Engineering of conotoxins for the treatment of pain.
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 University of Queensland, Institute for Molecular Bioscience, Brisbane QLD 4072, Australia.
Bodil B
BB
Carstens
Richard J
RJ
Clark
Norelle L
NL
Daly
Peta J
PJ
Harvey
Quentin
Q
Kaas
David J
DJ
Craik
D000595:Amino Acid Sequence; D000700:Analgesics / Q000138:chemical synthesis* / Q000737:chemistry / Q000302:isolation & purification / Q000627:therapeutic use; D000818:Animals; D020916:Conotoxins / Q000138:chemical synthesis* / Q000235:genetics / Q000302:isolation & purification / Q000627:therapeutic use; D052078:Conus Snail / Q000737:chemistry; D003500:Cyclization; D015195:Drug Design; D004355:Drug Stability; D006801:Humans; D008969:Molecular Sequence Data; D008978:Mollusk Venoms / Q000737:chemistry; D010146:Pain / Q000188:drug therapy*; D010456:Peptides, Cyclic / Q000138:chemical synthesis* / Q000235:genetics / Q000302:isolation & purification / Q000627:therapeutic use; D011487:Protein Conformation; D060327:Solid-Phase Synthesis Techniques
D000700:Analgesics; D020916:Conotoxins; D008978:Mollusk Venoms; D010456:Peptides, Cyclic