Chemokine receptor therapeutics

Figure 1 Molecular structures of chemokine receptor therapeutics AMD3100/plerixafor and maraviroc.

Chemokines have been shown to be associated with a number of autoinflammatory diseases including multiple sclerosis, rheumatoid arthritis, atherosclerosis, dermatitis, and organ transplant rejection. Evidence, reviewed below, is mounting that chemokines may play a major role in the pathophysiology of these diseases and thus chemokine receptor antagonists could prove to be useful therapeutics in treating these and other proinflammatory diseases. 

Chemokines/Chemokine Receptor Based Therapeutics Trials and Tribulations... 

As members of the GPCR superfamily have historically dominated drug development programs, so too has interest in chemokine receptors as therapeutic targets. 

Approximately 30% to 40% of currently licensed drugs are targeted at GPCRs and thus represent a highly significant source of income for many pharmaceutical companies (80). In the specific context of chemokine receptors, it is clear that they are involved in a number of prominent pathologies and thus represent an important therapeutic target (81). For example, chemokines and their receptors lie at the center of all immune and inflammatory disorders and are responsible for the aberrant accumulation of leukocytes at inflamed sites in autoimmune conditions. In addition, over the past 12 years, it has become clear... 

Until recently, it has been difficult to dissect the relative role of each che-mokine in the inflammatory processes leading to allograft rejection, especially as many chemokines and chemokine receptors are seemingly redundant (2,8). Indeed, during allograft rejection, the expression of many chemokines and chemokine receptors can be detected in the allograft—only a few of which represent viable targets for therapeutic intervention (5,6). 

Segerer S, Nelson PJ, Schlondorff D. Chemokines, chemokine receptors, and renal disease from basic science to pathophysiologic and therapeutic studies. J Am Soc Nephrol 2000 11 152-176. 

Quinones MP, Estrada CA, Kalkonde Y, et al. The complex role of the chemokine receptor CCR2 in collagen-induced arthritis implications for therapeutic targeting of CCR2 in rheumatoid arthritis. J Mol Med 2005 83(9) 672-681. 

Understanding the nature of the domains or elements on the chemokine receptor coreceptors is also of significant importance, especially with regard to the development of coreceptor-blocking therapeutics. HIV-1 gpl20 interacts with multiple extracellular domains of the chemokine receptors to mediate binding, and the N-terminus and extracellular loop (ECL) number 2 of CCR5... 

Fibrosis is a dynamic progression of dysregulated wound healing that results from chronic inflammation. It is a common pathology regardless of the tissue involved, and therefore, the mechanisms that progress to fibrosis can be widely applied. The recruitment, activation, and proliferation of inflammatory cells and their cooperation with resident cells appears to rely on the action of chemokines and the differential expression of the chemokine receptors by these cells. Thus, chemokine receptors make particularly attractive therapeutic targets. 

Chemokine Receptors in Cancer Pathobiology and Potential Therapeutic Targets... 

Niwa R, Shoji-Hosaka E, Sakurada M, et al. Defucosylated chimeric anti-CC chemokine receptor 4 IgGl with enhanced antibody-dependent cellular cytotoxicity shows potent therapeutic activity to T-cell leukemia and lymphoma. Cancer Res 2004 64 2127-2133. 

The success of chemokine receptor antagonists as therapeutics will depend on a number of factors. It is clear that CCR5 antagonists will probably pave the way as the first approved chemokine drugs to treat disease in man. Here the situation is quite clear. The AIDS virus, HIV, utilizes CCR5 as a coreceptor to... 

Ribeiro S, Horuk R. Chemokine receptor antagonists from the bench to the clinic. In Hannan A, Engelhardt B, eds. Leukocyte Trafficking-Molecular mechanism, therapeutic targets, and methods. Weinheim Wiley-VCH 2005 371 402. 

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