Journal article

Total Chemical Synthesis of a Nonfibrillating Human Glycoinsulin

Mohammed Akhter Hossain, Rio Okamoto, John A Karas, Praveen Praveen, Mengjie Liu, Briony E Forbes, John D Wade, Yasuhiro Kajihara

Journal of the American Chemical Society | AMER CHEMICAL SOC | Published : 2020


Glycosylation is an accepted strategy to improve the therapeutic value of peptide and protein drugs. Insulin and its analogues are life-saving drugs for all type I and 30% of type II diabetic patients. However, they can readily form fibrils which is a significant problem especially for their use in insulin pumps. Because of the solubilizing and hydration effects of sugars, it was thought that glycosylation of insulin could inhibit fibril formation and lead to a more stable formulation. Since enzymatic glycosylation results in heterogeneous products, we developed a novel chemical strategy to produce a homogeneous glycoinsulin (disialo-glycoinsulin) in excellent yield (∼60%). It showed a near-..

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Awarded by NHMRC (Australia)

Funding Acknowledgements

This work was performed in part (AFM sample preparation and imaging) at the Melbourne Centre for Nanofabrication (MCN) in the Victorian Node of the Australian National Fabrication Facility (ANFF). We would like to sincerely thank Dr Barbara Christianne Fam and Prof Sof Andrikopoulos for in vivo studies and Feng Lin for in vitro serum stability studies. We would also like to acknowledge and thank Glytech, Inc. Japan for providing us with some sugar derivatives used in this study. This research was funded by NHMRC (Australia) project grants (1163310, 1023321, and 1023078) to M.A.H., J.D.W., and B.F. J.D.W. is an NHMRC Principal Research Fellow (1117483). Studies at the FNI were supported by the Victorian Government's Operational Infrastructure Support Program.