Structure-Activity Analysis of N-Type Calcium Channel Inhibitor SO-3
Structure-Activity Analysis of N-Type Calcium Channel Inhibitor SO-3
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N型钙通道抑制剂SO-3的构效分析
DOI：
10.1021/acs.biochem.8b00803
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发表时间：
2018-11-06
期刊：
影响因子：
2.9
通讯作者：
Dai, Qiuyun
中科院分区：
文献类型：
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作者：
Dong, Minxing;Wang, Fei;Dai, Qiuyun
SO-3是从条纹芋螺（Conus striatus）中发现的一种ω-芋螺肽，由25个氨基酸残基和3个二硫键组成。我们以前的研究表明，这种肽在啮齿动物疼痛模型（小鼠和大鼠）中具有有效的镇痛活性，并且它特异性地抑制N型钙离子通道（Cav2.2）。在这里提出的研究中，我们研究了它们对HEK 293细胞中表达的Cav2.2的抑制活性和小鼠中的镇痛活性的关键氨基酸残基。为了提高SO-3的抑制活性，我们还评估了衍生自ω-肽MVIIA、CVID或GVIA的相应残基的一些氨基酸残基的作用。我们的数据表明，赖氨酸6，异亮氨酸11，和天冬酰胺14是SO-3的重要功能氨基酸残基。用CVID和GVIA的相应残基取代SO-3环1中的一些氨基酸残基，提高了SO-3的抑制活性。Cav2.2与环1和环2中的SO-3氨基酸的结合模式可能与MVIIA的结合模式有些不同。本研究扩展了我们对omega-肽的结构-活性关系的认识，并为提高Cav2.2抑制剂的效力提供了新的策略。
As an omega-conopeptide originally discovered from Conus striatus, SO-3 contains 25 amino acid residues and three disulfide bridges. Our previous study has shown that this peptide possesses potent analgesic activity in rodent pain models (mouse and rat), and it specifically inhibits an N-type calcium ion channel (Cav2.2). In the study presented here, we investigated the key amino acid residues for their inhibitory activity against Cav2.2 expressed in HEK 293 cells and analgesic activity in mice. To improve the inhibitory activity of SO-3, we also evaluated the effects of some amino acid residues derived from the corresponding residues of omega-peptide MVIIA, CVID, or GVIA. Our data reveal that Lys6, Ile11, and Asn14 are the important functional amino acid residues for SO-3. The replacement of some amino acid residues of SO-3 in loop 1 with the corresponding residues of CVID and GVIA improved the inhibitory activity of SO-3. The binding mode of Cav2.2 with SO-3 amino acids in loop 1 and loop 2 may be somewhat different from that of MVIIA. This study expanded our knowledge of the structure-activity relationship of omega-peptides and provided a new strategy for improving the potency of Cav2.2 inhibitors.