Conotoxins as Research Tools and Drug Leads

Abstract

The complex mixture of biologically active peptides that constitute the venom of Conus species provides a rich source of ion channel neurotoxins. These peptides, commonly known as conotoxins, exhibit a high degree of selectivity and potency for different ion channels and their subtypes making them invaluable tools for unravelling the secrets of the nervous system. Furthermore, several conotoxin molecules have profound applications in drug discovery, with some examples currently undergoing clinical trials. Despite their relatively easy access by chemical synthesis, rapid access to libraries of conotoxin analogues for use in structure-activity relationship studies still poses a significant limitation. This is exacerbated in conotoxins containing multiple disulfide bonds, which often require synthetic strategies utilising several steps. This review will examine the structure and activity of some of the known classes of conotoxins and will highlight their potential as neuropharmacological tools and as drug leads. Some of the classical and more recent approaches to the chemical synthesis of conotoxins, particularly with respect to the controlled formation of disulfide bonds will be discussed in detail. Finally, some examples of structure-activity relationship studies will be discussed, as well as some novel approaches for designing conotoxin analogues.

von Willebrand Factor Type C Domain-containing Proteins Regulate Bone Morphogenetic Protein Signaling through Different Recognition Mechanisms

“…It is tempting to speculate that the numerous disulfide bonds of VWC provide a scaffold for the attachments of a diversity of loops that can generate different binding specificities similar to an immunoglobulin. In the conotoxin superfamily comprising many hundreds of members with a disulfide-rich core, a similar principle has been established (38,39). Our in vitro results showed that the binding affinity and specificity of BMPs to different forms of chordin VWC domains are not influenced by the adjacent non-VWC sequences (Fig.…”

α4/7-conotoxin Lp1.1 is a novel antagonist of neuronal nicotinic acetylcholine receptors

“…Many of these peptides are disulfide-rich neurotoxins, termed conotoxins, that selectively inhibit ligandand voltage-gated ion channels. This high selectivity of conotoxins has lead to a great interest in the use of these molecules as pharmacological tools and the design of novel therapeutics [1,37].…”

α-Selenoconotoxins, a New Class of Potent α7 Neuronal Nicotinic Receptor Antagonists

“…Conotoxins are a class of disulfide-rich peptide neurotoxins isolated from the venom of carnivorous marine snails. They target a wide range of ion channels with a high degree of selectivity and potency and have profound therapeutic potential, with at least one example recently approved as a drug for the treatment of chronic pain and several others currently undergoing clinical trials (see Table 1) (22). In the present study, we have investigated the impact of substituting disulfide bonds with diselenide bonds on the structure, activity, and conformational stability of a model cysteine-rich peptide in relevant biological reducing environments.…”