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Research ArticleArticle

Identification and Characterization of a Potent, Selective Nonpeptide Agonist of the CC Chemokine Receptor CCR8

Christopher A. Haskell, Richard Horuk, Meina Liang, Mary Rosser, Laura Dunning, Imadul Islam, Leonor Kremer, Julio Gutiérrez, Gabriel Marquez, Carlos Martinez-A, Mark J. Biscone, Robert W. Doms and Sofia Ribeiro
Molecular Pharmacology January 2006, 69 (1) 309-316; DOI: https://doi.org/10.1124/mol.105.014779
Christopher A. Haskell
Departments of Immunology (C.A.H., R.H.), Molecular Pharmacology (M.L., S.R.), Cell Sciences (M.R.), Drug Metabolism and Pharmacology (L.D.), and Chemistry (I.I.), Berlex Biosciences, Richmond, California; Departamento de Inmunologiía y Oncología, Centro Nacional de Biotecnología/Consejo Superior de Investigaciones Científicas, Universidad Autónoma de Madrid, Cantoblanco, Madrid, Spain (L.K., J.G., G.M., C.M.-A.); and Department of Microbiology, University of Pennsylvania, Philadelphia, Pennsylvania (M.J.B., R.W.D.)
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Richard Horuk
Departments of Immunology (C.A.H., R.H.), Molecular Pharmacology (M.L., S.R.), Cell Sciences (M.R.), Drug Metabolism and Pharmacology (L.D.), and Chemistry (I.I.), Berlex Biosciences, Richmond, California; Departamento de Inmunologiía y Oncología, Centro Nacional de Biotecnología/Consejo Superior de Investigaciones Científicas, Universidad Autónoma de Madrid, Cantoblanco, Madrid, Spain (L.K., J.G., G.M., C.M.-A.); and Department of Microbiology, University of Pennsylvania, Philadelphia, Pennsylvania (M.J.B., R.W.D.)
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Meina Liang
Departments of Immunology (C.A.H., R.H.), Molecular Pharmacology (M.L., S.R.), Cell Sciences (M.R.), Drug Metabolism and Pharmacology (L.D.), and Chemistry (I.I.), Berlex Biosciences, Richmond, California; Departamento de Inmunologiía y Oncología, Centro Nacional de Biotecnología/Consejo Superior de Investigaciones Científicas, Universidad Autónoma de Madrid, Cantoblanco, Madrid, Spain (L.K., J.G., G.M., C.M.-A.); and Department of Microbiology, University of Pennsylvania, Philadelphia, Pennsylvania (M.J.B., R.W.D.)
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Mary Rosser
Departments of Immunology (C.A.H., R.H.), Molecular Pharmacology (M.L., S.R.), Cell Sciences (M.R.), Drug Metabolism and Pharmacology (L.D.), and Chemistry (I.I.), Berlex Biosciences, Richmond, California; Departamento de Inmunologiía y Oncología, Centro Nacional de Biotecnología/Consejo Superior de Investigaciones Científicas, Universidad Autónoma de Madrid, Cantoblanco, Madrid, Spain (L.K., J.G., G.M., C.M.-A.); and Department of Microbiology, University of Pennsylvania, Philadelphia, Pennsylvania (M.J.B., R.W.D.)
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Laura Dunning
Departments of Immunology (C.A.H., R.H.), Molecular Pharmacology (M.L., S.R.), Cell Sciences (M.R.), Drug Metabolism and Pharmacology (L.D.), and Chemistry (I.I.), Berlex Biosciences, Richmond, California; Departamento de Inmunologiía y Oncología, Centro Nacional de Biotecnología/Consejo Superior de Investigaciones Científicas, Universidad Autónoma de Madrid, Cantoblanco, Madrid, Spain (L.K., J.G., G.M., C.M.-A.); and Department of Microbiology, University of Pennsylvania, Philadelphia, Pennsylvania (M.J.B., R.W.D.)
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Imadul Islam
Departments of Immunology (C.A.H., R.H.), Molecular Pharmacology (M.L., S.R.), Cell Sciences (M.R.), Drug Metabolism and Pharmacology (L.D.), and Chemistry (I.I.), Berlex Biosciences, Richmond, California; Departamento de Inmunologiía y Oncología, Centro Nacional de Biotecnología/Consejo Superior de Investigaciones Científicas, Universidad Autónoma de Madrid, Cantoblanco, Madrid, Spain (L.K., J.G., G.M., C.M.-A.); and Department of Microbiology, University of Pennsylvania, Philadelphia, Pennsylvania (M.J.B., R.W.D.)
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Leonor Kremer
Departments of Immunology (C.A.H., R.H.), Molecular Pharmacology (M.L., S.R.), Cell Sciences (M.R.), Drug Metabolism and Pharmacology (L.D.), and Chemistry (I.I.), Berlex Biosciences, Richmond, California; Departamento de Inmunologiía y Oncología, Centro Nacional de Biotecnología/Consejo Superior de Investigaciones Científicas, Universidad Autónoma de Madrid, Cantoblanco, Madrid, Spain (L.K., J.G., G.M., C.M.-A.); and Department of Microbiology, University of Pennsylvania, Philadelphia, Pennsylvania (M.J.B., R.W.D.)
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Julio Gutiérrez
Departments of Immunology (C.A.H., R.H.), Molecular Pharmacology (M.L., S.R.), Cell Sciences (M.R.), Drug Metabolism and Pharmacology (L.D.), and Chemistry (I.I.), Berlex Biosciences, Richmond, California; Departamento de Inmunologiía y Oncología, Centro Nacional de Biotecnología/Consejo Superior de Investigaciones Científicas, Universidad Autónoma de Madrid, Cantoblanco, Madrid, Spain (L.K., J.G., G.M., C.M.-A.); and Department of Microbiology, University of Pennsylvania, Philadelphia, Pennsylvania (M.J.B., R.W.D.)
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Gabriel Marquez
Departments of Immunology (C.A.H., R.H.), Molecular Pharmacology (M.L., S.R.), Cell Sciences (M.R.), Drug Metabolism and Pharmacology (L.D.), and Chemistry (I.I.), Berlex Biosciences, Richmond, California; Departamento de Inmunologiía y Oncología, Centro Nacional de Biotecnología/Consejo Superior de Investigaciones Científicas, Universidad Autónoma de Madrid, Cantoblanco, Madrid, Spain (L.K., J.G., G.M., C.M.-A.); and Department of Microbiology, University of Pennsylvania, Philadelphia, Pennsylvania (M.J.B., R.W.D.)
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Carlos Martinez-A
Departments of Immunology (C.A.H., R.H.), Molecular Pharmacology (M.L., S.R.), Cell Sciences (M.R.), Drug Metabolism and Pharmacology (L.D.), and Chemistry (I.I.), Berlex Biosciences, Richmond, California; Departamento de Inmunologiía y Oncología, Centro Nacional de Biotecnología/Consejo Superior de Investigaciones Científicas, Universidad Autónoma de Madrid, Cantoblanco, Madrid, Spain (L.K., J.G., G.M., C.M.-A.); and Department of Microbiology, University of Pennsylvania, Philadelphia, Pennsylvania (M.J.B., R.W.D.)
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Mark J. Biscone
Departments of Immunology (C.A.H., R.H.), Molecular Pharmacology (M.L., S.R.), Cell Sciences (M.R.), Drug Metabolism and Pharmacology (L.D.), and Chemistry (I.I.), Berlex Biosciences, Richmond, California; Departamento de Inmunologiía y Oncología, Centro Nacional de Biotecnología/Consejo Superior de Investigaciones Científicas, Universidad Autónoma de Madrid, Cantoblanco, Madrid, Spain (L.K., J.G., G.M., C.M.-A.); and Department of Microbiology, University of Pennsylvania, Philadelphia, Pennsylvania (M.J.B., R.W.D.)
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Robert W. Doms
Departments of Immunology (C.A.H., R.H.), Molecular Pharmacology (M.L., S.R.), Cell Sciences (M.R.), Drug Metabolism and Pharmacology (L.D.), and Chemistry (I.I.), Berlex Biosciences, Richmond, California; Departamento de Inmunologiía y Oncología, Centro Nacional de Biotecnología/Consejo Superior de Investigaciones Científicas, Universidad Autónoma de Madrid, Cantoblanco, Madrid, Spain (L.K., J.G., G.M., C.M.-A.); and Department of Microbiology, University of Pennsylvania, Philadelphia, Pennsylvania (M.J.B., R.W.D.)
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Sofia Ribeiro
Departments of Immunology (C.A.H., R.H.), Molecular Pharmacology (M.L., S.R.), Cell Sciences (M.R.), Drug Metabolism and Pharmacology (L.D.), and Chemistry (I.I.), Berlex Biosciences, Richmond, California; Departamento de Inmunologiía y Oncología, Centro Nacional de Biotecnología/Consejo Superior de Investigaciones Científicas, Universidad Autónoma de Madrid, Cantoblanco, Madrid, Spain (L.K., J.G., G.M., C.M.-A.); and Department of Microbiology, University of Pennsylvania, Philadelphia, Pennsylvania (M.J.B., R.W.D.)
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Abstract

In this study, we report the first example of a nonpeptide chemokine receptor agonist, 2-{2-[4-(3-phenoxybenzyl)piperazin-1-yl]ethoxy}ethanol (ZK 756326), for the CC chemokine receptor CCR8. ZK 756326 inhibited the binding of the CCR8 ligand I-309 (CCL1), with an IC50 value of 1.8 μM. Furthermore, ZK 756326 was a full agonist of CCR8, dose-responsively eliciting an increase in intracellular calcium and cross-desensitizing the response of the receptor to CCL1. In addition, ZK 756326 stimulated extracellular acidification in cells expressing human CCR8. The ability of ZK 756326 to induce a response was receptor-specific and mediated through Gαi, because it could be blocked by treatment with pertussis toxin. The CCR8 agonist activated cells expressing murine CCR8, eliciting their chemotaxis and inducing phosphorylation of extracellular signal-regulated kinase ERK1/2. Like CCL1, ZK 756326 inhibited human immunodeficiency virus (HIV) fusion of cells expressing CD4 and CCR8. Finally, unlike mCCL1, ZK 756326 bound to and activated a form of mCCR8 that was mutated to eliminate O-linked sulfation at tyrosines 14 and 15. Therefore, ZK 756326 is most probably not binding in the same manner as CCL1 but can activate the switch mechanism involved in transducing signaling events. In summary, we have identified a nonpeptide agonist of CCR8. This compound may be useful in evaluating the physiological role of CCR8 in HIV infection, as well as in the general study of CCR8 biology without the constraints inherent to the use of protein agonists such as its natural ligand.

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Molecular Pharmacology: 69 (1)
Molecular Pharmacology
Vol. 69, Issue 1
1 Jan 2006
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Research ArticleArticle

Identification and Characterization of a Potent, Selective Nonpeptide Agonist of the CC Chemokine Receptor CCR8

Christopher A. Haskell, Richard Horuk, Meina Liang, Mary Rosser, Laura Dunning, Imadul Islam, Leonor Kremer, Julio Gutiérrez, Gabriel Marquez, Carlos Martinez-A, Mark J. Biscone, Robert W. Doms and Sofia Ribeiro
Molecular Pharmacology January 1, 2006, 69 (1) 309-316; DOI: https://doi.org/10.1124/mol.105.014779

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Research ArticleArticle

Identification and Characterization of a Potent, Selective Nonpeptide Agonist of the CC Chemokine Receptor CCR8

Christopher A. Haskell, Richard Horuk, Meina Liang, Mary Rosser, Laura Dunning, Imadul Islam, Leonor Kremer, Julio Gutiérrez, Gabriel Marquez, Carlos Martinez-A, Mark J. Biscone, Robert W. Doms and Sofia Ribeiro
Molecular Pharmacology January 1, 2006, 69 (1) 309-316; DOI: https://doi.org/10.1124/mol.105.014779
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