The E15R Point Mutation in Scorpion Toxin Cn2 Uncouples Its Depressant and Excitatory Activities on Human Nav1.6

被引：10

作者：

Israel, Mathilde R. ^{[1
]}

Thongyoo, Panumart ^{[1
]}

Deuis, Jennifer R. ^{[1
]}

Craik, David J. ^{[1
]}

Vetter, Irina ^{[1
,2
]}

Durek, Thomas ^{[1
]}

机构：

[1] Univ Queensland, Inst Mol Biosci, Brisbane, Qld 4072, Australia

[2] Univ Queensland, Sch Pharm, Woolloongabba, Qld 4102, Australia

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2018年 / 61卷 / 04期

基金：

澳大利亚研究理事会;

关键词：

NATIVE CHEMICAL LIGATION; GATED SODIUM-CHANNELS; VOLTAGE SENSOR; ENHANCED ACTIVATION; BETA-TOXIN; MODEL; AGONIST; MICE; NA;

D O I：

10.1021/acs.jmedchem.7b01609

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

We report the chemical synthesis of scorpion toxin Cn2, a potent and highly selective activator of the human voltage-gated sodium channel Na(v)1.6. In an attempt to decouple channel activation from channel binding, we also synthesized the first analogue of this toxin, Cn2[E15R]. This mutation caused uncoupling of the toxin's excitatory and depressant activities, effectively resulting in a Na(v)1.6 inhibitor. In agreement with the in vitro observations, Cn2[E15R] is antinociceptive in mouse models of Na(v)1.6-mediated pain.

引用

页码：1730 / 1736

页数：7