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  • Review Article
  • Published:

New therapeutics that modulate chemokine networks

Key Points

  • Chemokines are small cytokines that control a wide variety of biological and pathological processes, from immunosurveillance to inflammation, and from viral infection to cancer.

  • Chemokine receptors are seven-transmembrane-domain (7TM) G-protein-coupled receptors, and these are the only cytokines that work though such receptors. Because 7TM receptors are often tractable drug targets, chemokine receptors were seen as promising drug targets.

  • Small molecules (with molecular masses less < 500 Da) have been found as antagonists for many of the chemokine receptors, and many of these show receptor selectivity. In many cases, these have been shown to be active in animal models of disease.

  • The most advanced molecules in clinical development seem to be those that target the two HIV co-receptors, CCR5 and CXCR4. An analysis of the patent literature predicts that over the next few years, there should be a continued flow of chemokine antagonists for in vivo testing in animal models of disease.

  • Chemokines or modified chemokines still represent a therapeutic approach: one chemokine myeloid-progenitor inhibitory factor is now in Phase II clinical trials, and several others are set to enter clinical trials in the next few years.

Abstract

Chemokines are small cytokines that control a wide variety of biological and pathological processes, from immunosurveillance to inflammation, and from viral infection to cancer. The numerous known chemokine receptors have given hope that selective receptor antagonism might be possible, which could allow us to control which cells are recruited and activated at any time and in any place. As chemokine receptors are G-protein-coupled receptors, which are classical targets for the pharmaceutical industry, it is hoped that chemokines could be the first cytokines for which small-molecule receptor antagonists could be developed. Recently, reports of chemokine-receptor antagonists, both in vitro and in animal models of disease, have been published. It is anticipated that this field could produce clinically useful therapies in the next few years.

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Figure 1: Model of the interaction of a chemokine with its receptor, based on the molecular structures of CCR5 and RANTES.
Figure 2: Electrostatic models of the dimeric chemokines for IL-8, RANTES and MIP-1α.
Figure 3: Chemical structures of representative small-molecule chemokine-receptor antagonists.
Figure 4: Chemical structures of representative small-molecule chemokine-receptor antagonists.
Figure 5: The evolution of small-molecule chemokine-receptor-antagonist literature.

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Acknowledgements

The authors thank J. Shaw for Figures 1 and 2, and our colleagues in Geneva for useful discussions — especially A. Proudfoot for cigarettes.

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Correspondence to Timothy N. C. Wells.

Supplementary information

41573_2002_BFnrd795_MOESM1_ESM.pdf

Supplementary Box 1 | The following international patent applications claim small-molecule antagonists for chemokine recptors (PDF 22 kb)

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DATABASES

LocusLink

CCR1

CCR2

CCR3

CCR4

CCR5

CCR6

CCR7

CD4

CXCR1

CXCR2

CXCR3

CXCR4

CXCR5

Duffy-antigen receptor

Eotaxin

IL-1

IL-5

IL-8

MCP-1

MCP-3

MIP-1α

MPIF-1

neurokinins

RANTES

TNF-α

OMIM

asthma

atherosclerosis

glomerular nephritis

multiple sclerosis

psoriasis

rheumatoid arthritis

FURTHER INFORMATION

Cytokine Family Database

British Pharmacological Society

G Protein-Coupled Receptor Database (GPCRDB)

Glossary

CHEMOKINES

Chemokines are a large family of cytokines that have a wide variety of biological actions. Originally, they were identified as controllers of the routine transport of immune cells, and they directed the migration of cells during inflammatory response. This is how they get their name — it is a contraction of chemotactic cytokines.

CHEMOKINE RECEPTORS

All chemokine receptors identified so far belong to the superfamily of seven-transmembrane-domain G-protein-coupled receptors.

CXC AND CC CHEMOKINES

Chemokines were originally identified and classified on the basis of a cysteine motif near the amino terminus. The prototype chemokine, interleukin-8, has these two cysteines separated by a single amino acid, leading to a CXC motif. Soon after, monocyte chemotactic protein-1 was purified, and was shown to have the amino-terminal cysteines adjacent to each other; members of this family are therefore known as CC chemokines. Other configurations of the disulphide bonds have since been described, presenting a C and a CX3C motif.

EOTAXIN

A highly selective chemokine that was initially identified as an eosinophil attractant.

ELECTROSTATIC PROFILES

A pictorial representation of the electrostatic fields produced by proteins.

NEUTROPHIL

A phagocytic cell of the myeloid lineage that has an important role in the inflammatory response, undergoing chemotaxis towards sites of infection or wounding.

CHEMOATTRACTANT

An agent that attracts cells in tests of cellular migration.

NANOMOLAR ANTAGONISTS

An antagonist with a potency < 1 μM but > 1 nM.

EOSINOPHIL

An allergic effector cell that is strongly associated with allergic inflammation of many kinds.

BICYCLAM

A dimeric macrocycle, which contains (in this case) two polyamine rings.

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Schwarz, M., Wells, T. New therapeutics that modulate chemokine networks. Nat Rev Drug Discov 1, 347–358 (2002). https://doi.org/10.1038/nrd795

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