Facile synthesis of sulfotyrosine-containing α-conotoxins

Abstract

α-Conotoxins (Ctx) can selectively target distinct subtypes of nicotinic acetylcholine receptors (nAChRs), which are closely related to a number of neurological diseases, and they have been considered as ideal probes and model peptide drugs. Sulfotyrosine (sY) is an important post-translational modification and believed to modulate certain key protein–protein interactions. Although sY modification has been indicated in several α-Ctx, its biological consequence has largely remained unexplored, mostly because of the difficulties in both its extraction from biological samples and chemical synthesis. Herein, we report a facile synthesis and folding strategy for obtaining the sY modified α-Ctx. This strategy is based on the development of a simple and controlled deprotection of the neopentyl protecting group of the sulfate ester as well as its compatibility with a step-wise oxidative folding of the two disulfide bonds. Eight sY modified α-Ctx peptides were successfully synthesized in good yield and with high purity, and their serum stabilities were almost comparable with non-modified peptides.