Peptides derived from the venoms of marine cone snails have attracted recent attention as potential therapeutic agents for the treatment of chronic pain. These conotoxins are 12-40 amino acids in size and are typically stabilized by two or more disulfide bonds. Although conotoxins share the attractive features of peptides in general of having exquisite selectivity and potency for specific ion channels, membrane receptors or transporters, they also share the general disadvantages of peptides of short biological half-lives and poor oral bioavailability. Cyclization has been used in the past as a strategy in the pharmaceutical industry for stabilizing and locking the conformation of small peptides of 5-12 amino acids. This cyclization strategy can also be applied to conotoxins to produce additional stabilization, with the potential to dramatically increase the therapeutic potential of these molecules. In this study, we describe the development of a cyclic conotoxin analogue that has potent analgesic activity in the chronic constriction injury model of neuropathic pain in rats when administered orally. This result demonstrates the effectiveness of the cyclisation approach for the stabilization of peptide therapeutics. The cyclization approach has been successfully applied to a range of conotoxins, highlighting its broad potential in drug design.

Applications of conotoxins for the treatment of pain

247th National Meeting (2014)

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