Allosteric effects of antagonists on signalling by the chemokine receptor CCR5

Antagonists of the chemokine receptor, CCR5, may provide important new drugs for the treatment of HIV-1. In this study we have examined the mechanism of action of two functional antagonists of the chemokine receptor CCR5 (UK-396,794, UK-438,235) in signalling and internalisation assays using CHO cel...

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Bibliographic Details
Published in:Biochemical pharmacology 2007-09, Vol.74 (6), p.891-897
Main Authors: Haworth, Ben, Lin, Hong, Fidock, Mark, Dorr, Pat, Strange, Philip G.
Format: Article
Language:English
Subjects:
[ 35S]GTPγS binding
Allosteric Regulation
Animals
Antagonists
Biological and medical sciences
CCR5 Receptor Antagonists
Chemokine CCL5
Chemokine CCL8
Chemokine receptor (CCR5)
Chemokines
CHO Cells
Cricetinae
Cricetulus
Endocytosis
Guanosine 5'-O-(3-Thiotriphosphate) - metabolism
HIV
Human immunodeficiency virus 1
Human viral diseases
Immunodeficiencies
Immunodeficiencies. Immunoglobulinopathies
Immunopathology
Infectious diseases
Medical sciences
Pharmacology. Drug treatments
Receptor internalisation
Receptors, CCR5 - analysis
Receptors, CCR5 - metabolism
Signal Transduction - drug effects
Viral diseases
Viral diseases of the lymphoid tissue and the blood. Aids
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Summary:Antagonists of the chemokine receptor, CCR5, may provide important new drugs for the treatment of HIV-1. In this study we have examined the mechanism of action of two functional antagonists of the chemokine receptor CCR5 (UK-396,794, UK-438,235) in signalling and internalisation assays using CHO cells expressing CCR5. Both compounds were potent inverse agonists versus agonist-independent [ 35S]GTPγS binding to membranes of CHO cells expressing CCR5. Both compounds also acted as allosteric inhibitors of CCL5 (RANTES) and CCL8 (MCP-2)-stimulated [ 35S]GTPγS binding to CHO-CCR5 membranes, reducing the potency and maximal effects of the two chemokines. The data are consistent with effects of the allosteric inhibitors on both the binding and signalling of the chemokines. Both compounds inhibited CCR5 internalisation triggered by chemokines. When CHO-CCR5 cells were treated with either of the two compounds for prolonged periods of time (24 h) an increase (∼15%) in cell surface CCR5 was detected.
ISSN:0006-2952
1873-2968
DOI:10.1016/j.bcp.2007.06.032