Establishing regiocontrol of disulfide bond isomers of alpha-conotoxin ImI via the synthesis of N-to-C cyclic analogues

Armishaw, Christopher J., Dutton, Julie L., Craik, David J. and Alewood, Paul F. (2010) Establishing regiocontrol of disulfide bond isomers of alpha-conotoxin ImI via the synthesis of N-to-C cyclic analogues. Biopolymers: Peptide Science, 94 3: 307-313. doi:10.1002/bip.21360

Author Armishaw, Christopher J.
Dutton, Julie L.
Craik, David J.
Alewood, Paul F.
Title Establishing regiocontrol of disulfide bond isomers of alpha-conotoxin ImI via the synthesis of N-to-C cyclic analogues
Formatted title
Establishing regiocontrol of disulfide bond isomers of α-conotoxin ImI via the synthesis of N-to-C cyclic analogues
Journal name Biopolymers: Peptide Science   Check publisher's open access policy
ISSN 0006-3525
Publication date 2010-04-01
Year available 2009
Sub-type Article (original research)
DOI 10.1002/bip.21360
Volume 94
Issue 3
Start page 307
End page 313
Total pages 7
Editor Gary D. Glick
Place of publication Hoboken NJ, U.S.A.
Publisher Wiley Periodicals
Language eng
Subject C1
860899 Human Pharmaceutical Products not elsewhere classified
0304 Medicinal and Biomolecular Chemistry
Formatted abstract
α-Conotoxins are multiple disulfide bond containing peptides that are isolated from venomous marine cone snails. They display remarkable selectivity for different subtypes of nicotinic acetylcholine receptors (nAChRs). While α-conotoxins display poor resistance to in vivo degradation by proteases which limits their use as drug leads, N-to-C cyclization via an oligopeptide spacer unit has been previously shown to improve stability. However the effect of N-to-C cyclisation on the formation of the disulfide bond framework is not fully understood. Four N-to-C cyclic analogues of α-conotoxin ImI; cImI-βA, cImI-A, cImI-AG and cImI-AGG were synthesised to evaluate the effect of oligopeptide spacer length on disulfide bond selectivity and stability to proteolysis. Different ratios of disulfide bond isomers were obtained for each analogue using a non-selective random disulfide bond forming strategy, which was dependent on the length of the spacer. In order to identify each isomer obtained using the random strategy, and to gain access to disulfide bond isomers otherwise unattainable using the random strategy, both the native (globular) and ribbon isomers were synthesised in good yield and purity using a selective orthogonal cysteine protecting group strategy. As such, a random oxidation strategy showed a clear preference for the ribbon isomer in cImI-A. The cyclic globular isomers showed a high resistance to enzymatic degradation compared to the ribbon isomers, with the cImI-A and cImI-AG globular isomers demonstrating the highest stability. These results suggest that cyclisation can improve the biochemical stability of conotoxins with potential applications in the development of drugs. © 2009 Wiley Periodicals, Inc. Biopolymers (Pept Sci), 2010
Keyword Alpha-conotoxin
Disulfide bond
Peptide stability
Native chemical ligation
Nicotinic acetylcholine-receptors
Phase peptide-synthesis
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ
Additional Notes Article online in advance of print December 9, 2009

Document type: Journal Article
Sub-type: Article (original research)
Collections: 2010 Higher Education Research Data Collection
Institute for Molecular Bioscience - Publications
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Created: Mon, 15 Mar 2010, 23:20:52 EST by Susan Allen on behalf of Institute for Molecular Bioscience