Pharmacological modulation of chemokine receptor function

Abstract

G protein-coupled chemokine receptors and their peptidergic ligands are interesting therapeutic targets due to their involvement in various immune-related diseases, including rheumatoid arthritis, multiple sclerosis, inflammatory bowel disease, chronic obstructive pulmonary disease, HIV-1 infection and cancer. To tackle these diseases, a lot of effort has been focused on discovery and development of small-molecule chemokine receptor antagonists. This has been rewarded by the market approval of two novel chemokine receptor inhibitors, AMD3100 (CXCR4) and Maraviroc (CCR5) for stem cell mobilization and treatment of HIV-1 infection respectively. The recent GPCR crystal structures together with mutagenesis and pharmacological studies have aided in understanding how small-molecule ligands interact with chemokine receptors. Many of these ligands display behaviour deviating from simple competition and do not interact with the chemokine binding site, providing evidence for an allosteric mode of action. This review aims to give an overview of the evidence supporting modulation of this intriguing receptor family by a range of ligands, including small molecules, peptides and antibodies. Moreover, the computer-assisted modelling of chemokine receptor-ligand interactions is discussed in view of GPCR crystal structures. Finally, the implications of concepts such as functional selectivity and chemokine receptor dimerization are considered.

Chemokines in Wound Healing and as Potential Therapeutic Targets for Reducing Cutaneous Scarring

“…They can bind to and block their target protein, that is, direct targeted therapy, or they can influence critical biological processes that is, antibody-dependent cell-mediated cytotoxicity or complement-dependent toxicity. 157 Certain characteristics of chemokine receptors, including their limited availability as purified proteins and low immunogenicity, have hampered the development of novel therapeutic agents. 157 However, following increased interest in this area, neutralizing mAbs have been used to inhibit leukocyte recruitment in a number of disease processes in animal models and have been incorporated into human trials.…”

“…157 Certain characteristics of chemokine receptors, including their limited availability as purified proteins and low immunogenicity, have hampered the development of novel therapeutic agents. 157 However, following increased interest in this area, neutralizing mAbs have been used to inhibit leukocyte recruitment in a number of disease processes in animal models and have been incorporated into human trials. A mAb to CXCL8 (ABX-IL8, Abgenix) has been shown to inhibit neutrophil and monocyte infiltration into the lungs of patients suffering from COPD, reducing the severity of dyspnea, but having no influence on lung function or health status.…”

β-Arrestin Recruitment and G Protein Signaling by the Atypical Human Chemokine Decoy Receptor CCX-CKR

“…The 19 known human chemokine receptors and their ϳ50 endogenous peptide ligands form a complex system in which many chemokine receptors can bind multiple chemokines, and many chemokines can bind more than one receptor (1). Chemokine receptors signal predominantly via heterotrimeric G i proteins, resulting in an inhibition of cAMP production by adenylyl cyclases and induction of intracellular calcium mobilization (2).…”

Antibodies targeting G protein-coupled receptors: Recent advances and therapeutic challenges

“…18 CXCL12 binds to CXCR4 via interactions of the N-terminus and the extracellular loop 2 (ECL2). 18 Epitope mapping revealed that the CXCR4 targeting Nbs bind with high affinity and specificity to ECL2. The aspartic acid at position 187, involved in binding of CXCL12, appears to be critical for the CXCR4 targeting Nbs, underlining their competitive behavior.…”

“…These receptors are therefore attractive therapeutic targets. 18 Via DNA and whole cell immunization of llamas, phage display and counterselection, the first Nbs targeting the extracellular side of GPCRs, and more specifically chemokine receptors, were identified. The CXCR4-specific Nbs antagonize CXCL12-dependent binding and signaling, inhibit HIV-1 replication in vitro and induce stem cell mobilization in vivo.…”