Marine cone snails are a large family of gastropods that have evolved highly potent venoms for predation and defense. The cone snail venom has extraordinary molecular diversity in neuropharmacologically active compounds.
Cone snails are marine gastropods belonging to the Conidae family, which are found in tropical, subtropical, and temperate waters around the world. They use a specialized envenomation strategy to feed on worms (vermivorous), mollusks (molluscivorous), or fish (piscivorous).
α-Conotoxins are the largest group of natural product peptide inhibitors of the nAChRs. These disulfide-stabilized and highly structured molecules have naturally engineered potency at nAChRs in the nM–pM range and target a broad range of nAChR subtypes, making them excellent tools to dissect the physiological and pathological functions of the diverse nAChR subtypes.
Their abundant expression across cone-snail species has provided a natural combinatorial library of peptides with primary variable sequences, structures, pharmacology, and mode of action at nAChRs.
This library has underpinned synthetic chemistry approaches that are focused on the rational development of nAChR targeted lead molecules, research tools, and development of alternative/allosteric strategies for selective nAChR inhibition.
Application of α-conotoxins has also extended towards the development of stable peptidomimetics for other receptor types, such as the glucagon-like peptide-1 receptor as well as a medium of targeted drug delivery in breast cancer.
High-throughput venomics approaches have accelerated identification of α-conotoxins inhibiting other receptor classes, which promise to provide first-in-class molecules targeting multiple receptor classes to dissect cross-talk in complex cellular mechanisms underlying conditions such as chronic pain.
Targeted drug delivery
A recent study exploited the inherent high potency and specificity of α-conotoxins for nAChRs to obtain targeted drug delivery. Targeting α7 nAChRs over-expressed in breast cancer, the α7 selective 1mI was used in modified micelles to deliver paclitaxel chemotherapy selectively.
1mI modified micelles targeted α7 overexpressing tumor cells with higher specificity and efficacy. The selective targeting also resulted in low systemic toxicity and myelosuppression. This example paves the way for the application of selective conotoxins and analogs in targeted drug delivery for other diseases.
α-Conotoxins have been considered for development as drug leads. However, several challenges need to be overcome before the successful therapeutic application of these peptides.
The inherent selectivity profiles make α-conotoxins excellent tools for in vitro applications. However, selectivity windows of 10 to 30-fold may not always be sufficient for in vivo applications when considering the minimum effective doses required.