Blocking Chemokine Receptors

I n our first review on chemokines (1), we suggested that blockade of the IL-8 receptor or inhibition of IL-8 gene expression could be a new principle for designing antiin-flammatory agents. The unexpected growth of the chemo-kine family and consequent redundancy of the system eventually made it clear that acting at the level of chemo-kine gene expression was rather hopeless, but the idea of influencing inflammation with chemokine receptor antagonists has remained valid and inhibitors were recently put to the test. A new literature, including several articles in this issue of The Journal of Experimental Medicine , indicate that the idea was worth trying. How to Make a Chemokine Receptor Antagonist. By scanning mutagenesis (2) and selective deletion or substitution of NH 2-terminal residues (3, 4) it was shown that the Glu-Leu-Arg (ELR) motif preceding the first cysteine is essential for IL-8 activity. The ELR motif is conserved in all CXC chemokines that act on neutrophils (ELR chemo-kines) and is recognized by both IL-8 receptors, CXCR1 and CXCR2. It contributes to high-affinity binding and is the receptor triggering part of the molecule (5). The ELR motif alone, however, is not sufficient since linear and cyclic ELR-containing oligopeptides do not bind to the IL-8 receptors nor stimulate neutrophils (4). ELR chemokines have additional, selective binding sites, and it was not possible to confer activity on neutrophils to IP10 or monocyte chemoattractant protein (MCP)-1 by introducing the ELR motif at the NH 2 terminus (4). The three-dimensional nuclear magnetic resonance structure of IL-8 (6) shows that the conformationally disordered NH 2-terminal domain is anchored by the disulfide bonds to the well-ordered core of the protein. It is believed that interactions with domains of the core determine receptor selectivity and facilitate the access of the ELR motif to the receptor triggering site. The first chemokine antagonist was obtained by trunca-tion of IL-8. The analogue with an NH 2-terminal arginine followed by the first cysteine, (R)IL-8, is inactive on neu-trophils, but still has considerable receptor affinity and efficiently competes for binding with IL-8 and other ELR chemokines inhibiting their biological activities. Other antagonists were obtained by substitution within the ELR motif, and one of the most potent is (AAR)IL-8 (7). Antagonists are also generated by truncation of other ELR chemokines, which have high affinity for CXCR2, but only low affinity for CXCR1. Although (R)IL-8 blocks equally well, CXCR1 and CXCR2, the corresponding analogues of …