Isolation, characterization and total regioselective synthesis of the novel mu O-conotoxin MfVIA from Conus magnificus that targets voltage-gated sodium channels

The µO-conotoxins are notable for their unique selectivity for Na v1.8 over other sodium channel isoforms, making them attractive drug leads for the treatment of neuropathic pain. We describe the discovery of a novel µO-conotoxin, MfVIA, from the venom of Conus magnificus using high-throughput screening approaches. MfVIA was found to be a hydrophobic 32-residue peptide (amino acid sequence RDCQEKWEYCIVPILGFVYCCPGLICGPFVCV) with highest sequence homology to µO-conotoxin MrVIB. To overcome the synthetic challenges posed by µO-conotoxins due to their hydrophobic nature and difficult folding, we developed a novel regioselective approach for the synthesis of µO-conotoxins. Performing selective oxidative deprotections of the cysteine side-chain protecting groups of the fully protected peptide allowed manipulations in organic solvents with no chromatography required between steps. Using this approach, we obtained correctly folded MfVIA with increased synthetic yields.