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

Abstract

Voltage-gated sodium channels (NaVs) are a key determinant of neuronal signalling. Neurotoxins from diverse taxa that selectively activate or inhibit NaV channels have helped unravel the role of NaV 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 NaV 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 NaV subtypes in various chronic pain conditions. The exquisite inhibitory properties of spider knottins over key NaV subtypes make them the best venom peptide leads for the development of novel analgesics to treat chronic pain.

Selective Targeting of Nav1.7 with Engineered Spider Venom-Based Peptides

“…In brief, spider venoms contain complex mixtures of compounds, with a high percentage of which are peptides of a broad range of functions [ 41 ]. Many of these peptides are small, disulfide-rich toxins that impact voltage-gated sodium channel function [ 37 ]. Because these molecules serve to incapacitate prey and dissuade predation, some of them have evolved to target a broad array of sodium channels that are essential for vital functions [ 40 , 42 ].…”

An Economic Dilemma between Molecular Weapon Systems May Explain an Arachno-Atypical Venom in Wasp Spiders (Argiope bruennichi)

“…This evolutionary streamlining often results in high selectivity and target-specific bioactivity, meaning that animal venoms are now considered valuable bioresources in the field of drug discovery [7]. Several blockbuster drugs have been derived from venom components [7], but they were also investigated as research tools, cosmetics, industrial enzymes or bioinsecticides [8][9][10][11].…”

An economic dilemma between weapon systems may explain an arachno-atypical venom in wasp spiders (Argiope bruennichi)

“…Several blockbuster drugs have been derived from venom components (Holford et al, 2018), but they were also investigated as research tools, cosmetics, industrial enzymes or bioinsecticides (e.g. Duterte and Lewis, 2010;Pennington et al, 2018;Dongol et al, 2019;Saez and Herzig, 2019).…”