Expanding chemical diversity of conotoxins: peptoid-peptide chimeras of the sodium channel blocker μ-KIIIA and its selenopeptide analogues.

Abstract The μ-conotoxin KIIIA is a three disulfide-bridged blocker of voltage-gated sodium channels (VGSCs). The Lys 7 residue in KIIIA is an attractive target for manipulating the selectivity and efficacy of this peptide. Here, we report the design and chemical synthesis of μ-conopeptoid analogues (peptomers) in which we replaced Lys 7 with peptoid monomers of increasing side-chain size: N -methylglycine, N -butylglycine and N -octylglycine. In the first series of analogues, the peptide core contained all three disulfide bridges; whereas in the second series, a disulfide-depleted selenoconopeptide core was used to simplify oxidative folding. The analogues were tested for functional activity in blocking the Na v 1.2 subtype of mammalian VGSCs exogenously expressed in Xenopus oocytes. All six analogues were active, with the N -methylglycine analogue, [Sar 7 ]KIIIA, the most potent in blocking the channels while favouring lower efficacy. Our findings demonstrate that the use of N -substituted Gly residues in conotoxins show promise as a tool to optimize their pharmacological properties as potential analgesic drug leads.