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 -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.
Keywords: Conotoxin, cyclic peptides, cyclization, drug design, pain, venoms, conopeptides, neurodegenerative diseases, amide chemical shifts, oxytocin
Current Pharmaceutical Design
Title: Engineering of Conotoxins for the Treatment of Pain
Volume: 17 Issue: 38
Author(s): Bodil B. Carstens, Richard J. Clark, Norelle L. Daly, Peta J. Harvey, Quentin Kaas and David J. Craik
Affiliation:
Keywords: Conotoxin, cyclic peptides, cyclization, drug design, pain, venoms, conopeptides, neurodegenerative diseases, amide chemical shifts, oxytocin
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 -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.
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Cite this article as:
B. Carstens Bodil, J. Clark Richard, L. Daly Norelle, J. Harvey Peta, Kaas Quentin and J. Craik David, Engineering of Conotoxins for the Treatment of Pain, Current Pharmaceutical Design 2011; 17 (38) . https://dx.doi.org/10.2174/138161211798999401
DOI https://dx.doi.org/10.2174/138161211798999401 |
Print ISSN 1381-6128 |
Publisher Name Bentham Science Publisher |
Online ISSN 1873-4286 |
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