Spider-venom peptides that target voltage-gated sodium channels: Pharmacological tools and potential therapeutic leads

Voltage-gated sodium (Na_V) channels play a central role in the propagation of action potentials in excitable cells in both humans and insects. Many venomous animals have therefore evolved toxins that modulate the activity of Na_V channels in order to subdue their prey and deter predators. Spider venoms in particular are rich in Na_V channel modulators, with one-third of all known ion channel toxins from spider venoms acting on Na_V channels. Here we review the landscape of spider-venom peptides that have so far been described to target vertebrate or invertebrate Na_V channels. These peptides fall into 12 distinct families based on their primary structure and cysteine scaffold. Some of these peptides have become useful pharmacological tools, while others have potential as therapeutic leads because they target specific Na_V channel subtypes that are considered to be important analgesic targets. Spider venoms are conservatively predicted to contain more than 10 million bioactive peptides and so far only 0.01% of this diversity been characterised. Thus, it is likely that future research will reveal additional structural classes of spider-venom peptides that target Na_V channels.