Isolation and characterization of a novel conus peptide with apparent antinociceptive activity |
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Authors: | McIntosh J M Corpuz G O Layer R T Garrett J E Wagstaff J D Bulaj G Vyazovkina A Yoshikami D Cruz L J Olivera B M |
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Affiliation: | Departments of Psychiatry and Biology, University of Utah, Salt Lake City, Utah 84112, Cognetix, Inc., Salt Lake City, Utah, 84108, USA. mcintosh@biology.utah.edu |
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Abstract: | Cone snails are tropical marine mollusks that envenomate prey with a complex mixture of neuropharmacologically active compounds. We report the discovery and biochemical characterization of a structurally unique peptide isolated from the venom of Conus marmoreus. The new peptide, mr10a, potently increased withdrawal latency in a hot plate assay (a test of analgesia) at intrathecal doses that do not produce motor impairment as measured by rotarod test. The sequence of mr10a is NGVCCGYKLCHOC, where O is 4-trans-hydroxyproline. This sequence is highly divergent from all other known conotoxins. Analysis of a cDNA clone encoding the toxin, however, indicates that it is a member of the recently described T-superfamily. Total chemical synthesis of the three possible disulfide arrangements of mr10a was achieved, and elution studies indicate that the native form has a disulfide connectivity of Cys1-Cys4 and Cys2-Cys3. This disulfide linkage is unprecedented among conotoxins and defines a new family of Conus peptides. |
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