Chronic pain is a debilitating disease that affects one in five Australians and is associated with a financial cost exceeding $70 billion in 2018, highlighting the need to develop new pain therapeutics. Voltage-gated sodium-channels (NaV channels), including subtype NaV1.7, have shown great promise as targets for the treatment of neurological diseases, including chronic pain. Cone snail-derived µ-conotoxins, are small, potent peptide inhibitors of NaV channels, and are being pursued as potential drug leads for pain-related diseases. They act by blocking the pore of the channel and contain desirable drug-like features including the ability to act rapidly on their targets and intrinsic stability afforded by a complex intermolecular disulfide network. However, a limiting factor in their translation into therapies is the non-selective nature of this family of peptides and to date only µ-conotoxin KIIIA has been reported to act on NaV1.7, involved in chronic pain.
We have recently identified an exciting novel µ-conotoxin from Conus nigropunctatus, NgIIIA. Here we present the discovery and isolation of this peptide, analysis of the NMR solution structure and the characterisation of human NaV channel activity by Q-Patch electrophysiology. The NMR structure of NgIIIA contains a three-turn helix, similar to the characteristic alpha-helix seen in µ-conotoxin KIIIA. Interestingly, activity data reveals a NaV channel selectivity profile distinct from KIIIA as well as another closely related µ-conotoxin, SmIIIA. NgIIIA is the most potent NaV1.7 µ-conotoxin inhibitor reported to date and future investigation into structure-activity-relationships of this toxin could provide insights into residues important for NaV channel selectivity, thus providing exciting potential for future chronic pain drug development.