Cone snails are a large group of venomous marine mollusks that utilize a complex venom mixture of (mostly) peptide toxins called conotoxins. The subset of cone snails that prey on fish have been an invaluable source of bioactive peptides that can potently and selectively modulate various vertebrate targets. A selective blocker of the N-type calcium channel, MVIIA, identified in Conus magus was approved in 2004 by the FDA for treating intractable pain (Ziconotide, trade name Prialt), and several other conotoxins or conotoxin-derived compounds are in drug development pipelines.
We recently discovered that some fish hunting cone snails produce toxins that were recruited from their endogenous somatostatin-like signaling system (called ´consomatins´). Several of these can potently activate human somatostatin receptors (SST) and display diverse receptor subtype selectivities. Based on feature similarities with the vertebrate somatostatin, we selected promising consomatins, predicted their mature sequence, and screened them against the human SSTs. One of these, consomatin Fj1, from the venom gland transcripts of Conus fijisulcatus, a fish hunting cone snail of the Asprella clade, displayed a strong preference for SST4. This receptor has been gaining increasing attention as a new non-opioid target for treating various types of peripheral pain. Specifically activating this subtype is expected to avoid the endocrine side effects, or calcitonin and prolactin related side effects associated with activation of SST2,3,5 and SST1, respectively. Recent studies indicate that SST4 activation is effective at treating a wide range of pain indications by modulating the excitability of the dorsal root ganglion neurons and trigeminal nerve, thereby inhibiting the sensory information from entering the central nervous system. Here, we show that Fj1 is effective at alleviating pain responses in diverse rodent models of peripheral pain without entering the CNS, and suggest that Fj1 is a promising new lead for an analgesic therapeutic.