MedUni Vienna: New approach to the development of non-opioid painkillers
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. Unlike the related peptide MrIA, which requires direct administration into the cerebrospinal fluid, AoIA exerts its effect following peripheral administration beneath the skin.
In collaboration with researchers led by Eric Xu at the Shanghai Institute of Materia Medica, the team also determined for the first time the three-dimensional structure of the human noradrenaline transporter bound to AoIA using cryo-electron microscopy. This enabled the researchers to understand precisely how the peptide binds to the transporter and inhibits its function. The analyses further revealed why AoIA selectively targets the noradrenaline transporter without affecting the closely related serotonin or dopamine transporters, making it a promising candidate for the development of highly selective pain therapies.
Additional investigations demonstrated that AoIA does not interact with opioid receptors or other known targets involved in pain processing. In a mouse model, subcutaneous administration significantly reduced pain during inflammation-induced pain, while showing no effect in acute pain models. The researchers also found 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 used to treat chronic pain. The current study expands this field by identifying another promising peptide and deciphering its binding mechanism to the noradrenaline transporter in unprecedented detail. In addition to MedUni Vienna, researchers from Innsbruck, China, Australia, Turkey and the Philippines contributed to the study.