α-Conotoxin ImI incorporating stable cystathionine bridges maintains full potency and identical three-dimensional structure

Dekan, Zoltan, Vetter, Irina, Daly, Norelle L., Craik, David J., Lewis, Richard J., and Alewood, Paul F. (2011) α-Conotoxin ImI incorporating stable cystathionine bridges maintains full potency and identical three-dimensional structure. Journal of the American Chemical Society, 133 (40). pp. 15866-15869.

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Abstract

The two disulfide bonds of α-conotoxin ImI, a peptide antagonist of the α7 nicotinic acetylcholine receptor (nAChR), were systematically replaced with isosteric redox-stable cystathionine thioethers. Regioselective thioether formation was accomplished on solid support through substitution of a γ-chlorohomoalanine by an intramolecular cysteine thiol to produce hybrid thioether/disulfide analogues (2 and 3) as well as a dual cystathionine analogue (4) that were found to be structurally homologous to α-conotoxin ImI by (1)H NMR. The antagonistic activity at the α7 nAChR of cystathionine analogue 3 (pIC(50) = 6.41 ± 0.09) was identical to that of α-conotoxin ImI (1, pIC(50) = 6.41 ± 0.09), whereas those of 2 (pIC(50) = 5.96 ± 0.09) and 4 (pIC(50) = 5.89 ± 0.09) showed a modest decrease. The effect of oxidation of the thioethers to sulfoxides was also investigated, with significant changes in the biological activities observed ranging from a >30-fold reduction (2S═O) to a 3-fold increase (3S═O(B)) in potencies.

Item ID: 27013
Item Type: Article (Research - C1)
ISSN: 1520-5126
Funders: Australian Research Council (ARC)
Projects and Grants: DP1096866
Date Deposited: 24 May 2013 00:06
FoR Codes: 06 BIOLOGICAL SCIENCES > 0601 Biochemistry and Cell Biology > 060101 Analytical Biochemistry @ 100%
SEO Codes: 97 EXPANDING KNOWLEDGE > 970106 Expanding Knowledge in the Biological Sciences @ 50%
97 EXPANDING KNOWLEDGE > 970103 Expanding Knowledge in the Chemical Sciences @ 50%
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