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.