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.

BACKGROUND AND PURPOSEChronic pain is a serious worldwide health issue, with current analgesics having limited efficacy and dose-limiting side effects. Humans with loss-of-function mutations in the voltage-gated sodium channel NaV1.7 (hNaV1.7) are indifferent to pain, making hNaV1.7 a promising target for analgesic development. Since spider venoms are replete with NaV channel modulators, we examined their potential as a source of hNaV1.7 inhibitors. EXPERIMENTAL APPROACHWe developed a high-throughput fluorescent-based assay to screen spider venoms against hNaV1.7 and isolate 'hit' peptides. To examine the binding site of these peptides, we constructed a panel of chimeric channels in which the S3b-S4 paddle motif from each voltage sensor domain of hNaV1.7 was transplanted into the homotetrameric KV2.1 channel. KEY RESULTSWe screened 205 spider venoms and found that 40% contain at least one inhibitor of hNaV1.7. By deconvoluting 'hit' venoms, we discovered seven novel members of the NaSpTx family 1. One of these peptides, Hd1a (peptide μ-TRTX-Hd1a from venom of the spider Haplopelma doriae), inhibited hNaV1.7 with a high level of selectivity over all other subtypes, except hNaV1.1. We showed that Hd1a is a gating modifier that inhibits hNaV1.7 by interacting with the S3b-S4 paddle motif in channel domain II. The structure of Hd1a, determined using heteronuclear NMR, contains an inhibitor cystine knot motif that is likely to confer high levels of chemical, thermal and biological stability. CONCLUSION AND IMPLICATIONSOur data indicate that spider venoms are a rich natural source of hNaV1.7 inhibitors that might be useful leads for the development of novel analgesics. BJP

Over a period of more than 300 million years, spiders have evolved complex venoms containing an extraordinary array of toxins for prey capture and defense against predators. The major components of most spider venoms are small disulfide-bridged peptides that are highly stable and resistant to proteolytic degradation. Moreover, many of these peptides have high specificity and potency toward molecular targets of therapeutic importance. This unique combination of bioactivity and stability has made spider-venom peptides valuable both as pharmacological tools and as leads for drug development. This review describes recent advances in spider-venom-based drug discovery pipelines. We discuss spider-venom-derived peptides that are currently under investigation for treatment of a diverse range of pathologies including pain, stroke and cancer.

(2012) Localization of Na v 1.7 in the normal and injured rodent olfactory system indicates a critical role in olfaction, pheromone sensing and immune function, Channels, 6:2, 103-110,

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