Chemokine receptors as therapeutic targets.

Chemokines are a group of structurally related secretory and transmembrane proteins whose major tasks are to coordinately recruit various leukocyte populations into target tissue sites via specific receptors. In humans, there are close to 50 chemokines, 18 signal transducing receptors and 5 decoy/scavenger receptors. Functionally, chemokines are grouped into two major categories. Inflammatory chemokines are those attracting and activating cells such as neutrophils, monocytes, and eosinophils, and thus play major roles in acute-type inflammatory conditions. They are characterized by high ligand redundancy and receptor promiscuity. This probably enables robust recruitment of inflammatory cells in acute conditions. On the other hand, immune chemokines are those mainly attracting lymphoid cells and dendritic cells, and are thus involved in immune responses and chronic inflammatory diseases. Furthermore, their ligand-receptor relationships are relatively monogamous. Chemokine receptors are all seven-transmembrane G protein-couple receptors, the class of receptors frequently targeted by many successful drugs. Thus, chemokine receptors are considered to be highly promising drug targets for inflammatory and immunological diseases, and for the last two decades, many pharmaceutical companies have been trying to develop drugs blocking specific chemokine receptors. However, there are only few instances that have reached the approval for clinical use. There are several possible reasons for the present stalemate. For example, the intrinsic functional redundancy in the chemokine system may have made blocking a single receptor useless. Furthermore, the unprecedented species differences even between humans and mice may have caused problems in determination of clinical application of each chemokine receptor blockade from animal studies and also in conducting preclinical studies of candidate drugs in animals. Thus, the potential of the chemokine system as drug targets may still remain underexplored. This review first overviews current potential clinical applications of individual chemokine receptors and then describes in detail the drugs now in clinical use : Maraviroc (CCR5 antagonist), Plerixafor (CXCR4 antagonist), and Mogamulizmab (anti-CCR4).