From marine predator to pharmacology: Conotoxin diversity, discovery, and therapeutic potential

Cone snails ( Conus spp.) biosynthesize a highly specialized venom comprising a vast arsenal of neurotoxic peptides, termed conotoxins. These peptides exhibit exceptional structural and functional diversity, characterized by unique disulfide-bond architectures, highly variable amino acid sequences, and precise interactions with defined molecular targets. This review presents a comprehensive synthesis of current knowledge on conotoxin biology, beginning with evolutionary origin and proceeding through the classification systems used to define their gene superfamilies and pharmacological families. Advances in discovery methodologies are also examined, with particular emphasis on the transformative role of high-throughput multi-omics in expanding conotoxin identification and characterization. Furthermore, this review analyzes the pharmacological properties of representative conotoxins acting on key ion channels and receptors and evaluates the structure-activity relationships that determine their potency, selectivity, and functional profile. Mechanistic insights derived from these studies have established conotoxins as powerful neuropharmacological tools and a rich reservoir for drug discovery. Their significant therapeutic potential is underscored by efficacy in chronic pain management, exemplified by the US FDA-approved drug ziconotide, and by growing evidence supporting applications in neuroprotection in disorders such as Alzheimer's disease and Parkinson's disease, as well as in selected cardiovascular conditions. Future perspectives are also discussed, with progress likely dependent on the integration of computational design, peptide engineering, and bioengineering platforms to accelerate the translation of these marine peptides into next-generation clinical therapeutics.