[Ala¹²] MCD peptide: a lead peptide to inhibitors of IgE binding to mast cell receptors. Abstract: An effort was made to discover MCD peptide analogs that bind with high affinity to mast cell receptors without triggering secretion of histamine or other mediators of the allergic reaction initiated by IgE after mast cell activation. Such compounds could serve as inhibitors of IgE binding to mast cell receptors. An alanine scan of MCD peptide reported previously showed that the analog [Ala¹²]MCD was 120-fold less potent in histamine-releasing activity and five-fold more potent in binding affinity to mast cell receptors than the parent MCD peptide. Because this analog showed marginal intrinsic activity and good binding affinity it was subsequently tested in the present study as an IgE inhibitor. In contrast to MCD peptide, [Ala¹²]MCD showed a 50% inhibition of IgE binding to the IgE/FceRIa mast cell receptor by using RBL-2H3 mast cells and fluorescence polarization. Furthermore in a b-hexosaminidase secretory assay, the peptide also showed a 50% inhibition of the secretion of this enzyme caused by IgE. An attempt was made to relate structural changes and biological differences between the [Ala¹²]MCD analog and the parent MCD peptide. The present results show that [Ala¹²]MCD may provide a base for designing agents to prevent IgE/FceRIa interactions and, consequently, allergic conditions.