Development of Novel CXC Chemokine Receptor 7 (CXCR7) Ligands: Selectivity Switch from CXCR4 Antagonists with a Cyclic Pentapeptide Scaffold

Abstract

The CXC chemokine receptor 7 (CXCR7)/ACKR3 is a chemokine receptor that recognizes stromal cell-derived factor 1 (SDF-1)/CXCL12 and interferon-inducible T-cell α chemoattractant (I-TAC)/CXCL11. Here, we report the development of novel CXCR7-selective ligands with a cyclic pentapeptide scaffold through an SAR study of CXC chemokine receptor 4 (CXCR4) selective antagonist FC131 [cyclo(-d-Tyr-l-Arg-l-Arg-l-Nal-Gly-), Nal = 3-(2-naphthyl)alanine]. Substitution of Gly with l-Pro switched the receptor preference of the peptides from CXCR4 to CXCR7. The SAR study led to the identification of a potent CXCR7 ligand, FC313 [cyclo(-d-Tyr-l-Arg-l-MeArg-l-Nal-l-Pro-)], which recruits β-arrestin to CXCR7. Investigations via receptor mutagenesis and molecular modeling experiments suggest a possible binding mode of the cyclic pentapeptide CXCR7 agonist.

Different contributions of chemokine N‐terminal features attest to a different ligand binding mode and a bias towards activation of ACKR3/CXCR7 compared with CXCR4 and CXCR3

“…Our results as well as numerous previous studies conducted with non‐chemokine ligands demonstrated that in contrast to classical chemokine receptors, such as CXCR4 or CXCR3, ACKR3 is an ‘activation‐prone’ receptor (Figure B) and is able to accommodate a diverse set of ligands including small molecules, peptides and several chemokines, in each case resulting in receptor activation and ultimately arrestin recruitment (Burns et al, ; Wijtmans et al, ; Ikeda et al, ; Montpas et al, ; Oishi et al, ; Szpakowska et al, ; Benredjem et al, ; Gustavsson et al, ). Numerous CXCR4 antagonists, including AMD3100, TC14012 and vCCL2, act as agonists towards ACKR3.…”

Identification of Synthetic Activators of Cancer Cell Migration by Hybrid Deep Learning

“…Positive dataset : The set of CXCR4 ligands combined activity data from ChEMBL23, literature sources, and compounds from in‐house projects (together the “positive” set). Database entries were removed that contained ‘the blockade of HIV entry“ as an assay‐endpoint annotation in ChEMBL, and entries without a numeric activity value or without further information on the assay conducted in the corresponding publications.…”

Advances in CXCR7 Modulators

“…Peptide-based agonists at CXCR7 have also been developed. FC313 is a cyclic pentapeptide (Figure 3) that is a selective agonist for CXCR7 [86], which was developed from FC131, a cyclic pentapeptide CXCR4 antagonist [87]. The pentapeptides contain a phenol, two guanidines and a naphthalene.…”