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

JA Karas; NA Patil; J Tailhades; MA Sani; DB Scanlon; BE Forbes; J Gardiner; F Separovic; JD Wade; MA Hossain

Journal article

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

JA Karas, NA Patil, J Tailhades, MA Sani, DB Scanlon, BE Forbes, J Gardiner, F Separovic, JD Wade, MA Hossain

Angewandte Chemie International Edition | WILEY-V C H VERLAG GMBH | Published : 2016

DOI: 10.1002/anie.201607101

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 ..

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University of Melbourne Researchers

John Karas Author

Marco Sani Author

Akhter Hossain Author

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Grants

Awarded by NHMRC Project

Awarded by NHMRC Principal Research Fellowship

Funding Acknowledgements

This research was partially funded by the NHMRC Project grants 1023321 and 1023078 to M.A.H. and J.D.W., the CSIRO (Australia), a Florey Foundation Fellowship to M.A.H., and an NHMRC Principal Research Fellowship to J.D.W. (GNT5018148). Research at The Florey Institute of Neuroscience and Mental Health is supported by the Victorian Government Operational Infrastructure Support Program. The publication of this manuscript was supported by the David Lachlan Hay Memorial Fund (University of Melbourne).