Modulators of CXCR4 and CXCR7/ACKR3 Function

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 a US Food and Drug Administration approved therapeutic agent, the smallmolecule 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 STATEMENTTo 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.

The atypical chemokine receptor ACKR3/CXCR7 is a broad-spectrum scavenger for opioid peptides

“…4f). Therefore, LIH383 is a highly attractive and versatile tool for specific ACKR3 modulation or detection of ACKR3-expressing cells in human and rodent models and is particularly suitable for investigating the biological consequences of opioid peptide interactions with ACKR3 29,41 .…”

Overexpression of CXCR7 accelerates tumor growth and metastasis of lung cancer cells

“…Chemokines are a superfamily of chemoattractant cytokines with diversity of biological and pathological functions, relating to immunocyte migration, hematopoietic stem cells homing, angiogenesis and tumor progression. So far, over 50 chemokines have been characterized, and they are divided into 4 classes (CXC, CX3C, CC, and C) based on the position of 4 conserved cysteine residues [ 4 ]. Chemokine receptors are seven-span transmembrane receptors coupled with G-proteins that are major regulators of cellular trafficking.…”

“…Actually, when CXCR7 is activated by CXCL12, the β-arrestin pathway is activated and CXCL12 scavenging is observed. Besides, CXCR4 and CXCR7 can also form heterodimers, whereby CXCR7 regulates the signaling of CXCR4/G-protein complexes depending on different physiological conditions [ 4 ]. However, with development, literature findings have highlighted that CXCR7 participates in the transduction of some signaling pathways without relying on CXCR4, including PLC / MAPK, ERK1 / 2, STAT3, and AKT pathways.…”

Automated Synthesis of Fluorine-18 Labeled CXCR4 Ligand via the Conjugation with Nicotinic Acid N-Hydroxysuccinimide Ester (6-[18F]SFPy)

“…Numerous truncated peptide analogs that mimic the function of CXCL12 have been reported [ 17 , 21 ]. Tamamura et al described the synthesis of novel 14-amino acid peptide inhibitors (T134, T140) based on the structure of their previously reported 18-amino acid peptide, T22, for inhibitory activity against HIV-1 entry [ 22 , 23 ].…”