Design and synthesis of downsized metastin (45-54) analogs with maintenance of high GPR54 agonistic activity
Design and synthesis of downsized metastin (45-54) analogs with maintenance of high GPR54 agonistic activity
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DOI：
10.1016/j.bmcl.2005.09.054
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发表时间：
2006-01-01
影响因子：
2.7
通讯作者：
Fujii, N
中科院分区：
文献类型：
--
作者：
Niida, A;Wang, ZX;Fujii, N
Metastin已被鉴定为通过G蛋白偶联受体GPR 54介导其功能的转移抑制基因产物。为了进一步了解激活GPR 54的关键药效团，我们对生物活性转移蛋白片段进行了丙氨酸和D-氨基酸扫描（45-54）。基于这些数据和先前报道的激活GPR 54的肽的结构，合成了一系列缩短的metastin（45-54）衍生物，并测试了诱导GPR 54信号传导的能力。这些生物学实验在含有人GPR 54的酵母中进行，所述人GPR 54与信息素应答途径和信息素应答lacZ报告基因偶联。具有N-末端碱性基团和C-末端RW-酰胺基序的化合物32、33和39是强激动剂，类似于metastin的水平。这可能提供一种方法来逆转metastin缺失在多种恶性肿瘤中的促转移作用。(c)2005爱思唯尔有限公司保留所有权利。
Metastin has been identified as a metastasis suppressor gene product that mediates its function through a G protein coupled receptor, GPR54. To refine insight into the critical pharmacophore for the activation of GPR54, we have conducted alanine and D-amino acid scanning on a biologically active metastin fragment (45-54). Based on these data and structures of peptides previously reported to activate GPR54, a series of shortened metastin (45-54) derivatives were synthesized and tested for the ability to induce GPR54 signaling. These biological experiments were performed in yeast containing human GPR54 that was coupled to the pheromone response pathway and a pheromone responsive lacZ reporter gene. Compounds 32, 33, and 39, which possess an N-terminal basic group and a C-terminal RW-amide motif, were strong agonists, similar to the level of metastin. This may provide an approach to reverse the pro-metastatic effect of metastin deletion in multiple malignant tumors. (c) 2005 Elsevier Ltd. All rights reserved.