"Discovery, Characterization, and Engineering of LvIC, an alpha 4/4-Conotoxin That Selectively Blocks Rat alpha 6/alpha 3 beta 4 Nicotinic Acetylcholine Receptors"

作者全名："Zhu, Xiaopeng; Wang, Shuai; Kaas, Quentin; Yu, Jinpeng; Wu, Yong; Harvey, Peta J.; Zhangsun, Dongting; Craik, David J.; Luo, Sulan"

作者地址："[Zhu, Xiaopeng; Yu, Jinpeng; Wu, Yong; Zhangsun, Dongting; Luo, Sulan] Guangxi Univ, Sch Med, Nanning 530004, Peoples R China; [Zhangsun, Dongting; Luo, Sulan] Hainan Univ, Key Lab Trop Biol Resources, Minist Educ, Haikou 570228, Peoples R China; [Wang, Shuai] Chongqing Med Univ, Inst Life Sci, Ctr Novel Target & Therapeut Intervent, Chongqing 400016, Peoples R China; [Kaas, Quentin; Harvey, Peta J.; Craik, David J.] Univ Queensland, Inst Mol Biosci, Australian Res Council Ctr Excellence Innovat, Brisbane, Qld 4072, Australia"

通信作者："Luo, SL (通讯作者)，Guangxi Univ, Sch Med, Nanning 530004, Peoples R China.; Luo, SL (通讯作者)，Hainan Univ, Key Lab Trop Biol Resources, Minist Educ, Haikou 570228, Peoples R China."

来源：JOURNAL OF MEDICINAL CHEMISTRY

ESI学科分类：CHEMISTRY

WOS号：WOS:000925496800001

JCR分区：Q1

影响因子：6.8

年份：2023

卷号：　

期号：　

开始页：　

结束页：　

文献类型：Article; Early Access

关键词：　

摘要："alpha 6 beta 4 nicotinic acetylcholine receptors (nAChRs) are expressed in the central and peripheral nervous systems, but their functions are not fully understood, largely because of a lack of specific ligands. Here, we characterized a novel alpha-conotoxin, LvIC, and designed a series of analogues to probe structure-activity relationships at the alpha 6 beta 4 nAChR. The potency and selectivity of these conotoxins were tested using two-electrode voltage-clamp recording on nAChR subtypes expressed in Xenopus laevis oocytes. One of the analogues, [D1G,delta Q14]LvIC, potently blocked alpha 6/alpha 3 beta 4 nAChRs (alpha 6/alpha 3 is a chimera) with an IC50 of 19 nM, with minimal activity at other nAChR subtypes, including the structurally similar alpha 6/alpha 3 beta 2 beta 3 and alpha 3 beta 4 subtypes. Using NMR, molecular docking, and receptor mutation, structure-activity relationships of [D1G,delta Q14]LvIC at the alpha 6/alpha 3 beta 4 nAChR were defined. It is a potent and specific antagonist of alpha 6 beta 4 nAChRs that could potentially serve as a novel molecular probe to explore alpha 6 beta 4 nAChR-related neurophysiological and pharmacological functions."

基金机构："Major Inter-governmental Joint Research Project of National Key R & D Program of China [2022YFE0132700]; Guangxi Science and Technology Base Talents Fund [GUIKE AD22035948]; 111 Project [D20010]; National Natural Science Foundation of China [81872794, 41966003]; Australian Research Council [LE160100218, CE200100012]; NHMRC [2009564]; Australian Research Council [LE160100218] Funding Source: Australian Research Council"

基金资助正文："This research was funded in part by the Major Inter-governmental Joint Research Project of National Key R & D Program of China (2022YFE0132700) , Guangxi Science and Technology Base & Talents Fund (GUIKE AD22035948) , the 111 Project (D20010) , the National Natural Science Foundation of China (nos 81872794 and 41966003) , and the Australian Research Council (LE160100218 and CE200100012) . D.J.C. is funded by an NHMRC Investigator (2009564) ."