Total Chemical Synthesis of an Intra-A-Chain Cystathionine Human Insulin Analogue with Enhanced Thermal Stability

John Karas, Nitin Patil, Julien Tailhades, Marc-Antoine Sani, Denis Scanlon, Briony Forbes, James Gardiner, Frances Separovic, John Wade, Mohammed Hossain

    Research output: Contribution to journalArticle

    19 Citations (Scopus)

    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.

    Original languageEnglish
    Pages (from-to)14743-14747
    Number of pages5
    JournalAngewandte Chemie-International Edition
    Volume55
    Issue number14
    DOIs
    Publication statusPublished - 2016

    Fingerprint Dive into the research topics of 'Total Chemical Synthesis of an Intra-A-Chain Cystathionine Human Insulin Analogue with Enhanced Thermal Stability'. Together they form a unique fingerprint.

  • Cite this

    Karas, J., Patil, N., Tailhades, J., Sani, M-A., Scanlon, D., Forbes, B., Gardiner, J., Separovic, F., Wade, J., & Hossain, M. (2016). Total Chemical Synthesis of an Intra-A-Chain Cystathionine Human Insulin Analogue with Enhanced Thermal Stability. Angewandte Chemie-International Edition, 55(14), 14743-14747. https://doi.org/10.1002/anie.201607101