Molecular design of new sodium channel blockers |
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Authors: | Li Ping Zhu Shunyi |
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Institution: | 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 |
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Abstract: | 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. |
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Keywords: | Abbreviations: DRG dorsal root ganglion DrTx Drosotoxin EK enterokinase IPTG d-thiogalactopyranoside" target="_blank">isopropyl-beta-d-thiogalactopyranoside TTX-R tetrodotoxin-resistant TTX-S tetrodotoxin-sensitive VGSCs voltage-gated sodium channels |
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