Chapter 17. Chemokines: Targets for novel therapeutics

Publisher Summary This chapter analyzes the role of chemokines in therapeutics. The study of the chemokine superfamily has provided a clearer understanding of some of the mechanisms by which the migration of leukocytes is controlled, during normal immune function as well as in pathology. The human repertoire of chemokines comprises a family of approximately 50 small proteins that share a high degree of homology in sequence, tertiary structure, and function. The family is comprised of four sub-classes based on the pattern of conserved cysteine residues. This classification also tends to parallel the shared cell type activities. The activity of chemokines is mediated by cell surface receptors that comprise a subfamily of the G protein-coupled receptor (GPCR) superfamily. Chemokines have generally been characterized as being proinflammatory factors. Some chemokines have been found to influence normal leukocyte trafficking and immune function, promote or inhibit angiogenesis, and may play a role in the growth and metastasis of cancer cells. The chapter focuses on the progress made towards identifying low molecular weight antagonists for CCR1, one of the receptors for MIP-lα and RANTES, CXCR2, one of the IL-8 receptors, and CCR2, the MCP-1 receptor (CCR2). An overview of CCR1 receptor antagonists is presented and the CXCR2 receptor antagonists are also analyzed.