RT Journal Article
SR Electronic
T1 Modulators of CXCR4 and CXCR7/ACKR3 Function
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP 737
OP 752
DO 10.1124/mol.119.117663
VO 96
IS 6
A1 Ilze Adlere
A1 Birgit Caspar
A1 Marta Arimont
A1 Sebastian Dekkers
A1 Kirsten Visser
A1 Jeffrey Stuijt
A1 Chris de Graaf
A1 Michael Stocks
A1 Barrie Kellam
A1 Stephen Briddon
A1 Maikel Wijtmans
A1 Iwan de Esch
A1 Stephen Hill
A1 Rob Leurs
YR 2019
UL http://molpharm.aspetjournals.org/content/96/6/737.abstract
AB 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 a US Food and Drug Administration 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 on the basis of common structural motifs and available crystal structures. To date, no atypical chemokine receptor has been crystallized, which makes ligand design and predictions for these receptors more difficult. Next, the selectivity, receptor activation, and the resulting ligand-induced signaling output of chemokines and other peptide ligands are reviewed. Binding of pepducins, a class of lipid-peptides whose basis is the internal loop of a GPCR, to CXCR4 is also discussed. Finally, small-molecule modulators of CXCR4 and ACKR3 are reviewed. These modulators have led to the development of radio- and fluorescently labeled tool compounds, enabling the visualization of ligand binding and receptor characterization both in vitro and in vivo.SIGNIFICANCE STATEMENT 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.