Raising a red flag over TAP blocks.

Abstract

The two G protein-coupled receptors (GPCRs) C-X-C chemokine receptor type 4 (CXCR4) and atypical chemokine receptor 3 (ACKR3) are part of the class A chemokine GPCR family and represent important drug targets for human immunodeficiency virus (HIV) infection, cancer and inflammation diseases. CXCR4 is one of only three chemokine receptors with an FDA approved therapeutic agent, the small molecule modulator AMD3100. In this review, known modulators of the two receptors are discussed in detail. Initially, the structural relationship between receptors and ligands is reviewed based on common structural motifs and available crystal structures. To this date, no atypical chemokine receptor has been crystallised making ligand design and predictions for these receptors more difficult. Next, the selectivity, receptor activation and the resulting ligand-induced signalling output of chemokines and other peptide ligands are reviewed. Binding of pepducins, a class of lipid-peptides based on the internal loop of a GPCR, to CXCR4 are also discussed. Finally, small-molecule modulators of CXCR4 and ACKR3 are reviewed. These modulators have furthermore led to the development of radio- and fluorescently labelled tool compounds, enabling the visualization of ligand binding and receptor characterisation, both in vitro and in vivo. <h3>SIGNIFICANCE STATEMENT</h3> To investigate the pharmacological modulation of CXCR4 and ACKR3, significant effort has been focused on the discovery and development of a range of ligands, including small-molecule modulators, pepducins and synthetic peptides. Imaging tools, such as fluorescent probes, also play a pivotal role in the field of drug discovery. This review aims to provide an overview of the aforementioned modulators that facilitate the study of CXCR4 and ACKR3 receptors.