title: Drosotoxin, a selective inhibitor of tetrodotoxin-resistant sodium channels.
abstract: The design of animal toxins with high target selectivity has long been a goal in protein engineering. Based on evolutionary relationship between the Drosophila antifungal defensin (drosomycin) and scorpion depressant Na(+) channel toxins, we exploited a strategy to create a novel chimeric molecule (named drosotoxin) with high selectivity for channel subtypes, which was achieved by using drosomycin to substitute the structural core of BmKITc, a depressant toxin acting on both insect and mammalian Na(+) channels. Recombinant drosotoxin selectively inhibited tetrodotoxin-resistant (TTX-R) Na(+) channels in rat dorsal root ganglion (DRG) neurons with a 50% inhibitory concentration (IC(50)) of 2.6+/-0.5muM. This chimeric peptide showed no activity on K(+), Ca(2+) and TTX-sensitive (TTX-S) Na(+) channels in rat DRG neurons and Drosophila para/tipE channels at micromolar concentrations. Drosotoxin represents the first chimeric toxin and example of a non-toxic core scaffold with high selectivity on mammalian TTX-R Na(+) channels.
authors.affiliation: Group of Animal Innate Immunity, State Key Laboratory of Integrated Management of Pest Insects & Rodents, Institute of Zoology, Chinese Academy of Sciences, 1 Beichen West Road, Chaoyang District, Beijing 100101, China. Zhusy@ioz.ac.cn
authors.forename: Shunyi
authors.initials: S
authors.lastname: Zhu
authors.forename: Bin
authors.initials: B
authors.lastname: Gao
authors.forename: Meichun
authors.initials: M
authors.lastname: Deng
authors.forename: Yuzhe
authors.initials: Y
authors.lastname: Yuan
authors.forename: Lan
authors.initials: L
authors.lastname: Luo
authors.forename: Steve
authors.initials: S
authors.lastname: Peigneur
authors.forename: Yucheng
authors.initials: Y
authors.lastname: Xiao
authors.forename: Songping
authors.initials: S
authors.lastname: Liang
authors.forename: Jan
authors.initials: J
authors.lastname: Tytgat
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D005075:Biological Evolution; D008958:Models, Molecular; D008969:Molecular Sequence Data; D051381:Rats; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000494:pharmacology*; D012604:Scorpion Venoms / Q000737:chemistry; D012605:Scorpions / Q000235:genetics; D026941:Sodium Channel Blockers / Q000494:pharmacology*; D013779:Tetrodotoxin / Q000494:pharmacology*; D014118:Toxins, Biological / Q000737:chemistry / Q000494:pharmacology
chemical_list: D011993:Recombinant Fusion Proteins; D012604:Scorpion Venoms; D026941:Sodium Channel Blockers; D014118:Toxins, Biological; C552535:drosotoxin; D013779:Tetrodotoxin