The venom from carnivorous marine snails of the Conus genus is a cocktail of peptides, proteins and small molecules that is used by the snail to capture prey. The peptides within this venom have been the focus of many drug design efforts as they exhibit potent and selective targeting of therapeutically important receptors, transporters and channels, particularly in relation to the treatment of chronic pain. The most well studied class of Conus peptides are the conotoxins, which are disulfide-rich and typically have well-defined three dimensional structures that are important for both biological activity and stability. In this chapter we discuss the molecular engineering approaches that have been used to modify these conotoxins to improve their pharmacological properties, including potency, selectivity, stability, and minimisation of the bioactive pharmacophore. These engineering strategies include sidechain modifications, disulfide substitution and deletion, backbone cyclisation, and truncations. Several of these re-engineered conotoxins have progressed to pre-clinical or clinical studies, which demonstrates the promise of using these molecular engineering techniques for the development of therapeutic leads.
Keywords: Chronic pain; Cone snails; Conotoxins; Drug design; Peptide engineering; Stabilisation; Structure/activity relationships.