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Total Chemical Synthesis of an Intra‐A‐Chain Cystathionine Human Insulin Analogue with Enhanced Thermal Stability
Author(s) -
Karas John A.,
Patil Nitin A.,
Tailhades Julien,
Sani MarcAntoine,
Scanlon Denis B.,
Forbes Briony E.,
Gardiner James,
Separovic Frances,
Wade John D.,
Hossain Mohammed Akhter
Publication year - 2016
Publication title -
angewandte chemie
Language(s) - English
Resource type - Journals
eISSN - 1521-3757
pISSN - 0044-8249
DOI - 10.1002/ange.201607101
Subject(s) - chemistry , cystine , insulin , cystathionine beta synthase , isostere , yield (engineering) , combinatorial chemistry , thermal stability , biochemistry , cysteine , stereochemistry , organic chemistry , materials science , biology , metallurgy , enzyme , endocrinology
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.