Yoshie Osamu
Department of Microbiology, Kinki University Faculty of Medicine.
Nihon Rinsho Meneki Gakkai Kaishi. 2013;36(4):189-96. doi: 10.2177/jsci.36.189.
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).
趋化因子是一组结构相关的分泌性和跨膜蛋白，其主要任务是通过特定受体协同招募各种白细胞群体至靶组织部位。在人类中，有近50种趋化因子、18种信号转导受体和5种诱饵/清道夫受体。在功能上，趋化因子分为两大类。炎症趋化因子可吸引并激活嗜中性粒细胞、单核细胞和嗜酸性粒细胞等细胞，因此在急性炎症状态中起主要作用。它们的特点是配体冗余度高且受体混杂性高。这可能使急性状态下炎症细胞得以强劲募集。另一方面，免疫趋化因子主要吸引淋巴细胞和树突状细胞，因此参与免疫反应和慢性炎症疾病。此外，它们的配体-受体关系相对专一。趋化因子受体均为七跨膜G蛋白偶联受体，这类受体是许多成功药物的常见作用靶点。因此，趋化因子受体被认为是治疗炎症和免疫疾病极具前景的药物靶点，在过去二十年中，许多制药公司一直在尝试开发阻断特定趋化因子受体的药物。然而，仅有少数药物获批临床使用。目前的僵局可能有几个原因。例如，趋化因子系统内在的功能冗余可能导致阻断单一受体无效。此外，即使在人类和小鼠之间也存在前所未有的物种差异，这可能在根据动物研究确定每种趋化因子受体阻断剂的临床应用以及在动物中进行候选药物的临床前研究时引发问题。因此，趋化因子系统作为药物靶点的潜力可能仍未得到充分探索。本综述首先概述了各个趋化因子受体当前潜在的临床应用，然后详细介绍了目前正在临床使用的药物：马拉维若（CCR5拮抗剂）、普乐沙福（CXCR4拮抗剂）和莫加莫珠单抗（抗CCR4）。
