Engineering of Conotoxins for the Treatment of Pain

Abstract

The peptides present in the venoms of marine snails are used by the snails to capture prey, but they have also attracted the interest of drug designers because of their potent activity against therapeutically important targets. These peptides are typically disulfiderich and target a wide range of ion channels, transporters and receptors with exquisite selectivity. In this article, we discuss structural and biological studies on several classes of conotoxins that have potential as drug leads for the treatment of pain. The chemical re-engineering of conotoxins via cyclization has been particularly valuable in improving their biopharmaceutical properties. An excellent example is the α-conotoxin Vc1.1, for which several cyclized analogs have been made. One of them was shown to be orally active in a rat pain model and this analog is currently undergoing pre-clinical development for the treatment of neuropathic pain. Several other α-conotoxins, including ImI, AuIB and MII, have proved amenable to cyclization and in all cases improvements in stability are obtained upon cyclization, suggesting that cyclization is a generally applicable approach to conotoxin stabilization. A variety of other chemical re-engineering approaches have also been used. Minor re-engineering of χ-conotoxin MrIa to convert its N-terminal residue to pyroglutamic acid proved particularly successful and the modified derivative, Xen2174, is currently in clinical trials for neuropathic pain.

The Physiology, Pathology, and Pharmacology of Voltage-Gated Calcium Channels and Their Future Therapeutic Potential

“…Interestingly, the a-conotoxin Vc1.1 and the structurally related peptide Rg1A have been shown to activate peripheral GABA B , leading to Ca V 2.2 channel inhibition and analgesia when delivered intrathecally or intramuscularly (Callaghan et al, 2008;Callaghan and Adams, 2010;Klimis et al, 2011;Cuny et al, 2012;Berecki et al, 2014). To enhance oral bioavailability, a cyclized version of the Vc1.1 has been designed (Carstens et al, 2011); however, it is unclear whether these cyclized peptides could lead to similar central nervous side effects.…”

CHAPTER 6. The Molecular Diversity of Conoidean Venom Peptides and their Targets: From Basic Research to Therapeutic Applications

“…Increasingly, analogs of native m-conotoxins have been synthesized for structure activity studies and to understand subtype selectivity. [24][25][26][27] The m-conotoxins also have potential for dissecting specic combinations of Na V channel a-and b-subunits that are co-expressed in neurons. 18,19 Thus, the m-conotoxins comprise a key component of the pharmacological toolkit necessary for differentiating neuronal subclasses on the basis of the different Na V channel expression in individual neurons.…”

CHAPTER 11. Engineering Venom Peptides to Improve Their Stability and Bioavailability

“…25 MII is a 16-residue a-conotoxin from the cone snail Conus magus that targets a3b2 nicotinic acetylcholine receptors (nAChRs) and has been well characterized structurally and pharmacologically. [26][27][28][29] Three cyclic analogues with ve (cMII-5), six (cMII-6) or seven (cMII-7) residue linkers (GGAAG, GGAAGG and GAGAAGG) were synthesized by intramolecular NCL chemistry. 25 The cyclic analogues cMII-6 and cMII-7 preserved their native peptide fold, whereas cMII-5 showed random coil NMR chemical shi values, which were indicative of a more exible structure than the other two cyclic analogues.…”