Elsevier

Immunology Letters

Volume 65, Issues 1–2, 1 January 1999, Pages 35-40
Immunology Letters

Chemokine receptors and their role in leukocyte activation

https://doi.org/10.1016/S0165-2478(98)00121-7Get rights and content

Abstract

Chemokines were originally isolated based on their abilities to selectively attract and recruit leukocyte populations. Over the last few years there has been an explosion in the number of new chemokines identified, and as a result many receptors previously considered to be orphans have now been paired up with their ligands. Here we review some of the latest results in this area, illustrating with data from our laboratory. The central question from a drug discovery perspective, is to show whether inhibiting chemokine receptors leads to a change in disease status. Although we are still a long way from having candidate molecules to take into the clinic, a flavour of what may be possible can be inferred from mutant chemokines with antagonistic properties. We discuss recent data using two of these proteins, Met-RANTES which has anti-inflammatory properties, and AOP-RANTES which has been shown to prevent infection of macrophages and T-cells by M-tropic HIV strains.

Section snippets

Defining the players: new chemokines and their receptors

Chemokines are a large superfamily of small (8–10 kDa) proteins, which are involved in the trafficking and recruitment of leukocytes. The first chemokines to be identified came from cell culture media or leukocyte exudates, and include the two mainstays of chemokine biology, Interleukin-8 (IL-8) [1] and Monocyte Chemoattractant Protein -1 (MCP-1) [2]. Based on the spacings of a pair of amino terminal cysteines, they could be classified into CXC chemokines, and CC chemokines.

By 1995 a second

Modified chemokines as receptor antagonists

Clearly, one of the goals of pharmaceutical research in the chemokine area is to find small molecules which are orally active, as selective anti-inflammatory agents [11]. One set of useful tools that have come out of the work of many groups in the chemokine area, is based on the fact that modifications of the amino terminal region of chemokines has led to receptor antagonists, which often retain partial agonist activity. In our studies, we found that when RANTES is expressed in E. coli, the

Blockade of HIV infection

In late 1995 the chemokine world was shaken up by the discovery that chemokines could modulate infection of host cells by HIV-1 and other primate lentiviruses. Rapidly over the first few months of 1996, the fact that chemokine receptors are required as co-receptors for fusion between the virus and host cells emerged [19], [20]. The fusion of T-tropic HIV-1 viruses with the membrane of the host cell required the presence of CXCR4, whereas the fusion of the M-tropic viruses required CCR5.

Conclusion

Over the last 6 years, our group and many others have worked at trying to define as many as possible of the chemokines and their receptors using a variety of molecular biology techniques. Our hope is that specific inhibition of chemokine receptors using small molecules (which would be orally available therapeutics) will be possible and that will lead to new classes of anti-inflammatory and even anti-retroviral therapy. In the meantime, we have also generated several variants of human chemokines

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