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Total Chemical Synthesis of a Nonfibrillating Human Glycoinsulin

  • Mohammed Akhter Hossain*
    Mohammed Akhter Hossain
    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, Australia
    *Phone: +61 3 83440414. E-mail: [email protected] (M.A.H.)
  • Ryo Okamoto
    Ryo Okamoto
    Graduate School of Science, Osaka University, Toyonaka, Osaka 560-0043 Japan
    More by Ryo Okamoto
  • John A. Karas
    John A. Karas
    Department of Pharmacology and Therapeutics, The University of Melbourne, Victoria 3010, Australia
  • Praveen Praveen
    Praveen Praveen
    The Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Victoria 3010, Australia
  • Mengjie Liu
    Mengjie Liu
    The Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Victoria 3010, Australia
    More by Mengjie Liu
  • Briony E. Forbes
    Briony E. Forbes
    Discipline of Medical Biochemistry, College of Medicine and Public Health, Flinders University, Bedford Park, South Australia 5042, Australia
  • John D. Wade*
    John D. Wade
    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, Australia
    *Phone: +61 3 83440414. E-mail: [email protected] (J.D.W.)
    More by John D. Wade
  • Yasuhiro Kajihara
    Yasuhiro Kajihara
    Graduate School of Science, Osaka University, Toyonaka, Osaka 560-0043 Japan
Cite this: J. Am. Chem. Soc. 2020, 142, 3, 1164-1169
Publication Date (Web):December 18, 2019
https://doi.org/10.1021/jacs.9b11424
Copyright © 2019 American Chemical Society
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Abstract

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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.

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The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/jacs.9b11424.

  • Description of peptide synthesis, regioselective disulfide bond formation, optimized conditions for glycosylation and summary of peptide characterization by MALDI TOF MS, RP-HPLC, amino acid analysis, methods for insulin tolerance test insulin receptor binding assay, insulin tolerance test, atomic force microscopy fibrillation assay, circular dischroism and serum stability studies (PDF)

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