Conus regius-Derived Conotoxins: Novel Therapeutic Opportunities from a Marine Organism

Abstract

Conus regius is a marine venomous mollusk of the Conus genus that captures its prey by injecting a rich cocktail of bioactive disulfide bond rich peptides called conotoxins. These peptides selectively target a broad range of ion channels, membrane receptors, transporters, and enzymes, making them valuable pharmacological tools and potential drug leads. C. regius-derived conotoxins are particularly attractive due to their marked potency and selectivity against specific nicotinic acetylcholine receptor subtypes, whose signalling is involved in pain, cognitive disorders, drug addiction, and cancer. However, the species-specific differences in sensitivity and the low stability and bioavailability of these conotoxins limit their clinical development as novel therapeutic agents for these disorders. Here, we give an overview of the main pharmacological features of the C. regius-derived conotoxins described so far, focusing on the molecular mechanisms underlying their potential therapeutic effects. Additionally, we describe adoptable chemical engineering solutions to improve their pharmacological properties for future potential clinical translation.

Analgesic Peptides: From Natural Diversity to Rational Design

“…The very interesting molecules with antinociceptive activity are conotoxins (Table 3). These peptides from cone snails are potent and highly selective blockers or modulators of ion channel functions [46]. O represents hydroxyproline residue.…”

“…For example, α-conotoxin RgIA, the peptide containing 13 amino acid residues with two intramolecular disulfide bonds (Table 3), was isolated from Conus regius [46]. It has been reported that in rat models of neuropathy, RgIA is a potent pain-relieving compound.…”

α7- and α9-Containing Nicotinic Acetylcholine Receptors in the Functioning of Immune System and in Pain

“…The first indications of the analgesic effects mediated by α9α10 nAChR arose when this receptor subtype was identified as a molecular target for analgesic α-conotoxins Vc1.1 and RgIA, which alleviated neuropathic pain in rodent models (reviewed in [ 196 , 197 , 198 ]). In particular, α-conotoxin RgIA (daily i.m.…”

“…Although α-conotoxins specific to α9α10 nAChR hold great pharmacological potential, they are not ideal therapeutic drug leads due to a number of shortcomings, such as a short half-life in vivo, unstable disulfide bonds, limited modes of administration and poor potency at human nAChRs for some of them [ 230 , 231 , 232 ]. In recent reviews [ 197 , 198 ], the established strategies for improving the activity, selectivity and stability of α-conotoxins have been considered in detail. They include scanning mutagenesis, unnatural amino acid substitutions, disulfide bond modification, backbone and side-chain cyclization and polymerization.…”

Loop2 Size Modification Reveals Significant Impacts on the Potency of α-Conotoxin TxID

“…Each species of cone snail can secrete 50–200 different kinds of small molecule polypeptides, called conotoxins, in their venom duct, which possess rich pharmacological activities [ 19 , 20 ]. With the improved accuracy of detection technology, it is conservatively estimated that there are over hundreds of thousands of distinct neuroactive conopeptides [ 21 , 22 ]. Among the abundant conotoxins, α-conotoxins from the A-superfamily are the largest subfamily.…”