CXCR3 antagonist VUF10085 binds to an intrahelical site distinct from that of the broad spectrum antagonist TAK-779.

Background And Purpose: The chemokine receptor CXCR3 is implicated in a variety of clinically important diseases, notably rheumatoid arthritis and atherosclerosis. Consequently, antagonists of CXCR3 are of therapeutic interest. In this study, we set out to characterize binding sites of the specific low MW CXCR3 antagonist VUF10085 and the broad spectrum antagonist TAK-779 which blocks CXCR3 along with CCR2 and CCR5.

Recent progress in the development of antagonists to the chemokine receptors CCR3 and CCR4.

Introduction: The chemokine receptors CCR3 and CCR4 have been shown to be important therapeutic targets for the treatment of a variety of diseases. Although only two chemokine receptor inhibitors have been approved so far, there are numerous compounds that are in various stages of development.

Areas Covered: In this review article, the authors provide an update on the progress made in the identification of antagonists against the chemokine receptors CCR3 and CCR4 from 2009 to the present.

International Union of Basic and Clinical Pharmacology. [corrected]. LXXXIX. Update on the extended family of chemokine receptors and introducing a new nomenclature for atypical chemokine receptors.

Sixteen years ago, the Nomenclature Committee of the International Union of Pharmacology approved a system for naming human seven-transmembrane (7TM) G protein-coupled chemokine receptors, the large family of leukocyte chemoattractant receptors that regulates immune system development and function, in large part by mediating leukocyte trafficking. This was announced in Pharmacological Reviews in a major overview of the first decade of research in this field [Murphy PM, Baggiolini M, Charo IF, Hébert CA, Horuk R, Matsushima K, Miller LH, Oppenheim JJ, and Power CA (2000) Pharmacol Rev 52:145-176]. Since then, several new receptors have been discovered, and major advances have been made for the others in many areas, including structural biology, signal transduction mechanisms, biology, and pharmacology.

Cell-autonomous regulation of neutrophil migration by the D6 chemokine decoy receptor.

Chemokines, acting on their cognate receptors on infiltrating leukocytes, drive the inflammatory response. We have been interested in determining roles and potential mechanisms for the atypical chemokine-scavenging receptor D6 in the regulation of inflammation. In this study, we show that a psoriasis-like pathology that arises in inflamed skins of D6-deficient mice is characterized by a massive and aberrant localization of neutrophils to the dermal/epidermal junction, which is associated with development of the pathology.

Small molecule chemokine mimetics suggest a molecular basis for the observation that CXCL10 and CXCL11 are allosteric ligands of CXCR3.

Background And Purpose: The chemokine receptor CXCR3 directs migration of T-cells in response to the ligands CXCL9/Mig, CXCL10/IP-10 and CXCL11/I-TAC. Both ligands and receptors are implicated in the pathogenesis of inflammatory disorders, including atherosclerosis and rheumatoid arthritis. Here, we describe the molecular mechanism by which two synthetic small molecule agonists activate CXCR3.

Why CCR2 and CCR5 blockade failed and why CCR1 blockade might still be effective in the treatment of rheumatoid arthritis.

Background: The aim of this study was to provide more insight into the question as to why blockade of CCR1, CCR2, and CCR5 may have failed in clinical trials in rheumatoid arthritis (RA) patients, using an in vitro monocyte migration system model.

Methodology/principal Findings: Monocytes from healthy donors (HD; n = 8) or from RA patients (for CCR2 and CCR5 antibody n = 8; for CCR1 blockade n = 13) were isolated from peripheral blood and pre-incubated with different concentrations of either anti-CCR1, anti-CCR2, or anti-CCR5 blocking antibodies (or medium or isotype controls). In addition, a small molecule CCR1 antagonist (BX471) was tested.

4-Azetidinyl-1-heteroatom linked cyclohexane antagonists of CCR2: patent evaluation.

This application discloses a series of di- and tri-substituted cyclohexanes as CCR2 receptor antagonists which are stated to be useful in treating inflammation and autoimmune diseases, such as type 2 diabetes and asthma. Although receptor binding of the compounds to CCR2 is demonstrated, there are no data to support the idea that these molecules are functional antagonists.

The chemokine, CCL3, and its receptor, CCR1, mediate thoracic radiation-induced pulmonary fibrosis.

Patients receiving thoracic radiation often develop pulmonary injury and fibrosis. Currently, there are no effective measures to prevent or treat these conditions. We tested whether blockade of the chemokine, CC chemokine ligand (CCL) 3, and its receptors, CC chemokine receptor (CCR) 1 and CCR5, can prevent radiation-induced lung inflammation and fibrosis.

Small molecule antagonists of chemokine receptors--is promiscuity a virtue?

A major function of the chemokine system is to coordinate the recruitment of leukocytes to specific locations within the tissues. The involvement of chemokine receptors in a multitude of inflammatory diseases, coupled with their belonging to the highly "druggable" GPCR superfamily, makes them excellent candidates for the development of novel drugs by the pharmaceutical industry. Despite descriptions in the literature of many specific small molecule chemokine receptor antagonists, none have yet shown efficacy in the clinical inflammatory setting.

Duffy antigen inhibitors: useful therapeutics for malaria?

Plasmodium vivax accounts for 65% of all cases of malaria in Asia and South America. Although not usually deadly, this form of malaria continues to inflict misery on the millions of sufferers who have been infected. The paucity of treatments for malaria, coupled with the emerging resistance of the parasite to anti-malarial drugs such as chloroquine, demonstrates an urgent need to develop new and alternative approaches to combat this disease.

In vitro screening for chemokine antagonists.

Background: Chemokines play an important role in host defense coordinating the migration of immune cells. They do this by activating G-protein-coupled receptors and these proteins have attracted a huge investment in research and development by the pharmaceutical industry with the promise of new therapeutics for treating inflammatory diseases.

Objective: Here, we provide a brief perspective of the in vitro assays that have been used in drug discovery for identifying potent and specific chemokine receptor antagonists.

Drug discovery targeting the chemokine system--where are we?

The identification of a large cytokine sub-family responsible for the control of the directional migration of leukocytes over 20 years ago brought much excitement to the pharmaceutical industry with the promise of a new family of targets to treat inflammatory diseases. This family of small proteins, subsequently named chemokines, were identified as acting on seven transmembrane spanning (7TM) G protein-coupled receptors - one of the most druggable classes of receptors in the pharmaceutical industry. The interest in chemokines and their receptors as therapeutic targets subsequently evolved beyond inflammation to include cancer and infectious disease such as AIDS, as chemokine biology progressed to demonstrate their role in these processes.

Chapter 9 the duffy antigen receptor for chemokines.

The Duffy blood group antigen is a serpentine protein with seven transmembrane domains that is not coupled to G-proteins or other known intracellular effectors. In addition to erythrocytes, it is also expressed in endothelial cells and neurons. In recent years the Duffy antigen has received much attention because of its diverse roles in health and disease.

Modeling small molecule-compound binding to G-protein-coupled receptors.

G-protein-coupled receptors (GPCRs) form a superfamily of membrane proteins that play a crucial role in mediating physiological processes as well as pathogenesis of many critical diseases. They are one of the most successful drug targets, accounting for more than 30% of prescription drugs on the market today. Three-dimensional structural information on GPCRs will greatly aid the drug design process, and great strides are being made in obtaining crystallographic information on GPCRs.

Chemokine receptor antagonists: part 2.

Background: The first part of this two-part review discussed approaches to generating antagonists for some of the CC chemokine receptors, including CCR1, CCR2, CCR3, and CCR4.

Objective/method: This second part of the series concludes the review by describing antagonists for CCR5, CCR8, CCR9, CXCR3, CXCR4, and promiscuous antagonists.

Conclusion: Chemokine receptor antagonists have found mixed success as therapeutics.

Chemokine receptor antagonists: Part 1.

Background: Chemokines were originally defined as host defense proteins, however, their biological role goes well beyond this simple description of their function as immune cell chemoattractants, and they have since been shown to be involved in a number of other biological processes, including growth regulation, hematopoiesis, embryologic development, angiogenesis, and HIV-1 infection. Because of their diverse role in autoimmune diseases and AIDS, chemokines and their receptors, which belong to the G-protein-coupled receptor superfamily, have been considered good drug targets by the pharmaceutical industry.

Objective/method: In the first part of this two-part review, we highlight recent developments in the chemokine receptor antagonist field both in the peer reviewed and in the patent literature for the CC chemokine receptors CCR1, CCR2, CCR3, and CCR4.

Elucidation of binding sites of dual antagonists in the human chemokine receptors CCR2 and CCR5.

Design of dual antagonists for the chemokine receptors CCR2 and CCR5 will be greatly facilitated by knowledge of the structural differences of their binding sites. Thus, we computationally predicted the binding site of the dual CCR2/CCR5 antagonist N-dimethyl-N-[4-[[[2-(4-methylphenyl)-6,7-dihydro-5H-benzohepten-8-yl] carbonyl]amino]benzyl]tetrahydro-2H-pyran-4-aminium (TAK-779), and a CCR2-specific antagonist N-(carbamoylmethyl)-3-trifluoromethyl benzamido-parachlorobenzyl 3-aminopyrrolidine (Teijin compound 1) in an ensemble of predicted structures of human CCR2 and CCR5. Based on our predictions of the protein-ligand interactions, we examined the activity of the antagonists for cells expressing thirteen mutants of CCR2 and five mutants of CCR5.

Expression, purification and in vitro functional reconstitution of the chemokine receptor CCR1.

Chemokine receptors are a specific class of G-protein-coupled receptors (GPCRs) that control cell migration associated with routine immune surveillance, inflammation and development. In addition to their roles in normal physiology, these receptors and their ligands are involved in a large number of inflammatory diseases, cancer and AIDS, making them prime therapeutic targets in the pharmaceutical industry. Like other GPCRs, a significant obstacle in determining structures and characterizing mechanisms of activation has been the difficulty in obtaining high levels of pure, functional receptor.

Promiscuous drugs as therapeutics for chemokine receptors.

Chemokine receptor antagonists that held much promise for the treatment of autoimmune and inflammatory diseases have recently performed poorly in clinical trials, resulting in disappointment for both pharmaceutical companies and patients. This review focuses on the redundancy of the molecular target as one potential reason for the failure of some of these antagonists to fulfil their initial promise, and discusses the use of drugs that are capable of interacting with more than one drug target - so-called promiscuous drugs - as possible approaches to overcome this difficulty. Several clinically approved promiscuous drugs, such as aspirin and olanzapine, are already used successfully.

Chemokine receptor antagonists: overcoming developmental hurdles.

Chemokine receptors have a key role in the pathogenesis of autoimmune diseases, inflammation and viral infection. However, with the exception of selective CCR5 antagonists for HIV, the promise of obtaining new therapeutics related to chemokine receptors has not yet been realized. This article highlights some of the recent failures in the clinical trials of chemokine receptor antagonists and explores possible reasons as to why this might have occurred.

Chemokine receptor CCR1 regulates inflammatory cell infiltration after renal ischemia-reperfusion injury.

Neutrophils and macrophages rapidly infiltrate the kidney after renal ischemia-reperfusion injury, however specific molecular recruitment mechanisms have not been fully delineated for these cell types. Here we provide genetic and pharmacologic evidence supporting a positive role for the chemokine receptor CCR1 in macrophage and neutrophil infiltration in a 7 day mouse model of renal ischemia-reperfusion injury. By day 7, injured kidneys from mice lacking CCR1 contained 35% fewer neutrophils and 45% fewer macrophages than injured kidneys from wild-type control mice.

CCR5 deficiency aggravates crescentic glomerulonephritis in mice.

The chemokine receptor CCR5 is predominantly expressed on monocytes and Th1-polarized T cells, and plays an important role in T cell and monocyte recruitment in inflammatory diseases. To investigate the functional role of CCR5 in renal inflammation, we induced a T cell-dependent model of glomerulonephritis (nephrotoxic serum nephritis) in CCR5(-/-) mice. Induction of nephritis in wild-type mice resulted in up-regulation of renal mRNA expression of the three CCR5 chemokine ligands, CCL5 (15-fold), CCL3 (4.