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

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

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.

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