Trends in Immunology
Multi-faceted strategies to combat disease by interference with the chemokine system
Section snippets
Chemokines and disease
The holy grail of many biotechnology and pharmaceutical companies is to find the key targets that control pathologies and to develop appropriate therapeutics to control them. Recently, there have been several success stories, through the targeting of key proteins that are involved in autoimmune diseases with therapeutic antibodies. Antibody neutralization of the cytokine tumor necrosis factor-α (TNF-α) represents one such successful therapeutic platform, and attempts to inhibit specific
Modes of intervention
There are several approaches to interfering with identified targets (Figure 2), which are described in more detail in later sections. The approach taken depends on several factors, including whether the target is intracellular or extracellular, exemplified by the traditional division of anti-inflammatory strategies by the biotechnology companies and the pharmaceutical companies as ‘outside the cell’ and ‘inside the cell’ intervention, respectively. Interference with the activity of cytokines,
Small molecules
The most widely adopted approach to block the interaction of the chemokine with its receptor is using small molecule antagonists (Figure 3a). It has been an exciting and instructive experience to see the field evolve, from the identification of the first chemokine receptors in 1991 8, 9, until today, where several small molecule chemokine receptor antagonists are being evaluated in advanced human clinical trials. In the pioneering days, the main challenge consisted of designing small molecules
Modified chemokines
A second approach to block the chemokine–receptor interaction is by using chemokines that have been modified in such a way that they retain high affinity for their receptor but have abrogated signaling properties, thereby producing a receptor antagonist (Figure 3b). Traditionally, these have been chemokines modified at their N-terminus, the region, which in most chemokines, is responsible for signaling. The approach of producing N-terminally truncated chemokines was particularly suitable to
Antibodies
The use of neutralizing mAbs (Figure 3c), principally against the chemokines themselves, has been used extensively in animal models of disease, although surprisingly, few are being developed for therapeutic use – perhaps a reflection of the worry that orally available small molecule receptor inhibitors would supersede the use of antibodies. Therefore, the use of neutralizing antibodies against specific chemokines has, for the moment, been of more use in proving that inhibition of chemokine
Binding proteins
An interesting conundrum exists in the human system: the human genome has evolved several endogenous strategies to combat inflammation, in the guise of binding proteins that neutralize proinflammatory cytokines (Figure 3d). Examples of these are, IL-1 receptor α (IL-1Rα) [29], TNF-binding protein-I (TBP-I) and TBP-II [30], interferon receptor α (IFNRα) [31] and IL-18-binding protein (IL-18BP) [32]. Similarly, viruses have evolved to produce such proteins and their genomes encode binding
Perspectives
The initial discovery of chemokines led to the perhaps naïve hope that each leukocyte subtype would express a specific chemokine receptor, which would facilitate therapeutic intervention in an unprecedented manner. However, our knowledge of the system as it is today indicates that this is not the case. The chemokine system is highly complex. It is often described as redundant – this is certainly evident from in vitro studies, although we believe that there are certainly levels of control and
References (56)
Chemokine–receptor interactions: GPCRs, glycosaminoglycans and viral chemokine binding proteins
Adv. Protein Chem.
(2004)Chemokines: multiple levels of leukocyte migration control
Trends Immunol.
(2004)Searching for chemokine receptor binding antagonists by high throughput screening
J. Biomol. Screen.
(1997)Identification of a potent, selective non-peptide CXCR2 antagonist that inhibits interleukin-8-induced neutrophil migration
J. Biol. Chem.
(1998)Identification and characterization of small molecule functional antagonists of the CCR1 chemokine receptor
J. Biol. Chem.
(1998)Species selectivity of a small molecule antagonist for the CCR1 chemokine receptor
Eur. J. Pharmacol.
(2000)CCR1-specific non-peptide antagonist: efficacy in a rabbit allograft rejection model
Immunol. Lett.
(2001)A non-peptide functional antagonist of the CCR1 chemokine receptor is effective in rat heart transplant rejection
J. Biol. Chem.
(2001)Extension of recombinant human RANTES by the retention of the initiating methionine produces a potent antagonist
J. Biol. Chem.
(1996)Efficacy and safety of a monoclonal antibody recognizing interleukin-8 in COPD: a pilot study
Chest
(2004)
Interleukin-18 binding protein: a novel modulator of the Th1 cytokine response
Immunity
Inhibition of intimal hyperplasia in transgenic mice conditionally expressing the chemokine-binding protein M3
Am. J. Pathol.
Acute and relapsing experimental autoimmune encephalomyelitis are regulated by differential expression of the CC chemokines macrophage inflammatory protein-1α and monocyte chemotactic protein-1
J. Neuroimmunol.
Chemokines in innate and adaptive host defense: basic chemokinese grammar for immune cells
Annu. Rev. Immunol.
Cancer and the chemokine network
Nat. Rev. Cancer
Human interferon-inducible 10-kDa protein and human interferon-inducible T cell α chemoattractant are allotopic ligands for human CXCR3: differential binding to receptor states
Mol. Pharmacol.
Molecular characterization of the chemokine receptor CXCR3: evidence for the involvement of distinct extracellular domains in a multi-step model of ligand binding and receptor activation
Eur. J. Immunol.
A binding pocket for a small molecule inhibitor of HIV-1 entry within the transmembrane helices of CCR5
Proc. Natl. Acad. Sci. U. S. A.
Structure and functional expression of a human interleukin-8 receptor
Science
Cloning of complementary DNA encoding a functional human interleukin-8 receptor
Science
Strategies for the discovery of cytokine receptor antagonists
Drug News Perspect.
New therapeutics that modulate chemokine networks
Nat. Rev. Drug Discov.
Unraveling the chemistry of chemokine receptor ligands
Chem. Rev.
Nonpeptide CXCR2 antagonist prevents neutrophil accumulation in hyperoxia-exposed newborn rats
J. Pharmacol. Exp. Ther.
An antagonist of monocyte chemoattractant protein 1 (MCP-1) inhibits arthritis in the MRL-lpr mouse model
J. Exp. Med.
Gene therapy via blockade of monocyte chemoattractant protein-1 for renal fibrosis
J. Am. Soc. Nephrol.
Chemokine receptors: multifaceted therapeutic targets
Nat. Rev. Immunol.
Potent inhibition of HIV-1 infectivity in macrophages and lymphocytes by a novel CCR5 antagonist
Science
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