An international research team led by the Medical University of Vienna has investigated a new peptide derived from cone snail venom which significantly reduced inflammation-induced pain in an animal model. Crucially, its effect takes hold immediately after subcutaneous injection, whereas previously known cone snail peptides must be administered directly into the cerebrospinal fluid. The study results thus provide an important basis for the development of new non-opioid pain-relieving medicines that are significantly gentler to use, and have recently been published in the journal "Nature Structural and Molecular Biology".

Due to the considerable risks associated with the use of opioids for pain management, medical researchers are actively seeking alternative active substances. The international research team led by Harald Sitte from the Center for Physiology and Pharmacology at MedUni Vienna focused the recently published study on the previously isolated peptide AoIA, derived from the venom of the cone snail Conus araneosus. The study demonstrated that AoIA specifically inhibits the noradrenaline transporter and can thereby support the body’s own pain-inhibiting mechanisms. The key advantage for potential clinical application is that, unlike MrIA – a peptide from the same family of chi-conotoxins discovered 25 years ago, whose pharmacological properties require direct administration into the cerebrospinal fluid (CSF) – AoIA can exert its effect following peripheral administration beneath the skin.

In collaboration with the research group led by Eric Xu (Shanghai Institute of Materia Medica, Chinese Academy of Sciences, China), the three-dimensional structure of the human noradrenaline transporter in relation to AoIA was also determined for the first time using cryo-electron microscopy. This made it possible to understand precisely how the peptide binds to the transporter and inhibits its function. The analyses also explain why AoIA specifically targets only the noradrenaline transporter, but not the closely related transport proteins for serotonin or dopamine. This high selectivity makes the peptide a promising approach for the development of new active substances.

Further investigations also showed that AoIA does not act on opioid receptors or other known targets involved in pain processing. In a mouse model, following subcutaneous administration, the peptide significantly reduced pain during an inflammation-induced pain phase. By contrast, it showed no effect in models of acute pain stimuli. Furthermore, there was no evidence of sedation or impaired motor coordination.

Mechanism of action deciphered in detail for the first time
"Our results show how a naturally occurring peptide specifically influences the noradrenaline transporter and can thereby support the body’s own pain-inhibiting mechanisms. 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," said study leader Harald Sitte.

For several decades, cone snail venoms have been regarded in pharmacological research as a promising source of new active substances. A drug developed from a cone snail peptide is already in use today for the treatment of chronic pain. The current study expands this field of research to include a further peptide, the binding mechanism of which to the noradrenaline transporter has now been deciphered in detail for the first time. In addition to researchers from MedUni Vienna, scientists from Innsbruck, China, Australia, Turkey and the Philippines were also involved.