Group of Animal Innate Immunity, State Key Laboratory of Integrated Management of Pest Insects and Rodents, Institute of Zoology, Chinese Academy of Sciences, 1 Beichen West Road, Chaoyang District, Beijing 100101, China.
Biochem Biophys Res Commun. 2011 Oct 22;414(2):321-5. doi: 10.1016/j.bbrc.2011.09.052. Epub 2011 Sep 17.
Animal toxins targeting voltage-gated sodium channels (VGSCs) have been considered as valuable tools for studying pharmacological functions of VGSCs. Recently we have reported that Drosotoxin (DrTx), an evolution-guided chimeric peptide, exhibits highly selective blocking activity to tetrodotoxin-resistant (TTX-R) Na(+) channels in rat dorsal root ganglion (DRG) neurons. In this study, we constructed five new analogues of DrTx designed by altering amino-terminal sequences of DrTx, two of which have significant inhibitory effects on both TTX-R and tetrodotoxin-sensitive (TTX-S) Na(+) channels. Structure-activity relationship studies allow us to recognize key functional roles of a positive charge at site seven and a negative charge at site eight in evolving new blocking activity to TTX-S sodium channels. This work will enhance our understanding of the molecular determinants of toxins affecting VGSCs and aid the rational design of subtype-specific blockers of the channels.
动物毒素靶向电压门控钠离子通道（VGSCs）已被认为是研究 VGSCs 药理学功能的有价值的工具。最近，我们报道了一种进化导向的嵌合肽 Drosotoxin（DrTx），它对大鼠背根神经节（DRG）神经元中的河豚毒素抗性（TTX-R）Na+通道具有高度选择性的阻断活性。在这项研究中，我们构建了五个 DrTx 的新类似物，通过改变 DrTx 的氨基末端序列设计而成，其中两个对 TTX-R 和河豚毒素敏感（TTX-S）Na+通道均有显著的抑制作用。构效关系研究使我们能够认识到在进化过程中新的 TTX-S 钠通道阻断活性中第七位正电荷和第八位负电荷的关键功能作用。这项工作将增强我们对影响 VGSCs 的毒素的分子决定因素的理解，并有助于通道的亚型特异性阻断剂的合理设计。
