Voltage-gated sodium channels (NaV), including subtype NaV1.8, are emerging as promising therapeutic targets to treat chronic pain. However, as these channels are intimately involved in almost all aspects of physiology, only the most selective inhibitors are suitable as drug leads. We have recently isolated the µO-conotoxin, MfVIA, which inhibits NaV1.8 with high potency through interaction with the voltage sensor domain of the NaV1.8 channel. µO-conotoxin peptides are extremely hydrophobic and difficult to synthesize. In light of this we have pioneered a novel sophisticated approach to obtain synthetic MfVIA (1), allowing us to produce analogues of µO-conotoxin to conduct pharmacological characterization of µO-conotoxin peptides.
Peptide-interaction with the voltage sensor domains is likely driven by the peptide initially inserting into the cell membrane surrounding this domain. With this in mind, analogs with improved membrane-binding properties compared to MfVIA were designed. One of these analogs showed a striking improvement in selectivity towards NaV1.8 over all the other NaV subtypes, including the skeletal muscle subtype NaV1.4. Therefore we believe to have found the first peptide drug lead with potential to selectively target NaV1.8.
Synthesis, structure-activity in vitro results, membrane-binding interactions and in vivo results from animal pain studies will be discussed, highlighting that MfVIA binding sites on NaV1.8 and NaV1.4 are distinct and that that selectivity for NaV1.8 over NaV1.4 can be achieved resulting in peptides with proven efficacy in validated animal pain models.