title: "Chemokine receptors as therapeutic targets: Why aren't there more drugs?".
abstract: Chemokines are a family of around 40 small proteins, which are secreted by a variety of cells, including structural cell types and leukocytes of the immune system. Chemokines bind to their specific 7-transmembrane G protein-coupled receptors (GPCRs) and induce a variety of downstream signals which notably modulate polymerization of the actin cytoskeleton and thus drive cellular motility. Excessive or inappropriate release of chemokines is observed in many inflammatory diseases and so there has been a great effort in industry to target chemokine receptors. The large family of GPCRs regulate many physiological cellular processes and they have proved to be highly amenable to pharmacological intervention with small chemicals. Consequently GPCRs make attractive targets for drug discovery and indeed a large number of successful current therapeutics are either agonists or antagonists of GPCRs. The apparent lack of success with chemokine receptors has been frustrating and in this paper we discuss potential reasons for previous failures and also why there is considerable cause for optimism.
authors.affiliation: Airway Disease Infection Section, National Heart and Lung Institute, Imperial College, Norfolk Place, London W2 1 PG, UK. Electronic address: r.solari@imperial.ac.uk.
authors.forename: Roberto
authors.initials: R
authors.lastname: Solari
authors.affiliation: Leukocyte Biology Section, National Heart and Lung Institute, Imperial College London, South Kensington Campus, London SW7 2AZ, UK.
authors.forename: James E
authors.initials: JE
authors.lastname: Pease
authors.affiliation: Refractory Respiratory Inflammation DPU, Respiratory Therapy Area Unit, GlaxoSmithKline, Gunnels Wood Road, Stevenage, Herts SG1 2NY, UK.
authors.forename: Malcolm
authors.initials: M
authors.lastname: Begg
mesh_terms: D000818:Animals; D019380:Anti-HIV Agents / Q000009:adverse effects / Q000494:pharmacology* / Q000627:therapeutic use; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000009:adverse effects / Q000494:pharmacology* / Q000627:therapeutic use; D002986:Clinical Trials as Topic; D015195:Drug Design; D055808:Drug Discovery / Q000639:trends; D015507:Drugs, Investigational / Q000009:adverse effects / Q000494:pharmacology* / Q000627:therapeutic use; D057239:Early Termination of Clinical Trials; D006801:Humans; D007155:Immunologic Factors / Q000009:adverse effects / Q000494:pharmacology* / Q000627:therapeutic use; D008954:Models, Biological; D058990:Molecular Targeted Therapy / Q000009:adverse effects; D019707:Receptors, Chemokine / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D019380:Anti-HIV Agents; D000894:Anti-Inflammatory Agents, Non-Steroidal; D015507:Drugs, Investigational; D007155:Immunologic Factors; D019707:Receptors, Chemokine
keywords: Chemokine; Chemokine receptor; Drug discovery; Inflammation