Spider Knottin Pharmacology at Voltage-Gated Sodium Channels and Their Potential to Modulate Pain Pathways

Voltage-gated sodium channels (Na(V)s) are a key determinant of neuronal signalling. Neurotoxins from diverse taxa that selectively activate or inhibit Na(V) channels have helped unravel the role of Na(V) channels in diseases, including chronic pain. Spider venoms contain the most diverse array of inhibitor cystine knot (ICK) toxins (knottins). This review provides an overview on how spider knottins modulate Na(V) channels and describes the structural features and molecular determinants that influence their affinity and subtype selectivity. Genetic and functional evidence support a major involvement of Na(V) subtypes in various chronic pain conditions. The exquisite inhibitory properties of spider knottins over key Na(V) subtypes make them the best venom peptide leads for the development of novel analgesics to treat chronic pain.