Total Chemical Synthesis of an Intra‐A‐Chain Cystathionine Human Insulin Analogue with Enhanced Thermal Stability. Issue 47 (20th October 2016)

• Record Type: Journal Article
• Authors: Karas, John A.; Patil, Nitin A.; Tailhades, Julien; Sani, Marc‐Antoine; Scanlon, Denis B.; Forbes, Briony E.; Gardiner, James; Separovic, Frances; Wade, John D.; Hossain, Mohammed Akhter
• Is Part Of: Angewandte Chemie international edition. Volume 55:Issue 47(2016)
• Page Start: 14743
• Page End: 14747
• Publication Date: 2016-10-20
• Subjects: cystathionine -- cystine -- diabetes mellitus -- insulin -- solid-phase peptide synthesis; Chemistry -- Periodicals; 540
• DOI: 10.1002/anie.201607101
• Languages: English
• ISSNs: 1433-7851

Abstract

Abstract: Despite recent advances in the treatment of diabetes mellitus, storage of insulin formulations at 4 °C is still necessary to minimize chemical degradation. This is problematic in tropical regions where reliable refrigeration is not ubiquitous. Some degradation byproducts are caused by disulfide shuffling of cystine that leads to covalently bonded oligomers. Consequently we examined the utility of the non‐reducible cystine isostere, cystathionine, within the A‐chain. Reported herein is an efficient method for forming this mimic using simple monomeric building blocks. The intra‐A‐chain cystathionine insulin analogue was obtained in good overall yield, chemically characterized and demonstrated to possess native binding affinity for the insulin receptor isoform B. It was also shown to possess significantly enhanced thermal stability indicating potential application to next‐generation insulin analogues. Abstract : Standing the heat : An efficient synthesis of human insulin containing a non‐reducible cystathionine bridge using simple‐to‐prepare building blocks is reported. A[S‐CH2 ] insulin exhibits native binding affinity for insulin receptor isoform B, adopts a similar secondary structure, and is relatively stable in human serum in vitro. Thermal stability is improved which enhances its therapeutic potential.