Structure鈥揂ctivity Relationship Study of a CXC Chemokine Receptor Type 4 Antagonist, FC131, Using a Series of Alkene Dipeptide Isosteres

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• 作者：Kazuya Kobayashi ; Shinya Oishi ; Ryoko Hayashi ; Kenji Tomita ; Tatsuhiko Kubo ; Noriko Tanahara ; Hiroaki Ohno ; Yasushi Yoshikawa ; Toshio Furuya ; Masaru Hoshino ; Nobutaka Fujii
• 刊名：Journal of Medicinal Chemistry
• 出版年：2012
• 出版时间：March 22, 2012
• 年：2012
• 卷：55
• 期：6
• 页码：2746-2757
• 全文大小：529K
• 年卷期：v.55,no.6(March 22, 2012)
• ISSN：1520-4804

文摘

A structure鈥揳ctivity relationship study on a highly potent CXC chemokine receptor type 4 (CXCR4) antagonist, FC131 [cyclo(-d-Tyr¹-Arg²-Arg³-Nal⁴-Gly⁵-)], was carried out using a series of alkene isosteres of the d-Tyr¹-l/d-Arg² dipeptide to investigate the binding mode of FC131 and its derivatives with CXCR4. The structure鈥揳ctivity relationships of isostere-containing FC131 analogues were similar to those of the parent FC131 and its derivatives, suggesting that a trans-conformer of the d-Tyr¹鈥揂rg² peptide bond is the dominant contributor to the bioactive conformations of FC131. Although NMR analysis demonstrated that the two conformations of the peptidomimetic containing the d-Tyr¹-d-Arg² isostere are possible, binding-mode prediction indicated that the orientations of the alkene motif within d-Tyr¹-MeArg² peptidomimetics depend on the chirality of Arg² and the 尾-methyl group of the isostere unit, which makes the dominant contribution for binding to the receptor. The most potent FC122 [cyclo(-d-Tyr¹-d-MeArg²-Arg³-Nal⁴-Gly⁵-)] bound with CXCR4 by a binding mode different from that of FC131.