Cone snail venom-inspired somatostatin receptor 4 (SSTR<sub>4</sub>) agonists as new drug leads for peripheral pain.

Abstract

Persistent pain affects one in five people worldwide, often with severely debilitating consequences. While current treatments can be effective for mild or acute pain, they are largely inadequate for managing moderate to severe chronic pain, underscoring the urgent need for new therapeutics. The somatostatin receptor 4 (SSTR₄), expressed in sensory neurons of the peripheral nervous system, has recently emerged as a promising target for non-opioid pain relief. However, the presence of several closely related receptors with similar ligand-binding surfaces complicates the design of receptor-specific agonists. Here, we report the discovery of consomatin Fj1, a potent and selective SSTR₄-targeting peptide derived from the venom gene repertoire of marine cone snails. Consomatin Fj1 is a mimetic of the endogenous hormone somatostatin but features a minimized receptor binding motif that provides target selectivity. Peripheral administration of synthetic consomatin Fj1 provides analgesia in mouse models of postoperative and neuropathic pain. Using structure-activity studies, we designed and functionally evaluated several Fj1 analogs, resulting in compounds with further improved potency and selectivity. These findings highlight the therapeutic potential of venom-derived peptides as a novel strategy for targeting the SSTR₄ and open new avenues for the development of effective treatments for persistent pain.