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

ABSTRACT: The ?-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 ?-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 Nav1.2 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.

SUBMITTER: Walewska A

PROVIDER: S-EPMC4332556 | biostudies-literature | 2013 Jul

REPOSITORIES: biostudies-literature

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

Walewska Aleksandra A Han Tiffany S TS Zhang Min-Min MM Yoshikami Doju D Bulaj Grzegorz G Rolka Krzysztof K

European journal of medicinal chemistry 20130501

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 a ...[more]

PMID: 23707919

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Project description:In the preparation of synthetic conotoxins containing multiple disulfide bonds, oxidative folding can produce numerous permutations of disulfide bond connectivities. Establishing the native disulfide connectivities thus presents a significant challenge when the venom-derived peptide is not available, as is increasingly the case when conotoxins are identified from cDNA sequences. Here, we investigate the disulfide connectivity of ?-conotoxin KIIIA, which was predicted originally to have a [C1-C9,C2-C15,C4-C16] disulfide pattern based on homology with closely related ?-conotoxins. The two major isomers of synthetic ?-KIIIA formed during oxidative folding were purified and their disulfide connectivities mapped by direct mass spectrometric collision-induced dissociation fragmentation of the disulfide-bonded polypeptides. Our results show that the major oxidative folding product adopts a [C1-C15,C2-C9,C4-C16] disulfide connectivity, while the minor product adopts a [C1-C16,C2-C9,C4-C15] connectivity. Both of these peptides were potent blockers of Na(V)1.2 (K(d) values of 5 and 230 nM, respectively). The solution structure for ?-KIIIA based on nuclear magnetic resonance data was recalculated with the [C1-C15,C2-C9,C4-C16] disulfide pattern; its structure was very similar to the ?-KIIIA structure calculated with the incorrect [C1-C9,C2-C15,C4-C16] disulfide pattern, with an ?-helix spanning residues 7-12. In addition, the major folding isomers of ?-KIIIB, an N-terminally extended isoform of ?-KIIIA identified from its cDNA sequence, were isolated. These folding products had the same disulfide connectivities as ?-KIIIA, and both blocked Na(V)1.2 (K(d) values of 470 and 26 nM, respectively). Our results establish that the preferred disulfide pattern of synthetic ?-KIIIA and ?-KIIIB folded in vitro is 1-5/2-4/3-6 but that other disulfide isomers are also potent sodium channel blockers. These findings raise questions about the disulfide pattern(s) of ?-KIIIA in the venom of Conus kinoshitai; indeed, the presence of multiple disulfide isomers in the venom could provide a means of further expanding the snail's repertoire of active peptides.

Dataset Information

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

Publications

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

Similar Datasets

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