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. Epub 2015 Jun 18.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Arrestins / metabolism
  • 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
  • beta-Arrestins

Substances

  • ACKR3 protein, human
  • Arrestins
  • CXCL12 protein, human
  • CXCR4 protein, human
  • Chemokine CXCL12
  • Ligands
  • Peptides, Cyclic
  • Receptors, CXCR
  • Receptors, CXCR4
  • beta-Arrestins
  • cyclo(tyrosyl-arginyl-arginyl-3-(2-naphthyl)alanyl-glycyl)