Effective Mast Cell Degranulating Peptide
Inhibitors of the IgE/FceRI Receptor Interaction
Abstract:
Previous studies with mast cell degranulating
(MCD) peptide have shown that peptide [Ala12]MCD
8 was an inhibitor of IgE binding to mast cell recep-
tors. In an attempt to produce increased inhibition,
analogs were synthesized that maintained the ala-
nine residue in position 12 in the MCD peptide
sequence and were further modified at both ter-
mini. Analogs modified at the C-terminus were
[Ala12,desLys21]MCD 2 and [Ala12,D-Lys21]MCD 4.
N-terminus modifications were [desLys6Arg7
His8,Ala12]MCD 1,
[Ala6, Ala12]MCD 6, and [Val6,
Ala12]MCD 7.
To assess the role of the Proline12,
analogs [D-Ala12]MCD 3 and [Meleu12]MCD 5 were
also synthesized. The analogs were tested for bind-
ing to the IgE receptor in cultured mast cells. Inhibi-
tory activity of IgE-caused degranulation was
measured using a b-hexosaminidase assay. Circular
dichroism (CD) and molecular modeling of selected
analogs were used to follow possible structural dif-
ferences 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 b-hexosamini-
dase assay, analog [Val6, Ala12]MCD 7 proved to be
an excellent inhibitor of IgE-mediated mast cell
degranulation.