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

• Two series of peptoid–peptide chimeras of μ-conotoxin KIIIA were synthesized.
• Oxidative folding of μ-KIIIA peptomers was simplified using selenocysteines.
• All peptomer analogues blocked mammalian Nav1.2 sodium channels.
• One of the peptomer analogues presented unique pharmacological properties.

The μ-conotoxin KIIIA is a three disulfide-bridged blocker of voltage-gated sodium channels (VGSCs). The Lys7 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 Lys7 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 Nav1.2 subtype of mammalian VGSCs exogenously expressed in Xenopus oocytes. All six analogues were active, with the N-methylglycine analogue, [Sar7]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.

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