Pharmacological modulation of chemokine receptor function

Danny J Scholten, Meritxell Canals, David Maussang, Luc Roumen, Martine J Smit, Maikel Wijtmans, Chris De Graaf, Henry F Vischer, Rob Leurs

Research output: Contribution to journalArticleResearchpeer-review

164 Citations (Scopus)

Abstract

G protein-coupled chemokine receptors and their peptidergic ligands are interesting therapeutic targets due to their involvement in various immune-related diseases, including rheumatoid arthritis, multiple sclerosis, inflammatory bowel disease, chronic obstructive pulmonary disease, HIV-1 infection and cancer. To tackle these diseases, a lot of effort has been focused on discovery and development of small-molecule chemokine receptor antagonists. This has been rewarded by the market approval of two novel chemokine receptor inhibitors, AMD3100 (CXCR4) and Maraviroc (CCR5) for stem cell mobilization and treatment of HIV-1 infection respectively. The recent GPCR crystal structures together with mutagenesis and pharmacological studies have aided in understanding how small-molecule ligands interact with chemokine receptors. Many of these ligands display behaviour deviating from simple competition and do not interact with the chemokine binding site, providing evidence for an allosteric mode of action. This review aims to give an overview of the evidence supporting modulation of this intriguing receptor family by a range of ligands, including small molecules, peptides and antibodies. Moreover, the computer-assisted modelling of chemokine receptor-ligand interactions is discussed in view of GPCR crystal structures. Finally, the implications of concepts such as functional selectivity and chemokine receptor dimerization are considered.
Original languageEnglish
Pages (from-to)1617 - 1643
Number of pages27
JournalBritish Journal of Pharmacology
Volume165
Issue number6
DOIs
Publication statusPublished - 2012
Externally publishedYes

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