Isolation and characterization of a novel Conus peptide with apparent antinociceptive activity

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, acid 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.