Advances in the synthesis and engineering of conotoxins

Conotoxins, isolated from the venom of carnivorous marine snails of the Conus genus, are disulfide-rich peptides and proteins with well-defined three-dimensional structures. Conotoxins’ ability to target a wide range of ion channels and receptors, including voltage- and ligand-gated ion channels, G protein-coupled receptors, monoamine transporters, and enzyme, at exquisite potency and selectivity make them valuable research and therapeutic tools. Despite their potentials, Conus venom peptides are present in limited quantities in nature and possess structural complexity that raises significant synthetic challenges for both chemical synthesis and recombinant expression. Here, we document recent advances in the expression and synthesis of conotoxins, particularly focusing on directed formation of disulfide bonds, chemical ligation techniques, and the integration of non-native functional groups. These advances can provide access to even the most complex conotoxins, accelerating conotoxin-based drug discovery and functional analysis, as well as opening new avenues for the development of drug candidates.