title: α-Conotoxin ImI incorporating stable cystathionine bridges maintains full potency and identical three-dimensional structure.
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.
authors: Institute for Molecular Bioscience, The University of Queensland, St Lucia 4072, Queensland, Australia.
authors: Zoltan
authors: Z
authors: Dekan
authors: Irina
authors: I
authors: Vetter
authors: Norelle L
authors: NL
authors: Daly
authors: David J
authors: DJ
authors: Craik
authors: Richard J
authors: RJ
authors: Lewis
authors: Paul F
authors: PF
authors: Alewood
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D020916:Conotoxins / Q000737:chemistry*; D052078:Conus Snail / Q000737:chemistry; D003540:Cystathionine / Q000737:chemistry*; D008958:Models, Molecular; D018733:Nicotinic Antagonists / Q000737:chemistry*; D019906:Nuclear Magnetic Resonance, Biomolecular; D011487:Protein Conformation; D011978:Receptors, Nicotinic / Q000378:metabolism; D064569:alpha7 Nicotinic Acetylcholine Receptor
chemical_list: D020916:Conotoxins; D018733:Nicotinic Antagonists; D011978:Receptors, Nicotinic; D064569:alpha7 Nicotinic Acetylcholine Receptor; C087686:alpha-conotoxin ImI; D003540:Cystathionine