µ-TRTX-Tsp1a

μ-theraphotoxin-Tsp1a (Tsp1a) is a 28 amino acid peptidyl toxin originally isolated from the venom of the Thrixopelma spec. (Peru) spider venom. Tsp1a is a potent (IC50 = 10 nM) and highly specific inhibitor of Na_V1.7 channels, with a selectivity of >100-fold over hNa_V1.3−hNa_V1.6 and hNa_V1.8, 45-fold over hNa_V1.1, and 24-fold over hNa_V1.2¹.

Tsp1a is a gating modifier toxin that inhibits hNa_V1.7 by stabilizing the channel in its inactivated state, inducing a hyperpolarizing shift in the voltage-dependence of channel inactivation and slowing recovery from fast inactivation¹.

Spider peptides modulate an array of ion channels and receptor proteins. Knottins, which are a subtype of spider peptides, are also referred to as inhibitor cystine knot (ICK) peptides. ICK peptides harbor a disulfide-rich structural motif that forms a “knot”, which confers high structural, thermal, and proteolytic stability. NMR studies revealed that Tsp1a adopts a classical knottin fold, and like many knottin peptides, it is exceptionally stable in human serum¹.

Na_V1.7 is expressed in the PNS, dorsal root ganglia neurons, visceral sensory neurons, olfactory sensory neurons, trigeminal ganglia, and sympathetic neurons. Gain-of-function mutations in SCN9A, the gene encoding Na_V1.7, have been identified in patients with various pain disorders, such as inherited erythromelalgia (IEM), paroxysmal extreme pain disorder (PEPD), small fiber neuropathy (SFN), and painful diabetic peripheral neuropathy. Na_v 1.7 loss-of-function mutations lead to a congenital indifference to pain^2,3. Tsp1a toxin was shown to reduce visceral hypersensitivity in a model of irritable bowel syndrome. This suggests that pharmacological inhibition of hNa_V1.7 at peripheral sensory nerve endings might be a viable approach for eliciting analgesia in patients suffering from chronic visceral pain¹.