title: Maleimide conjugates of saxitoxin as covalent inhibitors of voltage-gated sodium channels.
abstract: (+)-Saxitoxin, a naturally occurring guanidinium poison, functions as a potent, selective, and reversible inhibitor of voltage-gated sodium ion channels (NaVs). Modified forms of this toxin bearing cysteine-reactive maleimide groups are available through total synthesis and are found to irreversibly inhibit sodium ion conductance in recombinantly expressed wild-type sodium channels and in hippocampal nerve cells. Our findings support a mechanism for covalent protein modification in which toxin binding to the channel pore precedes maleimide alkylation of a nucleophilic amino acid. Second-generation maleimide-toxin conjugates, which include bioorthogonal reactive groups, are also found to block channel function irreversibly; such compounds have potential as reagents for selective labeling of NaVs for live cell imaging and/or proteomics experiments.
authors.affiliation: Department of Chemistry, Stanford University, 333 Campus Drive, Stanford, California 94305-5080, USA.
authors.forename: William H
authors.initials: WH
authors.lastname: Parsons
authors.forename: J
authors.initials: J
authors.lastname: Du Bois
mesh_terms: D000818:Animals; D016466:CHO Cells; D003412:Cricetulus; D006801:Humans; D008301:Maleimides / Q000737:chemistry* / Q000494:pharmacology*; D008958:Models, Molecular; D009474:Neurons / Q000187:drug effects; D051381:Rats; D012530:Saxitoxin / Q000737:chemistry* / Q000494:pharmacology*; D026941:Sodium Channel Blockers / Q000737:chemistry* / Q000494:pharmacology*; D015222:Sodium Channels / Q000378:metabolism
chemical_list: D008301:Maleimides; D026941:Sodium Channel Blockers; D015222:Sodium Channels; C043592:maleimide; D012530:Saxitoxin