Total Chemical Synthesis of a Nonfibrillating Human Glycoinsulin
- Mohammed Akhter Hossain*Mohammed Akhter Hossain*Phone: +61 3 83440414. E-mail: [email protected] (M.A.H.)The Florey Institute of Neuroscience and Mental Health, The Florey Department of Neuroscience and Mental Health, School of Chemistry, The University of Melbourne, Victoria 3010, AustraliaMore by Mohammed Akhter Hossain
- Ryo OkamotoRyo OkamotoGraduate School of Science, Osaka University, Toyonaka, Osaka 560-0043 JapanMore by Ryo Okamoto
- John A. KarasJohn A. KarasDepartment of Pharmacology and Therapeutics, The University of Melbourne, Victoria 3010, AustraliaMore by John A. Karas
- Praveen PraveenPraveen PraveenThe Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Victoria 3010, AustraliaMore by Praveen Praveen
- Mengjie LiuMengjie LiuThe Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Victoria 3010, AustraliaMore by Mengjie Liu
- Briony E. ForbesBriony E. ForbesDiscipline of Medical Biochemistry, College of Medicine and Public Health, Flinders University, Bedford Park, South Australia 5042, AustraliaMore by Briony E. Forbes
- John D. Wade*John D. Wade*Phone: +61 3 83440414. E-mail: [email protected] (J.D.W.)The Florey Institute of Neuroscience and Mental Health, The Florey Department of Neuroscience and Mental Health, School of Chemistry, The University of Melbourne, Victoria 3010, AustraliaMore by John D. Wade
- Yasuhiro KajiharaYasuhiro KajiharaGraduate School of Science, Osaka University, Toyonaka, Osaka 560-0043 JapanMore by Yasuhiro Kajihara
Abstract

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-native binding affinity for insulin receptors A and B in vitro and high glucose-lowering effects in vivo, irrespective of the route of administration (s.c. vs i.p.). The glycoinsulin retained insulin-like helical structure and exhibited improved stability in human serum. Importantly, our disialo-glycoinsulin analogue does not form fibrils at both high concentration and temperature. Therefore, it is an excellent candidate for clinical use in insulin pumps.




