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

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 alpha 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 beta-arrestin to CXCR7. Investigations via receptor mutagenesis and molecular modeling experiments suggest a possible binding mode of the cyclic pentapeptide CXCR7 agonist.