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Establishing regiocontrol of disulfide bond isomers of α‐conotoxin ImI via the synthesis of N‐to‐C cyclic analogs
Author(s) -
Armishaw Christopher J.,
Dutton Julie L.,
Craik David J.,
Alewood Paul F.
Publication year - 2009
Publication title -
peptide science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.556
H-Index - 125
eISSN - 1097-0282
pISSN - 0006-3525
DOI - 10.1002/bip.21360
Subject(s) - chemistry , stereochemistry , cyclic peptide , thiazolidine , conotoxin , cysteine , combinatorial chemistry , peptide , organic chemistry , enzyme , biochemistry
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 cyclization on the formation of the disulfide bond framework is not fully understood. Four N‐to‐C cyclic analogs of α‐conotoxin ImI; cImI‐A, cImI‐βA, cImI‐AG, and cImI‐AGG were synthesized 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 analog using a nonselective random disulfide bond forming strategy, which was dependent on the length of the spacer. 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 synthesized 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 cyclization can improve the biochemical stability of conotoxins with potential applications in the development of drugs. © 2010 Wiley Periodicals, Inc. Biopolymers (Pept Sci) 94: 307–313, 2010. This article was originally published online as an accepted preprint. The “Published Online” date corresponds to the preprint version. You can request a copy of the preprint by emailing the Biopolymers editorial office at biopolymers@wiley.com