An efficient synthetic scheme for natural alpha-conotoxins and their analogues

An efficient scheme for the synthesis of alpha -conotoxins, containing 12-1 8 amino acid residues and two disulfide bridges, was proposed. Its advantag es are: (1) the avoidance of orthogonal protections of Cys residues; (2) a lower number of stages in a cycle of the peptide chain elongation by the me thod of solid phase synthesis; (3) the linear product is sufficiently pure for being used at the next stage of the disulfide bond formation without ad ditional purification; and (4) a substantially reduced time of oxidation to disulfides at pH 10, which led to the target product in a high yield. A nu mber of natural alpha -conotoxins (GI, ImI, EI, MII, and SIA), affecting th e muscle and neuronal nicotinic acetylcholine receptors of various types, a nd several new analogues of these conotoxins tin particular, [Tyr10]ImI, [G ln12]GI, and [Ser1]GI) were synthesized by this scheme. They were used for elucidating the spatial structure of alpha -conotoxins by H-1 NMR spectrosc opy and for studying the ligand-binding sites of their receptors.