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

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• 作者：Shinya Oishi ; Tomoko Kuroyanagi ; Tatsuhiko Kubo ; Nicolas Montpas ; Yasushi Yoshikawa ; Ryosuke Misu ; Yuka Kobayashi ; Hiroaki Ohno ; Nikolaus Heveker ; Toshio Furuya ; Nobutaka Fujii
• 刊名：Journal of Medicinal Chemistry
• 出版年：2015
• 出版时间：July 9, 2015
• 年：2015
• 卷：58
• 期：13
• 页码：5218-5225
• 全文大小：363K
• ISSN：1520-4804

文摘

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 伪 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 尾-arrestin to CXCR7. Investigations via receptor mutagenesis and molecular modeling experiments suggest a possible binding mode of the cyclic pentapeptide CXCR7 agonist.