Microwave-Assisted Solid Phase Peptide Synthesis of Insulin Superfamily Peptides
Dr. John D. Wade, Professor, Laboratory Head, Peptide Laboratory, Howard Florey Institute, University of Melbourne, Victoria, Australia

With the recent completion of sequencing of the human genome, it was subsequently confirmed that there exists ten members of the insulin superfamily. These include insulin, insulin-like growth factors (IGFs) I and II, relaxins-1, 2 and 3, and insulin-like peptides 3, 4, 5 and 6. With the exception of IGF I and II which are single chain peptides, each of the members comprise of the classic two peptide chain (A- and B-) structure that are held together by three disulfide bonds in the distinctive insulin crosslinked pattern. There is an intramolecular disulfide bond within the A-chain and two interchain disulfides between the A- and B-chains. The chemical synthesis of such a peptide is a major challenge and considerable effort has been expended to not only successfully assemble the two chains but also to link these in the correct orientation [1]. Insulin represents a particularly difficult example given that its A-chain has a high propensity to aggregate and fibrillize [2] making yields low and complicating subsequent combination with the corresponding B-chain. These physicochemical properties have severely limited detailed structure-function studies and the development of novel analogues with improved properties. We have developed a number of novel design strategies for the high yield preparation of insulin-like peptides that are successfully mediated only by microwave-assisted solid phase synthesis. These will be described in detail.