role of the Proline(12), analogs [D-Ala(12)]MCD 3 and [Meleu(12)]MCD 5 were also synthesized. The analogs were tested for binding to the IgE receptor in cultured mast cells. Inhibitory activity of IgE-caused degranulation was measured using a beta-hexosaminidase assay. Circular dichroism (CD) and molecular modeling of selected analogs were used to follow possible structural differences among these analogs. All analogs showed binding affinity to the IgE receptor and inhibition of IgE-induced mast cell degranulation at different levels. Differences in inhibition were most likely because of diverse interactions of the analogs with the receptor as inferred by the CD and modeling studies. Based on the results of the beta-hexosaminidase assay, analog [Val(6), Ala(12)]MCD 7 proved to be an excellent inhibitor of IgE-mediated mast cell degranulation.
authors.affiliation: Department of Structural and Chemical Biology, Mount Sinai School of Medicine, New York, NY 10029, USA. Angeliki.Buku@mssm.edu
authors.forename: Angeliki
authors.initials: A
authors.lastname: Buku
authors.forename: Inna
authors.initials: I
authors.lastname: Keselman
authors.forename: Dmitry
authors.initials: D
authors.lastname: Lupyan
authors.forename: Mihaly
authors.initials: M
authors.lastname: Mezei
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Price
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002942:Circular Dichroism; D007073:Immunoglobulin E / Q000276:immunology*; D008958:Models, Molecular; D010455:Peptides / Q000737:chemistry* / Q000494:pharmacology*; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D051381:Rats; D017455:Receptors, IgE / Q000037:antagonists & inhibitors* / Q000276:immunology*; D001619:beta-N-Acetylhexosaminidases / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D010455:Peptides; D017455:Receptors, IgE; C008331:mast cell degranulating peptide; D007073:Immunoglobulin E; D001619:beta-N-Acetylhexosaminidases