Histamine-releasing activity and binding to the FcεRIα human mast cell receptor subunit of mast cell degranulating peptide analogues with alanine substitutions

A. Buku, M. Mendlowitz, B. A. Condie, Joseph Price

Research output: Contribution to journalArticle

10 Citations (Scopus)

Abstract

We have investigated the effects on mast cell binding and the histamine-releasing activity of L-alanine substitutions for the five lysine residues and the proline residue in the MCD peptide (1) sequence. All synthesized analogues Ala2 (2), Ala6 (3), Ala11 (4), Ala12 (5), Ala17 (6), and Ala21 (7) showed a loss of histamine release compared to the parent MCD peptide 1. The order of decreased potency was 1 > 6 > 7 > 4 > 2 > 3 > 5. The alanine-substituted analogues showed a 5- to 6-fold decrease in histamine release for analogues 6, 7, and 4 and a 10-fold decrease for analogue 2. A more significant loss was observed in analogue 3 with a 75-fold loss of activity. The greatest loss of activity was observed with alanine substituting for proline in position 12. This analogue 5 showed a 130-fold loss of histamine release compared to the parent peptide 1. The ability of each analogue to interact with the FcεRIα subunit of the human mast cell receptor was analyzed by competitive binding of the fluorescent peptide 1 and the alanine analogues using fluorescence polarization. The binding affinities of analogues 4, 6, and 7 for the mast cell receptor were less than the affinity of the native peptide 1. Analogues 2, 3, and 5 showed an increase in binding affinity, with analogue 5 showing the highest increase compared to the native peptide 1. The order of increased affinity was 5 > 3 > 2 > 1 > 4, 6, 7. On the basis of these results, the possibility that analogue 5 inhibits peptide 1-stimulated histamine release was examined. We found that peptide 5 did not inhibit histamine release by peptide 1. The analogues 2, 3, and especially analogue 5 may be useful leads toward study of agents that prevent binding of IgE to mast cell receptors.

Original languageEnglish
Pages (from-to)3008-3012
Number of pages5
JournalJournal of Medicinal Chemistry
Volume46
Issue number14
DOIs
StatePublished - 3 Jul 2003

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Mast Cells
Alanine
Histamine
Substitution reactions
Histamine Release
Peptides
Proline
mast cell degranulating peptide receptor
mast cell degranulating peptide
Fluorescence Polarization
Competitive Binding
Immunoglobulin E
Lysine
Fluorescence
Polarization

Cite this

@article{2fb2efbf206f473597d816757f13e5ff,
title = "Histamine-releasing activity and binding to the FcεRIα human mast cell receptor subunit of mast cell degranulating peptide analogues with alanine substitutions",
abstract = "We have investigated the effects on mast cell binding and the histamine-releasing activity of L-alanine substitutions for the five lysine residues and the proline residue in the MCD peptide (1) sequence. All synthesized analogues Ala2 (2), Ala6 (3), Ala11 (4), Ala12 (5), Ala17 (6), and Ala21 (7) showed a loss of histamine release compared to the parent MCD peptide 1. The order of decreased potency was 1 > 6 > 7 > 4 > 2 > 3 > 5. The alanine-substituted analogues showed a 5- to 6-fold decrease in histamine release for analogues 6, 7, and 4 and a 10-fold decrease for analogue 2. A more significant loss was observed in analogue 3 with a 75-fold loss of activity. The greatest loss of activity was observed with alanine substituting for proline in position 12. This analogue 5 showed a 130-fold loss of histamine release compared to the parent peptide 1. The ability of each analogue to interact with the FcεRIα subunit of the human mast cell receptor was analyzed by competitive binding of the fluorescent peptide 1 and the alanine analogues using fluorescence polarization. The binding affinities of analogues 4, 6, and 7 for the mast cell receptor were less than the affinity of the native peptide 1. Analogues 2, 3, and 5 showed an increase in binding affinity, with analogue 5 showing the highest increase compared to the native peptide 1. The order of increased affinity was 5 > 3 > 2 > 1 > 4, 6, 7. On the basis of these results, the possibility that analogue 5 inhibits peptide 1-stimulated histamine release was examined. We found that peptide 5 did not inhibit histamine release by peptide 1. The analogues 2, 3, and especially analogue 5 may be useful leads toward study of agents that prevent binding of IgE to mast cell receptors.",
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Histamine-releasing activity and binding to the FcεRIα human mast cell receptor subunit of mast cell degranulating peptide analogues with alanine substitutions. / Buku, A.; Mendlowitz, M.; Condie, B. A.; Price, Joseph.

In: Journal of Medicinal Chemistry, Vol. 46, No. 14, 03.07.2003, p. 3008-3012.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Histamine-releasing activity and binding to the FcεRIα human mast cell receptor subunit of mast cell degranulating peptide analogues with alanine substitutions

AU - Buku, A.

AU - Mendlowitz, M.

AU - Condie, B. A.

AU - Price, Joseph

PY - 2003/7/3

Y1 - 2003/7/3

N2 - We have investigated the effects on mast cell binding and the histamine-releasing activity of L-alanine substitutions for the five lysine residues and the proline residue in the MCD peptide (1) sequence. All synthesized analogues Ala2 (2), Ala6 (3), Ala11 (4), Ala12 (5), Ala17 (6), and Ala21 (7) showed a loss of histamine release compared to the parent MCD peptide 1. The order of decreased potency was 1 > 6 > 7 > 4 > 2 > 3 > 5. The alanine-substituted analogues showed a 5- to 6-fold decrease in histamine release for analogues 6, 7, and 4 and a 10-fold decrease for analogue 2. A more significant loss was observed in analogue 3 with a 75-fold loss of activity. The greatest loss of activity was observed with alanine substituting for proline in position 12. This analogue 5 showed a 130-fold loss of histamine release compared to the parent peptide 1. The ability of each analogue to interact with the FcεRIα subunit of the human mast cell receptor was analyzed by competitive binding of the fluorescent peptide 1 and the alanine analogues using fluorescence polarization. The binding affinities of analogues 4, 6, and 7 for the mast cell receptor were less than the affinity of the native peptide 1. Analogues 2, 3, and 5 showed an increase in binding affinity, with analogue 5 showing the highest increase compared to the native peptide 1. The order of increased affinity was 5 > 3 > 2 > 1 > 4, 6, 7. On the basis of these results, the possibility that analogue 5 inhibits peptide 1-stimulated histamine release was examined. We found that peptide 5 did not inhibit histamine release by peptide 1. The analogues 2, 3, and especially analogue 5 may be useful leads toward study of agents that prevent binding of IgE to mast cell receptors.

AB - We have investigated the effects on mast cell binding and the histamine-releasing activity of L-alanine substitutions for the five lysine residues and the proline residue in the MCD peptide (1) sequence. All synthesized analogues Ala2 (2), Ala6 (3), Ala11 (4), Ala12 (5), Ala17 (6), and Ala21 (7) showed a loss of histamine release compared to the parent MCD peptide 1. The order of decreased potency was 1 > 6 > 7 > 4 > 2 > 3 > 5. The alanine-substituted analogues showed a 5- to 6-fold decrease in histamine release for analogues 6, 7, and 4 and a 10-fold decrease for analogue 2. A more significant loss was observed in analogue 3 with a 75-fold loss of activity. The greatest loss of activity was observed with alanine substituting for proline in position 12. This analogue 5 showed a 130-fold loss of histamine release compared to the parent peptide 1. The ability of each analogue to interact with the FcεRIα subunit of the human mast cell receptor was analyzed by competitive binding of the fluorescent peptide 1 and the alanine analogues using fluorescence polarization. The binding affinities of analogues 4, 6, and 7 for the mast cell receptor were less than the affinity of the native peptide 1. Analogues 2, 3, and 5 showed an increase in binding affinity, with analogue 5 showing the highest increase compared to the native peptide 1. The order of increased affinity was 5 > 3 > 2 > 1 > 4, 6, 7. On the basis of these results, the possibility that analogue 5 inhibits peptide 1-stimulated histamine release was examined. We found that peptide 5 did not inhibit histamine release by peptide 1. The analogues 2, 3, and especially analogue 5 may be useful leads toward study of agents that prevent binding of IgE to mast cell receptors.

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DO - 10.1021/jm0204892

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JF - Journal of Medicinal Chemistry

SN - 0022-2623

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