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      Targeting chemokine receptors in disease – a case study of CCR4

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          Abstract

          Since their early 1990s, the chemokine receptor family of G protein-coupled receptors (GPCRs) has been the source of much pharmacological endeavour. Best known for their key roles in recruiting leukocytes to sites of infection and inflammation, the receptors present themselves as plausible drug targets for therapeutic intervention. In this article, we will focus our attention upon CC Chemokine Receptor Four (CCR4) which has been implicated in diseases as diverse as allergic asthma and lymphoma. We will review the discovery of the receptors and their ligands, their perceived roles in disease and the successful targeting of CCR4 by both small molecule antagonists and monoclonal antibodies. We will also discuss future directions and strategies for drug discovery in this field.

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          Most cited references105

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          Chemokines: a new classification system and their role in immunity.

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            International Union of Basic and Clinical Pharmacology. [corrected]. LXXXIX. Update on the extended family of chemokine receptors and introducing a new nomenclature for atypical chemokine receptors.

            Sixteen years ago, the Nomenclature Committee of the International Union of Pharmacology approved a system for naming human seven-transmembrane (7TM) G protein-coupled chemokine receptors, the large family of leukocyte chemoattractant receptors that regulates immune system development and function, in large part by mediating leukocyte trafficking. This was announced in Pharmacological Reviews in a major overview of the first decade of research in this field [Murphy PM, Baggiolini M, Charo IF, Hébert CA, Horuk R, Matsushima K, Miller LH, Oppenheim JJ, and Power CA (2000) Pharmacol Rev 52:145-176]. Since then, several new receptors have been discovered, and major advances have been made for the others in many areas, including structural biology, signal transduction mechanisms, biology, and pharmacology. New and diverse roles have been identified in infection, immunity, inflammation, development, cancer, and other areas. The first two drugs acting at chemokine receptors have been approved by the U.S. Food and Drug Administration (FDA), maraviroc targeting CCR5 in human immunodeficiency virus (HIV)/AIDS, and plerixafor targeting CXCR4 for stem cell mobilization for transplantation in cancer, and other candidates are now undergoing pivotal clinical trials for diverse disease indications. In addition, a subfamily of atypical chemokine receptors has emerged that may signal through arrestins instead of G proteins to act as chemokine scavengers, and many microbial and invertebrate G protein-coupled chemokine receptors and soluble chemokine-binding proteins have been described. Here, we review this extended family of chemokine receptors and chemokine-binding proteins at the basic, translational, and clinical levels, including an update on drug development. We also introduce a new nomenclature for atypical chemokine receptors with the stem ACKR (atypical chemokine receptor) approved by the Nomenclature Committee of the International Union of Pharmacology and the Human Genome Nomenclature Committee.
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              Transduction of receptor signals by beta-arrestins.

              The transmission of extracellular signals to the interior of the cell is a function of plasma membrane receptors, of which the seven transmembrane receptor family is by far the largest and most versatile. Classically, these receptors stimulate heterotrimeric G proteins, which control rates of generation of diffusible second messengers and entry of ions at the plasma membrane. Recent evidence, however, indicates another previously unappreciated strategy used by the receptors to regulate intracellular signaling pathways. They direct the recruitment, activation, and scaffolding of cytoplasmic signaling complexes via two multifunctional adaptor and transducer molecules, beta-arrestins 1 and 2. This mechanism regulates aspects of cell motility, chemotaxis, apoptosis, and likely other cellular functions through a rapidly expanding list of signaling pathways.
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                Author and article information

                Contributors
                Journal
                Eur J Pharmacol
                Eur. J. Pharmacol
                European Journal of Pharmacology
                Elsevier Science
                0014-2999
                1879-0712
                15 September 2015
                15 September 2015
                : 763
                : Pt B
                : 169-177
                Affiliations
                [a ]Airway Disease Infection Section, MRC-Asthma UK Centre in Allergic Mechanisms of Asthma, National Heart and Lung Institute, Imperial College London, Norfolk Place, London W2 1PG, United Kingdom
                [b ]Leukocyte Biology Section, MRC-Asthma UK Centre in Allergic Mechanisms of Asthma, National Heart and Lung Institute, Imperial College London, South Kensington Campus, London SW7 2AZ, United Kingdom
                Author notes
                [* ]Corresponding author. j.pease@ 123456imperial.ac.uk
                Article
                S0014-2999(15)30011-X
                10.1016/j.ejphar.2015.05.018
                4784718
                25981299
                984f4c8f-f21c-4840-8cab-d29d0a259d43
                © 2015 The Authors

                This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

                History
                : 31 January 2015
                : 17 April 2015
                : 12 May 2015
                Categories
                Article

                Pharmacology & Pharmaceutical medicine
                chemokine,receptor,signaling,antagonist,inflammation,asthma leukaemia

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