Maleimide Conjugates of Saxitoxin as Covalent Inhibitors of Voltage-Gated Sodium Channels

J Am Chem Soc. 2013 Jul 24;135(29):10582-5. doi: 10.1021/ja4019644. Epub 2013 Jul 15.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • CHO Cells
  • Cricetulus
  • Humans
  • Maleimides / chemistry*
  • Maleimides / pharmacology*
  • Models, Molecular
  • Neurons / drug effects
  • Rats
  • Saxitoxin / chemistry*
  • Saxitoxin / pharmacology*
  • Sodium Channel Blockers / chemistry*
  • Sodium Channel Blockers / pharmacology*
  • Sodium Channels / metabolism

Substances

  • Maleimides
  • Sodium Channel Blockers
  • Sodium Channels
  • maleimide
  • Saxitoxin