Effective Mast Cell Degranulating Peptide Inhibitors of the IgE/FcɛRI Receptor Interaction

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 β‐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 β‐hexosaminidase assay, analog [Val 6 , Ala 12 ]MCD 7 proved to be an excellent inhibitor of IgE‐mediated mast cell degranulation.