Alpha-selenoconotoxins, a new class of potent alpha(7) neuronal nicotinic receptor antagonists

Armishaw, Christopher J., Daly, Norelle L., Nevin, Simon T., Adams, David J., Craik, David J. and Alewood, Paul F. (2006) Alpha-selenoconotoxins, a new class of potent alpha(7) neuronal nicotinic receptor antagonists. Journal of Biological Chemistry, 281 20: 14136-14143.


Author Armishaw, Christopher J.
Daly, Norelle L.
Nevin, Simon T.
Adams, David J.
Craik, David J.
Alewood, Paul F.
Title Alpha-selenoconotoxins, a new class of potent alpha(7) neuronal nicotinic receptor antagonists
Journal name Journal of Biological Chemistry   Check publisher's open access policy
ISSN 0021-9258
1083-351X
Publication date 2006-05-19
Sub-type Article (original research)
DOI 10.1074/jbc.M512419200
Volume 281
Issue 20
Start page 14136
End page 14143
Total pages 8
Editor Herbert Taylor
Place of publication Bethesda
Publisher The American Society for Biochemistry and Molecular Biology
Collection year 2006
Language eng
Subject C1
250302 Biological and Medical Chemistry
780105 Biological sciences
780103 Chemical sciences
Abstract Disulfide bonds are important structural motifs that play an essential role in maintaining the conformational stability of many bioactive peptides. Of particular importance are the conotoxins, which selectively target a wide range of ion channels that are implicated in numerous disease states. Despite the enormous potential of conotoxins as therapeutics, their multiple disulfide bond frameworks are inherently unstable under reducing conditions. Reduction or scrambling by thiol-containing molecules such as glutathione or serum albumin in intracellular or extracellular environments such as blood plasma can decrease their effectiveness as drugs. To address this issue, we describe a new class of selenoconotoxins where cysteine residues are replaced by selenocysteine to form isosteric and non-reducible diselenide bonds. Three isoforms of alpha-conotoxin ImI were synthesized by t-butoxycarbonyl chemistry with systematic replacement of one([ Sec(2,8)] ImI or [Sec(3,12)] ImI), or both([Sec(2,3,8,12)] ImI) disulfide bonds with a diselenide bond. Each analogue demonstrated remarkable stability to reduction or scrambling under a range of chemical and biological reducing conditions. Three-dimensional structural characterization by NMR and CD spectroscopy indicates conformational preferences that are very similar to those of native ImI, suggesting fully isomorphic structures. Additionally, full bioactivity was retained at the alpha(7) nicotinic acetylcholine receptor, with each seleno-analogue exhibiting a dose-response curve that overlaps with wild-type ImI, thus further supporting an isomorphic structure. These results demonstrate that selenoconotoxins can be used as highly stable scaffolds for the design of new drugs.
Keyword Selenoconotoxins
Neronal Nicotinic Receptor Antagonist
Drug Design
Biochemistry & Molecular Biology
Native Chemical Ligation
Solid-phase Synthesis
Conotoxin-imi
Thioredoxin Reductase
Acetylcholine-receptors
Biological-activities
Structural Stability
Containing Peptide
Cyclic-peptides
Selenocysteine
Q-Index Code C1

 
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