Development of novel CXC chemokine receptor 7 (CXCR7) ligands: selectivity switch from CXCR4 antagonists with a cyclic pentapeptide scaffold

  • J Med Chem. 2015 Jul 9;58(13):5218-25. doi: 10.1021/acs.jmedchem.5b00216.
Shinya Oishi  1 ,  Tomoko Kuroyanagi  1 ,  Tatsuhiko Kubo  1 ,  Nicolas Montpas  2  3 ,  Yasushi Yoshikawa ,  Ryosuke Misu  1 ,  Yuka Kobayashi  1 ,  Hiroaki Ohno  1 ,  Nikolaus Heveker  2  3 ,  Toshio Furuya ,  Nobutaka Fujii  1
Affiliations
  • 1. †Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto, 606-8501, Japan.
  • 2. ‡Département de Biochimie, Université de Montréal, Montréal, H3T 1J4, Canada.
  • 3. §Research Centre, Sainte-Justine Hospital, University of Montreal, Montréal, H3T 1C5, Canada.
PMID: 26042340 DOI: 10.1021/acs.jmedchem.5b00216
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.