Conotoxins: A Pharmacological Arsenal Yet to be Fully Explored

Conotoxins are bioactive peptides derived from the venom of cone snails. Since its first biochemical characterization approximately 50 years ago, they have displayed a wide variety of neuronal and neuromuscular target specificities. Despite extensive research, conotoxins continue to remain a potential goldmine for pharmacology research and drug discovery. Their precise modulation of ion channels, receptors, and proteins positions them as promising candidates for treating chronic pain, diabetes, cardiovascular diseases, and neurological disorders. Of particular relevance is their role in addressing the current American opioid crisis, with conotoxins like ω-MVIIA (marketed as Prialt®) offering effective, non-addictive pain relief, showcasing their potential as alternatives to traditional opioids. Conotoxins also hold immense potential as blueprints for novel pharmaceuticals, but challenges remain in translating these peptides into clinical use. We provide a comprehensive literature review, focusing on how these peptides selectively interact with physiological targets located primarily in the nervous system. We chart the evolution of conotoxin research, highlighting significant progress and discussing key conotoxins like ω-MVIIA, Contulakin-G, α-RgIA4, mini-Ins, κO-PVIIA and αO-GeXIVA. Disulfide bridge pairings and sequences are included from ConoServer, the database of conotoxins, providing a comprehensive overview of the current research. After discussing the future application of AI in conotoxin research, advancements in computational modelling, and the importance of conservation efforts, we emphasize the need for continuing research to harness nature’s pharmacological arsenal fully and to set the stage for coming breakthroughs.