Venom Peptide Synthesis

The composition of Conus venom is extremely complex. It has been estimated that the venom of a single Conus species may contain between 50-200 different toxin components. Thus, the total number of conotoxins among the entire genus may consist of over 50,000 distinct neurologically active peptides. Scorpion and snake venom also contain a complex array of peptides. Multiple disulfide bonds and Post translational modifications (sulfation, phosphorylation, etc) adds to the complexity of these compounds and the challenges for the peptide chemist.

Cone snail
            EpI           GCCSDPRCNMNNPDY(SO3)C-NH2
            CVID        CKSKGAKCSKLMYDCCSGSCSGTVGRC-NH2       

Spider
            Atx-1         CAKKRNWCGKNEDCCCPMKCIYAWYNQQGSCQTTITGLFKKC-OH

Scorpion
            CnERG    DRDSCVDKSRCAKYGYYQECQDCCKNAGHNGGTCMFFKCKCA-OH

Disulfide bond formation

A majority of the venom peptides contain disulfide bonds. Controlling the formation of these bonds is essential in their chemical synthesis.

This is particularly important in larger peptides  containing multiple disulfide bonds, since as the number of disulfide bonds increases in a peptide, so too does the number of possible disulfide bond isomers.  eg. For a peptide containing two disulfide bonds (eg α-, χ- and ρ-conotoxins), 3 possible isomers can form, and for three disulfide bonds (eg δ-, μ-, μO- and ω-conotoxins) there are 15 possible isomers. Snake and scorpion venom peptides can contain up to 6 or more disulfide bonds.

Therefore control of the disulfide bonding framework is essential for obtaining the correct  (native) isomer, however engineering the disulfide connectivity to a non-native arrangement also presents new opportunities for structure activity studies. An interesting example of this approach is the study of non-native disulfide bond isomers of α-Ctx AuIB, where it was shown that the unnatural 1-4,2-3 isomer was approximately 10 times more potent than the native conotoxin. A number of strategies are available to control the formation of disulfide bonds (see Armishaw and Alewood Curr Protein Pept Sci. 2005 Jun;6(3):221-40 for further details.)