title: Development of novel CXC chemokine receptor 7 (CXCR7) ligands: selectivity switch from CXCR4 antagonists with a cyclic pentapeptide scaffold.
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.
authors.affiliation: †Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto, 606-8501, Japan.
authors.forename: Shinya
authors.initials: S
authors.lastname: Oishi
authors.affiliation: †Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto, 606-8501, Japan.
authors.forename: Tomoko
authors.initials: T
authors.lastname: Kuroyanagi
authors.affiliation: †Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto, 606-8501, Japan.
authors.forename: Tatsuhiko
authors.initials: T
authors.lastname: Kubo
authors.affiliation: ‡Département de Biochimie, Université de Montréal, Montréal, H3T 1J4, Canada.|§Research Centre, Sainte-Justine Hospital, University of Montreal, Montréal, H3T 1C5, Canada.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Montpas
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Yoshikawa
authors.affiliation: †Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto, 606-8501, Japan.
authors.forename: Ryosuke
authors.initials: R
authors.lastname: Misu
authors.affiliation: †Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto, 606-8501, Japan.
authors.forename: Yuka
authors.initials: Y
authors.lastname: Kobayashi
authors.affiliation: †Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto, 606-8501, Japan.
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Ohno
authors.affiliation: ‡Département de Biochimie, Université de Montréal, Montréal, H3T 1J4, Canada.|§Research Centre, Sainte-Justine Hospital, University of Montreal, Montréal, H3T 1C5, Canada.
authors.forename: Nikolaus
authors.initials: N
authors.lastname: Heveker
authors.forename: Toshio
authors.initials: T
authors.lastname: Furuya
authors.affiliation: †Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto, 606-8501, Japan.
authors.forename: Nobutaka
authors.initials: N
authors.lastname: Fujii
mesh_terms: D019390:Arrestins / Q000378:metabolism; D054377:Chemokine CXCL12 / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D015394:Molecular Structure; D010456:Peptides, Cyclic / Q000138:chemical synthesis / Q000494:pharmacology*; D011487:Protein Conformation; D054387:Receptors, CXCR / Q000235:genetics / Q000378:metabolism*; D019718:Receptors, CXCR4 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism*; D013329:Structure-Activity Relationship; D013379:Substrate Specificity; D000071557:beta-Arrestins
chemical_list: C501896:ACKR3 protein, human; D019390:Arrestins; C515255:CXCL12 protein, human; C527276:CXCR4 protein, human; D054377:Chemokine CXCL12; D008024:Ligands; D010456:Peptides, Cyclic; D054387:Receptors, CXCR; D019718:Receptors, CXCR4; D000071557:beta-Arrestins; C496951:cyclo(tyrosyl-arginyl-arginyl-3-(2-naphthyl)alanyl-glycyl)