کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
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2066497 | 1077189 | 2009 | 9 صفحه PDF | دانلود رایگان |
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 μ-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 μ-conotoxins known to target the voltage-gated Na channel skeletal muscle subtype Nav1.4. Our preliminary results indicate that BuIIIB and BuIIIC are potent inhibitors of Nav1.4 (average block ∼96%, at a 1 μM concentration of peptide), displaying a very slow off-rate not seen in previously characterized μ-conotoxins that block Nav1.4. In addition, the three new C. bullatus μ-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 μ-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.
Journal: Toxicon - Volume 53, Issue 1, January 2009, Pages 90–98