A novel ω-conotoxin Bu8 inhibiting N-type voltage-gated calcium channels displays potent analgesic activity

作     者：Jinqin Chen Xinhong Liu Shuo Yu Jia Liu Rongfang Chen Yunxiao Zhang Ling Jiang Qiuyun Dai Jinqin Chen;Xinhong Liu;Shuo Yu;Jia Liu;Rongfang Chen;Yunxiao Zhang;Ling Jiang;Qiuyun Dai

作者机构：Beijing Institute of BiotechnologyBeijing 100071China Key Laboratory of Magnetic Resonance in Biological SystemState Key Laboratory of Magnetic Resonance and Atomic and Molecular PhysicsWuhan Center for Magnetic ResonanceInnovation Academy for Precision Measurement Science and TechnologyChinese Academy of SciencesWuhan 430071China College of Life ScienceHunan Normal UniversityChangsha 410081China University of Chinese Academy of SciencesBeijing 100049China 

出 版 物：《Acta Pharmaceutica Sinica B》 (药学学报（英文版）)

年 卷 期：2021年第11卷第9期

页      面：2685-2693页

核心收录：

学科分类：1008[医学-中药学(可授医学、理学学位)] 1006[医学-中西医结合] 100602[医学-中西医结合临床] 10[医学] 

基　　金：supported by the National Natural Science Foundation of China(grant number 81473192) the National Basic Research Program of China(grant number 2010CB529802) 

主　　题：N-type calcium ion channel ω-conotoxin Bu8 Analgesic activity Structure-activity relationship 

摘      要：ω-Conotoxins inhibit N-type voltage-gated calcium(Ca_(v)2.2)channels and exhibit efficacy in attenuating neuropathic pain but have a low therapeutic ***,we synthesized and characterized a novelω-conotoxin,Bu8 from Conus bullatus,which consists of 25 amino acid residues and three disulfide ***8 selectively and potently inhibits depolarization-activated Ba^(2+ )currents mediated by rat Ca_(v)2.2 expressed in HEK293 T cells(IC_(50)=89 nmol/L).Bu8 is two-fold more potent thanω-conotoxin MVIIA,aω-conotoxin currently used for the treatment of severe chronic *** also displays potent analgesic activity in animal pain models of hot plate and acetic acid writhing but has fewer side effects on mouse motor function and lower toxicity in *** lower side effects may be attributed to its faster binding rate and higher recovery *** NMR structure demonstrates that Bu8 contains a small irregular tripleβ-*** structure-activity relationships of Bu8 Ala mutants and Bu8/MVIIA hybrid mutants demonstrate that the binding mode of Ca_(v)2.2 with the amino acid residues in loop 1 and loop 2 of Bu8 is different from that of *** study characterizes a novel,more potentω-conotoxin and provides new insights for designing Ca_(v)2.2 antagonists.