Identification of potent, selective non-peptide CC chemokine receptor-3 antagonist that inhibits eotaxin-, eotaxin-2-, and monocyte chemotactic protein-4-induced eosinophil migration
- PMID: 10969084
- DOI: 10.1074/jbc.M006613200
Identification of potent, selective non-peptide CC chemokine receptor-3 antagonist that inhibits eotaxin-, eotaxin-2-, and monocyte chemotactic protein-4-induced eosinophil migration
Abstract
Eosinophils have been implicated in the pathogenesis of asthma and other allergic diseases. Several CC chemokines including eotaxin (CCL-11), eotaxin-2 (CCL-24), RANTES (CCL-5), and monocyte chemotactic protein-3 (MCP-3, CCL-7) and 4 (MCP-4, CCL-13) are potent eosinophil chemotactic and activating peptides acting through CC chemokine receptor-3 (CCR3). Thus, antagonism of CCR3 could have a therapeutic role in asthma and other eosinophil-mediated diseases. A high throughput, cellular functional screen was configured using RBL-2H3 cells stably expressing CCR3 (RBL-2H3-CCR3) to identify non-peptide receptor antagonists. A small molecule CCR3 antagonist was identified, SK&F 45523, and chemical optimization led to the generation of a number of highly potent, selective CCR3 antagonists including SB-297006 and SB-328437. These compounds were further characterized in vitro and demonstrated high affinity, competitive inhibition of (125)I-eotaxin and (125)I-MCP-4 binding to human eosinophils. The compounds were potent inhibitors of eotaxin- and MCP-4-induced Ca(2+) mobilization in RBL-2H3-CCR3 cells and eosinophils. Additionally, SB-328437 inhibited eosinophil chemotaxis induced by three ligands that activate CCR3 with similar potencies. Selectivity was affirmed using a panel of 10 seven-transmembrane receptors. This is the first description of a non-peptide CCR3 antagonist, which should be useful in further elucidating the pathophysiological role of CCR3 in allergic inflammatory diseases.
Similar articles
-
Cloning and functional characterization of a novel human CC chemokine that binds to the CCR3 receptor and activates human eosinophils.J Leukoc Biol. 1997 Nov;62(5):667-75. doi: 10.1002/jlb.62.5.667. J Leukoc Biol. 1997. PMID: 9365122
-
Migration of eosinophils across endothelial cell monolayers: interactions among IL-5, endothelial-activating cytokines, and C-C chemokines.J Immunol. 2000 Apr 1;164(7):3847-54. doi: 10.4049/jimmunol.164.7.3847. J Immunol. 2000. PMID: 10725746
-
CCL26/eotaxin-3 is more effective to induce the migration of eosinophils of asthmatics than CCL11/eotaxin-1 and CCL24/eotaxin-2.J Leukoc Biol. 2013 Aug;94(2):213-22. doi: 10.1189/jlb.0212074. Epub 2013 Mar 26. J Leukoc Biol. 2013. PMID: 23532518
-
Eotaxin and asthma.Curr Opin Pharmacol. 2001 Jun;1(3):248-53. doi: 10.1016/s1471-4892(01)00044-3. Curr Opin Pharmacol. 2001. PMID: 11712747 Review.
-
Eotaxins and CCR3 receptor in inflammatory and allergic skin diseases: therapeutical implications.Curr Drug Targets Inflamm Allergy. 2003 Mar;2(1):81-94. doi: 10.2174/1568010033344480. Curr Drug Targets Inflamm Allergy. 2003. PMID: 14561178 Review.
Cited by
-
Pharmacological management of nasal polyposis.Drugs. 2005;65(11):1537-52. doi: 10.2165/00003495-200565110-00006. Drugs. 2005. PMID: 16033291 Review.
-
The Chemokine (C-C Motif) Receptor 2 Antagonist INCB3284 Reduces Fluid Requirements and Protects From Hemodynamic Decompensation During Resuscitation From Hemorrhagic Shock.Crit Care Explor. 2022 May 18;4(5):e0701. doi: 10.1097/CCE.0000000000000701. eCollection 2022 May. Crit Care Explor. 2022. PMID: 35620770 Free PMC article.
-
Novel peptide nanoparticle-biased antagonist of CCR3 blocks eosinophil recruitment and airway hyperresponsiveness.J Allergy Clin Immunol. 2019 Feb;143(2):669-680.e12. doi: 10.1016/j.jaci.2018.05.003. Epub 2018 May 17. J Allergy Clin Immunol. 2019. PMID: 29778505 Free PMC article.
-
Chemokines and their receptors in the allergic airway inflammatory process.Clin Rev Allergy Immunol. 2011 Aug;41(1):76-88. doi: 10.1007/s12016-010-8202-6. Clin Rev Allergy Immunol. 2011. PMID: 20352527 Review.
-
Chemokines induce axon outgrowth downstream of Hepatocyte Growth Factor and TCF/β-catenin signaling.Front Cell Neurosci. 2013 Apr 30;7:52. doi: 10.3389/fncel.2013.00052. eCollection 2013. Front Cell Neurosci. 2013. PMID: 23641195 Free PMC article.
MeSH terms
Substances
LinkOut - more resources
Full Text Sources
Other Literature Sources
Miscellaneous