Syntheses And Modifications Of Conotoxins From South China Sea

Conotoxins have been intensively studied during last twenty years. Conotoxin excreted from the venom gland of the venom canal are mostly small, disulfide-rich peptides with 12～40 amino acids in length, and specifically target nicotinic acetylcholine receptors, ion-channels and their subunits, such as calcium, sodium and potassium ion channel. Conus resources exist widely in the world, specifically, are mainly distributed in the Paracel Islands, South China Sea and the waters around Taiwan. A series of studies on conotoxins including: the collection of conus, toxin isolation, purification, gene cloning, synthesis and activity assay, have been carried on in our laboratory. The thesis mainly focused on the three aspects in conotoxins: (1) The structure-activity relationship of theω-conotoxins SO-3; (2) Syntheses and modifications ofα-conotoxins from South China Sea; (3) Syntheses of several new conotoxins from South China Sea.In the studies of the structure-activity relationship of theω-conotoxins SO-3, seven variants of SO-3 and MⅦA were designed and synthesized, toxicity and analgesic activity were evaluated, and the effect of key amino acids in 1 and 2 on the toxicity of SO-3 were discovered.In the studies of syntheses and modifications ofα-conotoxins from South China sea: (1) Sevenα-conotoxins were synthesized and evaluated for their analgesic activity, and four peptides of them were found to have significant analgesic activity. (2) A low molecular difunctional peptide, which a small-molecule sodium channel inhibitor is attached in the N-terminal of GI, was designed and synthesized and showed inhibitory activity in sodium channels and low toxicity to the goldfish compared with GI. (3) Two variants of Vc1.1 and GI were designed and synthesized. (4) A small peptide of 11 amino acids has been designed and synthesized based on cysteine framework (CC-C-C) ofα-conotoxins disulfide connectivity and exhibited high analgesic activity.In the studies of several novel conotoxins from South China Sea: (1) Six T-superfamily conotoxins were synthesized and their toxicity were determined with goldfish. The results indicated that these T-superfamily conotoxins have no toxicity and some of them show exciting activity. (2) Six novel conotoxin linear peptides were synthesized but four final products were not obtained because of the difficulty in folding. The analgesic activity of a M-superfamily conotoxin L-6 (Mr6) was determined with PNL model in rats. The results indicated that Mr6 has potent analgesic activity in dose-dependent mode.The above studies will contribute to determination ofω-conotoxins SO-3 toxicity and active site, and discovery of novel analgesic conus peptides.