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Toxicon
2009 Jan 01;531:90-8. doi: 10.1016/j.toxicon.2008.10.017.
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Pruning nature: Biodiversity-derived discovery of novel sodium channel blocking conotoxins from Conus bullatus.
Holford M, Zhang MM, Gowd KH, Azam L, Green BR, Watkins M, Ownby JP, Yoshikami D, Bulaj G, Olivera BM.
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Described herein is a general approach to identify novel compounds using the biodiversity of a megadiverse group of animals; specifically, the phylogenetic lineage of the venomous gastropods that belong to the genus Conus ("cone snails"). Cone snail biodiversity was exploited to identify three new mu-conotoxins, BuIIIA, BuIIIB and BuIIIC, encoded by the fish-hunting species Conus bullatus. BuIIIA, BuIIIB and BuIIIC are strikingly divergent in their amino acid composition compared to previous mu-conotoxins known to target the voltage-gated Na channel skeletal muscle subtype Na(v)1.4. Our preliminary results indicate that BuIIIB and BuIIIC are potent inhibitors of Na(v)1.4 (average block approximately 96%, at a 1muM concentration of peptide), displaying a very slow off-rate not seen in previously characterized mu-conotoxins that block Na(v)1.4. In addition, the three new C. bullatus mu-conopeptides help to define a new branch of the M-superfamily of conotoxins, namely M-5. The exogene strategy used to discover these Na channel-inhibiting peptides was based on both understanding the phylogeny of Conus, as well as the molecular genetics of venom mu-conotoxin peptides previously shown to generally target voltage-gated Na channels. The discovery of BuIIIA, BuIIIB and BuIIIC Na channel blockers expands the diversity of ligands useful in determining the structure-activity relationship of voltage-gated sodium channels.
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