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March 1, 2010
Volume 88, Number 9
p. 13

New Way To Screen α-conotoxins

Drug Discovery: Work could lead to medications based on these neuroactive peptides

Stu Borman

A synthesized linear α-conotoxin can form disulfide bonds (yellow) in various ways, yielding different structures. Markus Muttenthaler
A synthesized linear α-conotoxin can form disulfide bonds (yellow) in various ways, yielding different structures.
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A new way to synthesize snail-based peptides called α-conotoxins, fold them into their native structures, and screen them for biological activity has been developed by an Australian research group. The approach could lead to new medications for neurological disorders and other conditions.

α-Conotoxins are one of many families of conotoxins—neurotoxic peptides made by predatory cone snails, which use them to immobilize their prey. Conotoxins have attracted considerable attention for their bioactivity, especially pain relief. One conotoxin, Prialt (ziconotide), is an approved drug for severe chronic pain, and a conotoxin analog called Xen2174 is in Phase II human clinical trials, also as a pain reliever.

Although those two agents belong to other conotoxin families, α-conotoxins also relieve pain. But it has been difficult to synthesize α-conotoxins in their natively folded forms to assess their prospects as drug candidates. The peptides each have two disulfide links, and when they are synthesized as linear peptides, their disulfide-forming cysteines often combine with the “wrong” cysteine partners, yielding nonnative, misfolded α-conotoxins with impaired biological activity.

Bioactive-peptide specialist Paul F. Alewood of the University of Queensland and coworkers have now found a workaround (J. Am. Chem. Soc., DOI: 10.1021/ja910602h). They synthesize α-conotoxins in which one pair of cysteine residues has been replaced by a pair of selenocysteines. The selenocysteines combine to form diselenides more readily than cysteines react to form disulfides. So when a linear α-conotoxin is oxidized, the diselenide forms first, preventing mismatches, and the disulfide forms later, yielding a correct structure.

The diselenide analogs generally have conformations and bioactivities similar to those of the corresponding native α-conotoxins, and in some cases, the analogs’ bioactivities are better.

Alewood and coworkers also report the first method for synthesizing selenocysteine analogs of α-conotoxins on solid-support beads and then folding them while they are still on the resin. Having the folded analogs on solid-support particles makes it possible to screen the compounds for biological activity more quickly and conveniently than has been previously possible.

The use of diselenides as disulfide replacements in synthetic peptides was pioneered in the late 1990s by bioorganic chemist Luis Moroder of the Max Planck Institute of Biochemistry, in Martinsried, Germany. But the technique has only recently been applied to conotoxins—in one earlier study by the Alewood group and in another by conotoxin specialist Grzegorz Bulaj of the University of Utah and coworkers.

Of the new work, Bulaj says: “Having selenoconotoxins on-resin is a very nice advance. The solid-support-based approach can probably be extended to other di­sulfide-bridged peptides as well. It’s an important step toward the discovery and development of cysteine-rich peptides as future drugs.”

Chemical & Engineering News
ISSN 0009-2347
Copyright © 2011 American Chemical Society
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