Chemical synthesis of peptides within the insulin superfamily

Abstract

The synthesis of insulin has inspired fundamental advances in the art of peptide science while simultaneously revealing the structure-function relationship of this centrally important metabolic hormone. This review highlights milestones in the chemical synthesis of insulin that can be divided into two separate approaches: (i) disulfide bond formation driven by protein folding and (ii) chemical reactivity-directed sequential disulfide bond formation. Common to the two approaches are the persistent challenges presented by the hydrophobic nature of the individual A-chain and B-chain and the need for selective disulfide formation under mildly oxidative conditions. The extension and elaboration of these synthetic approaches have been ongoing within the broader insulin superfamily. These structurally similar peptides include the insulin-like growth factors and also the related peptides such as relaxin that signal through G-protein-coupled receptors. After a half-century of advances in insulin chemistry, we have reached a point where synthesis is no longer limiting structural and biological investigation within this family of peptide hormones. The future will increasingly focus on the refinement of structure to meet medicinal purposes that have long been pursued, such as the development of a glucose-sensitive insulin. Copyright © 2016 European Peptide Society and John Wiley & Sons, Ltd.

Chemical synthesis of the crustacean insulin‐like peptide with four disulfide bonds

“…In our previous study, we used DPDS in trifluoromethanesulfonic acid (TfOH)/TFA solution for deprotecting MeOBn group . However, this reaction conditions were quite similar to those for the removal of Bu t group reported previously . In order to remove MeOBn group specifically, the reaction conditions were examined.…”

Chemically Precise Glycoengineering Improves Human Insulin

“…36,37,50,51 In order to expedite our study, we first systematically optimized the reagents, procedures, and conditions to obtain simple and effective routes for the synthesis of all the glycosylated insulin analogs in this study. 30,52 As shown in Scheme 1A, the glycosylated and unglycosylated insulin chains were prepared at 0.2 g scale through the use of preloaded NovaSyn TGT resins (EMD Millipore), and HATU as the coupling agent.…”

Total Solid-Phase Synthesis of Biologically Active Drosophila Insulin-Like Peptide 2 (DILP2)

“…The chemical synthesis of heterodimeric, insulin-like peptides has long been a significant challenge given the complexity of its two-chain, three-disulfide structure [20] . Our laboratory has developed efficient protocols that exploit the availability of cysteine S-thiol protecting groups that are orthogonal to one another and which allows the sequential, directed disulfide bond formation of separately assembled A- and B-chains (Scheme 1) [21] .…”