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

• Published in: Journal of medicinal chemistry 2015-07, Vol.58 (13), p.5218-5225
• Main Authors: Oishi, Shinya, Kuroyanagi, Tomoko, Kubo, Tatsuhiko, Montpas, Nicolas, Yoshikawa, Yasushi, Misu, Ryosuke, Kobayashi, Yuka, Ohno, Hiroaki, Heveker, Nikolaus, Furuya, Toshio, Fujii, Nobutaka
• Format: Article
• Language: English
• Subjects: Arrestins - metabolism; beta-Arrestins; Chemokine CXCL12 - genetics; Chemokine CXCL12 - metabolism; Humans; Ligands; Models, Molecular; Molecular Dynamics Simulation; Molecular Structure; Peptides, Cyclic - chemical synthesis; Peptides, Cyclic - pharmacology; Protein Conformation; Receptors, CXCR - genetics; Receptors, CXCR - metabolism; Receptors, CXCR4 - antagonists & inhibitors; Receptors, CXCR4 - genetics; Receptors, CXCR4 - metabolism; Structure-Activity Relationship; Substrate Specificity
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/acs.jmedchem.5b00216

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.