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

Cone snails are tropical marine mollusks that envenomate prey with a comple x mixture of neuropharmacologically active compounds. We report the discove ry and biochemical characterization of a structurally unique peptide isolat ed from the venom of Conus marmoreus, The new peptide, mr10a, potently incr eased withdrawal latency in a hot plate assay (a test of analgesia) at intr athecal doses that do not produce motor impairment as measured by rotarod t est. The sequence of mr10a is NGVCCGYKLCHOC, where O is 4-trans-hydroxyprol ine. This sequence is highly divergent from all other known conotoxins, Ana lysis of a cDNA clone encoding the toxin, however, indicates that it is a m ember of the recently described T-superfamily, Total chemical synthesis of the three possible disulfide arrangements of mr10a was achieved, acid eluti on studies indicate that the native form has a disulfide connectivity of Cy s1-Cys4 and Cys2-Cys3, This disulfide linkage is unprecedented among conoto xins and defines a new family of Conus peptides.