title: Molecular design of new sodium channel blockers.
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.
authors.affiliation: 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.
authors.forename: Ping
authors.initials: P
authors.lastname: Li
authors.forename: Shunyi
authors.initials: S
authors.lastname: Zhu
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D015195:Drug Design; D008969:Molecular Sequence Data; D011487:Protein Conformation; D051381:Rats; D011993:Recombinant Fusion Proteins / Q000737:chemistry* / Q000494:pharmacology; D026941:Sodium Channel Blockers / Q000737:chemistry* / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: D011993:Recombinant Fusion Proteins; D026941:Sodium Channel Blockers; C552535:drosotoxin