The
venom of the marine predatory cone snails (genus Conus) has evolved for prey capture and defense,
providing the basis for survival and rapid diversification of the
now estimated 750+ species. A typical Conus venom contains hundreds to thousands of bioactive peptides known
as conotoxins. These mostly disulfide-rich and well-structured peptides
act on a wide range of targets such as ion channels, G protein-coupled
receptors, transporters, and enzymes. Conotoxins are of interest to
neuroscientists as well as drug developers due to their exquisite
potency and selectivity, not just against prey but also mammalian
targets, thereby providing a rich source of molecular probes and therapeutic
leads. The rise of integrated venomics has accelerated conotoxin discovery
with now well over 10,000 conotoxin sequences published. However,
their structural and pharmacological characterization lags considerably
behind. In this review, we highlight the diversity of new conotoxins
uncovered since 2014, their three-dimensional structures and folds,
novel chemical approaches to their syntheses, and their value as pharmacological
tools to unravel complex biology. Additionally, we discuss challenges
and future directions for the field.