Glycosylation Improves the Proteolytic Stability of Exenatide

  • Chaitra Chandrashekar
    The Florey Institute of Neuroscience and Mental Health, Parkville, Victoria 3052, Australia
  • Yuji Nishiuchi
    GlyTech, Inc., 134 Chudoji Minamimachi, Kyoto 600-8813, Japan
  • Barbara Fam White
    Department of Medicine (Austin Health), The University of Melbourne, Heidelberg, Victoria 3084, Australia
  • Yanni Arsenakis
    Department of Medicine (Austin Health), The University of Melbourne, Heidelberg, Victoria 3084, Australia
  • Feng Lin
    The Florey Institute of Neuroscience and Mental Health, Parkville, Victoria 3052, Australia
  • Samantha M. McNeill
    Monash Institute of Pharmaceutical Sciences, 381 Royal Parade, Parkville, Victoria 3052, Australia
  • Peishen Zhao
    Monash Institute of Pharmaceutical Sciences, 381 Royal Parade, Parkville, Victoria 3052, Australia
  • Sam van Dun
    EnzyTag B.V., Daelderweg 9, 6361HK Nuth, The Netherlands
  • Anna Koijen
    EnzyTag B.V., Daelderweg 9, 6361HK Nuth, The Netherlands
  • Yasuhiro Kajihara
    Graduate School of Science, Osaka University, Toyonaka, Osaka 560-0043 Japan
  • Denise Wootten
    Monash Institute of Pharmaceutical Sciences, 381 Royal Parade, Parkville, Victoria 3052, Australia
  • Leendert J. van den Bos
    EnzyTag B.V., Daelderweg 9, 6361HK Nuth, The Netherlands
  • John D. Wade
    The Florey Institute of Neuroscience and Mental Health, Parkville, Victoria 3052, Australia
  • Mohammed Akhter Hossain
    The Florey Institute of Neuroscience and Mental Health, Parkville, Victoria 3052, Australia

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説明

Exenatide was the first marketed GLP-1 receptor agonist for the treatment of type 2 diabetes. Modification to the chemical structure or the formulation has the potential to increase the stability of exenatide. We introduced human complex-type sialyloligosaccharide to exenatide at the native Asn28 position. The synthesis was achieved using both solid phase peptide synthesis (SPPS) and Omniligase-1-mediated chemoenzymatic ligation. The results demonstrate that glycosylation increases the proteolytic stability of exenatide while retaining its full biological activity.

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