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Total Chemical Synthesis of an Intra‐A‐Chain Cystathionine Human Insulin Analogue with Enhanced Thermal Stability |
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| Authors: | Dr John A Karas Nitin A Patil Dr Julien Tailhades Dr Marc‐Antoine Sani Dr Denis B Scanlon Prof Briony E Forbes Dr James Gardiner Prof Frances Separovic Prof John D Wade Dr Mohammed Akhter Hossain |
| Institution: | 1. The Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Melbourne, VIC, Australia;2. School of Chemistry, Bio21 Institute, University of Melbourne, Melbourne, VIC, Australia;3. CSIRO, Materials Science and Engineering, Clayton, VIC, Australia;4. Department of Chemistry, University of Adelaide, Adelaide, SA, Australia;5. School of Medicine, Flinders University, Bedford Park, SA, Australia |
| 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. |
| Keywords: | cystathionine cystine diabetes mellitus insulin solid-phase peptide synthesis |