TY - JOUR
T1 - Effective mast cell degranulating peptide inhibitors of the IgE/FcεRI receptor interaction
AU - Buku, Angeliki
AU - Keselman, Inna
AU - Lupyan, Dmitry
AU - Mezei, Mihaly
AU - Price, Joseph A.
PY - 2008/8
Y1 - 2008/8
N2 - Previous studies with mast cell degranulating (MCD) peptide have shown that peptide [Ala12]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 [Ala12,desLys21]MCD 2 and [Ala 12,d-Lys21]MCD 4. N-terminus modifications were [desLys6-Arg7-His8,Ala12]MCD 1, [Ala6, Ala12]MCD 6, and [Val6,Ala 12]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 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 [Val6, Ala12]MCD 7 proved to be an excellent inhibitor of IgE-mediated mast cell degranulation.
AB - Previous studies with mast cell degranulating (MCD) peptide have shown that peptide [Ala12]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 [Ala12,desLys21]MCD 2 and [Ala 12,d-Lys21]MCD 4. N-terminus modifications were [desLys6-Arg7-His8,Ala12]MCD 1, [Ala6, Ala12]MCD 6, and [Val6,Ala 12]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 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 [Val6, Ala12]MCD 7 proved to be an excellent inhibitor of IgE-mediated mast cell degranulation.
KW - FcεRI receptor
KW - Fluorescence binding
KW - IgE
KW - MCD peptides
KW - β-hexosaminidase
UR - http://www.scopus.com/inward/record.url?scp=47949124268&partnerID=8YFLogxK
U2 - 10.1111/j.1747-0285.2008.00684.x
DO - 10.1111/j.1747-0285.2008.00684.x
M3 - Article
C2 - 18624811
AN - SCOPUS:47949124268
SN - 1747-0277
VL - 72
SP - 133
EP - 139
JO - Chemical Biology and Drug Design
JF - Chemical Biology and Drug Design
IS - 2
ER -