NMR Structure of VarI, a Novel Bioactive Peptide Toxin from Terebrid Marine Snails

Peptide toxins display great specificity in both targeting and function, and are a viable resource for enriching the available arsenal of pharmaceutical compounds. For example Ziconotide (Prialt), a peptide toxin derived from cone snails (conotoxin), is the first FDA approved conotoxin drug used to treat chronic pain in cancer and HIV patients by targeting voltage dependent Ca2+ channels. Cone snail toxins have long been identified as effective compounds for characterizing ion channels and receptors. However, the Terebridae, a less studied, related venomous snail family, are also a pharmacologically relevant source of toxins. Similar to cone snails, genomic and proteomic analyses of terebrid venom reveal a vibrant diversity of peptide toxins (teretoxins). Here, we present the first structural elucidation of a teretoxin, VarI. VarI was chemically synthesized, oxidatively refolded, and structurally characterized by nuclear magnetic resonance (NMR) spectroscopy. Standard homonuclear NMR methods were used in the structure determination, and the final bundle of lowest energy structures revealed an unusual pattern of disulfide bond connectivities potentially unique to teretoxins. The NMR structure of Var1 will assist in understanding the toxin's pharmacological properties, and is being used to guide the search for functional receptors of VarI.