Emerging concepts and approaches for chemokine-receptor drug discovery

Abstract

Importance of the field: Chemokine receptors are most noted for their role in cell migration. However, inappropriate utilization or regulation of these receptors is implicated in many inflammatory diseases, cancer and HIV, making them important drug targets.

Areas covered in this review: Allostery, oligomerization and ligand bias are presented as they pertain to chemokine receptors and their associated pathologies.Specific examples of each are described from the recent literature and their implications are discussed in terms of drug discovery efforts targeting chemokine receptors.

What the reader will gain: Insight into the expanding view of the multitude of pharmacological variables that need to be considered or that may be exploited in chemokine receptor drug discovery.

Take home message: Since 2007, two drugs targeting chemokine receptors have been approved by the FDA, Maraviroc for preventing HIV infection and Mozobil™ for hematopoietic stem cell mobilization. While these successes permit optimism for chemokine receptors as drug targets, only recently has the complexity of this system begun to be appreciated. The concepts of allosteric inhibitors, biased ligands and functional selectivity raise the possibility that drugs with precisely-defined properties can be developed. Other complexities such as receptor oligomerization and tissue-specific functional states of receptors also offer opportunities for increased target and response specificity, although it will be more challenging to translate these ideas into approved therapeutics compared to traditional approaches.

Keywords: G protein-coupled receptors; allosteric inhibitors; chemokine receptors; drug discovery; functional selectivity; ligand bias; oligomerization.

Figure 1

Cartoon depicting various scenarios for the inhibition of chemokine binding and signaling by small molecules. The N- and C-termini of the receptor are labeled. Chemokine ligands are shown in blue, receptors in grey, orthosteric antagonists in purple, and allosteric antagonists in yellow. Green signal icons below receptor indicate activated signaling, red signal icons indicate blocked signaling. Panel A depicts orthosteric inhibition of chemokine binding. Panel B shows allosteric inhibition of signaling with and without concomitant blocking of chemokine binding. Panel C depicts partial blockage of the chemokine:receptor interaction by orthosteric and allosteric compounds. Sites 1 and 2 in the two-site model are labeled. Different generic signaling profiles highlight the idea that functional selectivity may be observed with both orthosteric and allosteric molecules.

Figure 2

Potential scenarios of functional selectivity of chemokine receptor signaling. Panel A depicts a scenario for ligand bias in which one ligand may induce typical G-protein activation and β-arrestin recruitment leading to receptor desensitization and internalization while another ligand for the same receptor activates G-proteins but does not recruit β-arrestins or lead to receptor internalization. Alternatively, another ligand for the receptor could activate β-arrestins, GRKs and receptor internalization but not G-protein signaling as shown in Panel B. It is also possible that two different ligands may similarly activate G-protein and β-arrestin pathways, but then the trafficking of the receptor could differ. For example, as depicted in Panel C, the receptor could be targeted to the lysosome for degradation or recycled to the cell surface through recycling endosomes. Internalization is depicted as a slight indentation of the membrane, and the three panels are meant to be independent scenarios.

Figure 3

Potential effects of hetero-oligomerization on chemokine receptor signaling responses. As depicted in Panel A, binding of a ligand specific for one receptor in a heterodimer could prevent the binding of ligands to the other receptor and/or alter its ability to interact with/signal through intracellular modulators, such as G-proteins. Another potential effect of hetero-oligomerization or receptor cross-desensitization is the internalization of one receptor (purple) through ligand activation of another receptor (green) as represented in Panel B. Here, internalization is depicted as a slight indentation of the membrane. Alternatively, hetero-oligomerization of a ligand activated receptor (green) with another receptor (purple) could prevent desensitization of the activated receptor (green) in the complex (Panel C). This is effectively the scenario described in WHIM syndrome where heterodimers occur between WT and C-terminally truncated forms of CXCR4.

Figure 4

Structure of CXCR4 bound to a small molecule isothiourea compound [94]. Panel A illustrates a side view of the receptor (grey) with the isothiourea compound shown as a cpk model. Panel B shows the binding pocket which is formed primarily by polar residues from transmembrane (TM) helices 1, 2, 3, and 7 and extracellular loop 2 (ECL2), with the ligand being stabilized by a network of hydrogen bonds, including the critical hydrogen bonding interactions with E288 (7.39 in Ballesteros notation) and D97 (2.63).