Researchers are exploring a new route to non-opioid painkillers after an international team showed that a cone-snail-derived compound can ease inflammation-driven pain when injected under the skin. The urgency of finding alternatives stems from the considerable risks associated with conventional opioid therapies.
Discovery of a skin-administered agent
The work was led by Harald Sitte at the Center for Physiology and Pharmacology, Medical University of Vienna. The group focused on AoIA, a peptide isolated from the venom of the cone snail Conus araneosus. Unlike earlier cone-snail peptides that required direct delivery into the cerebrospinal fluid, AoIA produced an effect after subcutaneous injection.
This peripheral route matters because it avoids the need for invasive procedures like those required for the related chi-conotoxin MrIA, discovered 25 years ago, which must be administered directly into the cerebrospinal fluid.
How the compound works
In collaboration with Eric Xu’s lab at the Shanghai Institute of Materia Medica, scientists used cryo-electron microscopy to determine the three-dimensional structure of the human noradrenaline transporter in complex with AoIA. The images revealed how the peptide binds to the transporter and inhibits its function, explaining its specificity for the noradrenaline transporter over the closely related serotonin and dopamine transporters.
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“Our results show how a naturally occurring peptide specifically influences the noradrenaline transporter and can thereby support the body’s own pain-inhibiting mechanisms,” Harald Sitte said. “The fact that we were able to demonstrate both its mode of action at the molecular level and its pain-relieving effect following subcutaneous administration in an animal model lays an important foundation for the development of new non-opioid pain medications that are significantly easier to administer. However, further preclinical and clinical studies are required before it can potentially be used in humans.”
Cone snail venoms have long been a source of pharmacological leads; one peptide-based drug is already in use for chronic pain. The current study expands this field by detailing the binding mechanism of AoIA to the noradrenaline transporter, with contributions from researchers in Austria, China, Australia, Turkey, and the Philippines.
The full findings appear in Nature Structural and Molecular Biology (2026 Jul 21) under the title “Structural and functional basis of antinociceptive action of χ-conotoxin AoIA at the noradrenaline transporter.”
