Key Laboratory of Tropical Biological Resources of Ministry of Education, Key Laboratory for Marine Drugs of Haikou, School of Life and Pharmaceutical Sciences, Hainan University, Haikou 570228, China.
Medical School, Guangxi University, Nanning 530004, China.
J Med Chem. 2021 May 13;64(9):5620-5631. doi: 10.1021/acs.jmedchem.0c02079. Epub 2021 Apr 26.
The α7 nicotinic acetylcholine receptor (nAChR) is present in the central nervous system and plays an important role in cognitive function and memory. α-Conotoxin LvIB, identified from genomic DNA of , its three isomers and four globular isomer analogues were synthesized and screened at a wide range of nAChR subtypes. One of the analogues, amidated [Q1G,ΔR14]LvIB, was found to be a potent blocker of rat α7 nAChRs. Importantly, it differentiates between α7 nAChRs of human (IC: 1570 nM) and rat (IC: 97 nM). Substitutions between rat and human α7 nAChRs at three key mutation sites revealed that no single mutant could completely change the activity profile of amidated [Q1G,ΔR14]LvIB. Rather, we found that the combined influence of Gln141, Asn184, and Lys186 determines the α7 nAChR species specificity of this peptide. This engineered α4/4 conotoxin has potential applications as a template for designing ligands to selectively block human α7 nAChRs.
α7 型烟碱型乙酰胆碱受体 (nAChR) 存在于中枢神经系统中，在认知功能和记忆中发挥着重要作用。从 基因组 DNA 中鉴定出 α-芋螺毒素 LvIB，其三种异构体和四个球状异构体类似物已被广泛合成并筛选到 nAChR 亚型。类似物之一，酰胺化 [Q1G，ΔR14]LvIB，被发现是一种有效的大鼠 α7 nAChR 阻断剂。重要的是，它能区分人和大鼠的 α7 nAChRs（IC：1570 nM 和 97 nM）。在三个关键突变位点上，大鼠和人类 α7 nAChR 之间的取代表明，没有单个突变体可以完全改变酰胺化 [Q1G，ΔR14]LvIB 的活性谱。相反，我们发现 Gln141、Asn184 和 Lys186 的共同影响决定了这种肽对人类 α7 nAChR 的物种特异性。这种工程化的 α4/4 芋螺毒素有可能作为设计选择性阻断人类 α7 nAChR 配体的模板。
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