Many organisms including snakes, spiders, scorpions, cone snails, anemones and some mammalian species have evolved venom as either a defence mechanism or a weapon for prey capture1. These venoms typically contain a complex cocktail of bioactive disulfide-bond rich polypeptides called toxins that target a wide range of receptors including enzymes, ion channels, GPCRs and transporters. Of interest to drug designers is their high potency and selectivity for ion channels and receptors combined with their resistance to many proteases.
Of particular interest are the venom peptides (conotoxins) from the Conidae2,3, most with small polypeptide chains containing 10-40 amino acids that are highly constrained by one to five disulfide bridges and are structurally well defined. Their high potency and exquisite selectivity has led to two drug candidates4,5 from our laboratories.
In this presentation I will outline our program of discovery using a venomics strategy3, describe the amazing diversity of molecular structures being discovered as well as regioselective chemistry6,7 that has facilitated the determination of structure-function relationships. This has led to the availability of potent molecules with novel function8 and exceptional stability when exposed to reducing environments and in plasma. Together, these results underpin the development of more stable and potent peptide mimetics suitable for new drug therapies, and highlight the application of this technology more broadly to disulfide-bonded peptides and proteins.