From Marine Predator to Pharmacology: Conotoxin Diversity, Discovery, and Therapeutic Potential

Cone snails (Conus spp.) produce a sophisticated venom with a vast arsenal of neurotoxic peptides (also known as conotoxins). These peptides are renowned for their exceptional structural and functional diversity, characterized by unique disulfide bond frameworks, varied amino acid sequences, and highly specific molecular targets. This review provides a comprehensive overview of the multifaceted nature of conotoxins, beginning with their evolutionary origins, and the classification systems that define their gene superfamilies and pharmacological families. We trace the evolution of discovery methodologies, highlighting how the integration of high-throughput multi-omics is revolutionizing the identification of novel peptides. Furthermore, the review elucidates the detailed pharmacological activities of representative conotoxins on key ion channels and receptors, and explores the critical structure-activity relationships that govern their potency and selectivity. The profound understanding of these mechanisms has established conotoxins as valuable neuropharmacological tools and a rich source for novel therapeutics. We highlight their significant therapeutic potential in managing chronic pain, as exemplified by the US FDA-approved drug Ziconotide, as well as their emerging applications in neuroprotection for various diseases (like Alzheimer's and Parkinson's diseases) and treating certain cardiovascular disorders. Finally, we discuss future perspectives, emphasizing how computational design and bioengineering are poised to accelerate the translation of these marine peptides into next-generation therapies.