Authors: Courtney Johnson
Findings of a new study, carried out at the University of Queensland in Brisbane, Australia and presented recently at the Biophysical Society’s 60th Annual Meeting (Los Angeles, CA, USA, 27 February-2 March 2016), have demonstrated that the peptide toxin ProTx-II found in the venom of the Peruvian green velvet tarantula, Thrixopelma pruriens, serves as a potent and selective inhibitor of pain receptors in the brain. The results suggest that the development of novel peptides with a simulated mechanism of action may provide effective therapy for the treatment of pain.
Peptide toxins derived from the venom of spiders, snakes or cone snails injected via a bite or harpoon, can cause serious reactions and even have lethal effects if no treatment is provided. However, these peptide toxins may also be effective in targeting neural pain receptors, reducing pain and potentially serving as painkillers in the treatment of chronic and neuropathic pain. Given the limited relief provided by currently available painkillers in addition to the side-effects experienced and the extremely addictive qualities of these drugs, the recent study was an effort to further investigate the Peruvian green velvet tarantula toxin’s mechanism of neuropathic pain relief so as to develop new therapies of treatment.
“Our group is specifically interested in understanding the mode of action of this toxin to gain information that can guide us in the design and optimization of novel pain therapeutics,” commented Sónia Troeira Henriques (University of Queensland’s Institute for Molecular Bioscience).
“Our results show that the cell membrane plays an important role in the ability of ProTx-II to inhibit the pain receptor. In particular, the neuronal cell membranes attract the peptide to the neurons, increase its concentration close to the pain receptors, and lock the peptide in the right orientation to maximize its interaction with the target,” remarked Henriques.
When asked how ProTx-II works, “It binds to the pain receptor located within the membrane of neuronal cells, but the precise peptide-receptor binding site and the importance of the cell membrane in the inhibitory activity of ProTx-II is unknown,” explained Henriques.
The researchers focused on its structure-activity relationship by “exploring the structure, the membrane-binding properties, and the inhibitory activity of ProTx-II and a series of analogues,” Henriques stated.
The group investigated the importance of the structure in the inhibitory function of the peptide using nuclear magnetic resonance spectroscopy. Further surface plasmon resonance and fluorescence methodologies were also utilized in order to explore the molecular interactions between the peptide and the neuronal cell membrane as well as the molecular properties of the peptide which affect these interactions.
The significance of the membrane-binding properties of ProTx-II in its potency and inhibition of the important pain receptor Nav 1.7 was discovered. “Until now, studies characterizing the inhibitory activity of venom toxins have ignored the potential role of the cell membrane in their potency and activity,” Henriques noted.
In addition to Nav 1.7, “other voltage-gated ion channels are located at the cell membrane and involved in a range of physiological processes such as muscle and nerve relaxation, regulation of blood pressure, and sensory transduction,” Henriques highlighted. “Their ‘faulty’ activity is, however, associated with several disorders, so other ion channels are actively being pursued as drug targets for the treatment of neuromuscular disease, neurological disorders, and inflammatory and neuropathic pain.”
Subsequent work inspired by the results of the current study is now underway to design novel toxins with greater affinity for the cell membrane and that have an improved potency over ProTx-II, but with fewer side-effects.
“Our work creates an opportunity to explore the importance of the cell membrane in the activity of peptide toxins that target other voltage-gated ion channels involved in important disorders,” commented Henriques.
Sources: Biophysical Society Press Release