Development and evaluation of pharmacological agents targeting chemokine receptors
Section snippets
Chemokines and their receptors
Chemokines belong to a large family of small, chemotactic cytokines characterized by a distinctive pattern of four conserved cysteine residues [2]. They are divided into two major (CXC and CC) and two minor (C and CX3C) groups, dependent on the number and spacing of the first two conserved cysteine residues. Although originally identified on the basis of their ability to regulate the trafficking of immune cells, the biological role of chemokines goes well beyond this simple description of their
Drug development
The development of a drug, from its first identification in a high capacity screen to its approval by the Food and Drug Administration as an authorized therapeutic for use in humans, is a long and arduous process involving numerous stages that include the following steps.
(1) Drug specificity—The drug should have high specificity for the chosen target, i.e., the drug is tested in multiple screens against a variety of related and unrelated enzymes, receptors, etc., to ensure that it is highly
CCR1 antagonists
Insight into the physiological and pathophysiological roles of CCR1 have been provided by studies with potent CCR1 antagonists (Fig. 1, compound 1) [18], [20], [21], [22] and confirmed by targeted gene-disruption studies [23], [24], [25].
Three separate studies with potent CCR1 receptor antagonists have illuminated the role of CCR1 in the pathophysiology of multiple sclerosis and organ transplant rejection [18], [21], [22]. Several potent nonpeptide CCR1 antagonists have been reported (Fig. 1)
CCR5 antagonists
The unmasking, several years ago, of the chemokine receptors CCR5 and CXCR4 as major coreceptors, along with CD4, for HIV-1 invasion provided a strong impetus for the rapid development of chemokine receptor antagonists by the pharmaceutical industry. The early stages of HIV-1 infection appear to involve macrophage-tropic strains of HIV-1, known as R5, which use mainly CCR5 as coreceptors [28].
HIV-1 resistance exhibited by some exposed but uninfected individuals [29] is due, in part, to a 32-bp
Conclusion
The immune system is the first line of defense in infection and disease; however, when this process breaks down defenders become attackers and immune cells can target and destroy normal healthy host cells, resulting in inflammation and leading to autoimmune diseases like multiple sclerosis and diabetes. With the discovery of chemokines and the central role they play in leukocyte recruitment came the realization that small-molecule inhibitors that blocked these effects could be very useful
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Structural dynamics of chemokine receptors
2023, Vitamins and HormonesChemokine receptor oligomerization: A further step toward chemokine function
2012, Immunology LettersCitation Excerpt :Given the correlation between the expression of specific chemokines and the specific recruitment of cell populations in the course of certain disease processes, the chemokines and their receptors have become a major focus in research and pharmaceutical laboratories. Their medical importance has led to intense effort to obtain structural information that could aid the development and optimization of therapeutics to inhibit their functions [20–22]. Conclusions drawn from animal models unfortunately cannot always be extrapolated to man, and although there are several molecules in clinical trials to target chemokines and their receptors in inflammatory diseases, results so far are very disappointing.
Chemokine Receptor CCR5 Mediates AlloImmune Responses in Graft-versus-Host Disease
2010, Biology of Blood and Marrow TransplantationCitation Excerpt :Chemokines and their receptors are important in many human diseases, including HIV, autoimmune disease, inflammatory disease, and organ graft rejection [35]. Currently, small molecule antagonists and humanized monoclonal antibodies (mAbs) targeting chemokine receptors are developed by industry and tested in preclinical models as well as in phase I trials [36-39]. Our data demonstrated that CCR5+ T cells are important in mediating GVHD in humans.
Allosteric inhibitors of chemoattractant receptors: opportunities and pitfalls
2008, Trends in Pharmacological SciencesMonocyte Chemoattractant Protein-1 and Macrophage Inflammatory Protein-1α as Possible Biomarkers for the Chronic Pelvic Pain Syndrome
2008, Journal of UrologyCitation Excerpt :Hence, both CPPS subtypes may represent part of the same clinical spectrum and the chemokines MCP-1 and MIP-1α may be initiating the early inflammatory process. Cytokine modulators including MCP-1 receptor antagonists, anti-MCP-1 antibodies, and MIP-1α receptor antagonists that are currently in clinical trials may serve as potential targets for therapeutic intervention against inflammatory and hyperalgesic pathways in both CPPS subtypes.12 Our study also represents the first of its kind to reveal a correlation between clinical pain and cytokine levels.
Physiological immunity or pathological autoimmunity - A question of balance
2007, Autoimmunity ReviewsCitation Excerpt :The CKR, a member of the G-protein Coupled Receptor (GPCR) family, has a drug target pedigree. More than forty five percent of all marketed drugs target GPCRs [10]. Given that the ligands of GPCRs are low molecular weight peptides (histamine, dopamine, serotonin), it was predicted that CKRs would be tractable targets for small molecule drugs [11].