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

Zoltan Dekan, Irina Vetter, Norelle L Daly, David J Craik, Richard J Lewis, Paul F Alewood

Institute for Molecular Bioscience, The University of Queensland, St Lucia 4072, Queensland, Australia.

Journal of the American Chemical Society 2011 Oct 12

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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.

Citation

Zoltan Dekan, Irina Vetter, Norelle L Daly, David J Craik, Richard J Lewis, Paul F Alewood. α-Conotoxin ImI incorporating stable cystathionine bridges maintains full potency and identical three-dimensional structure. Journal of the American Chemical Society. 2011 Oct 12;133(40):15866-9