Enhanced microwave-assisted method for on-bead disulfide bond formation: synthesis of alpha-conotoxin MII

A novel enhanced microwave-assisted disulfide bridge formation method has been developed. To optimize the synthesis of the biologically important bicyclic peptide alpha-conotoxin MII (alpha-CtxMII), several cyclization methods have been tested and are discussed herein. By using m.w.-assisted heating, we achieved high yields for the first loop cyclization of alpha-CtxMII on-bead. This method has the advantage of avoiding intermolecular by-products during the cyclization step. Furthermore, the method gives higher yields compared with the common on-bead cyclization methods. The second disulfide bridge of alpha-CtxMII was formed using a simple oxidation method after the cleavage of the intermediate monocyclic peptide from the resin. This method has the potential to be efficient for the synthesis of other disulfide rich biologically important peptides.