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Convergent chemoenzymatic synthesis of a library of glycosylated analogues of pramlintide: structure-activity relationships for amylin receptor agonism.

Abstract
Pramlintide (Symlin®), a synthetic analogue of the naturally occurring pancreatic hormone amylin, is currently used with insulin in adjunctive therapy for type 1 and type 2 diabetes mellitus. Herein we report a systematic study into the effect that N-glycosylation of pramlintide has on activation of amylin receptors. A highly efficient convergent synthetic route, involving a combination of solid phase peptide synthesis and enzymatic glycosylation, delivered a library of N-glycosylated variants of pramlintide bearing either GlcNAc, the core N-glycan pentasaccharide [Man3(GlcNAc)2] or a complex biantennary glycan [(NeuAcGalGlcNAcMan)2Man(GlcNAc)2] at each of its six asparagine residues. The majority of glycosylated versions of pramlintide were potent receptor agonists, suggesting that N-glycosylation may be used as a tool to optimise the pharmacokinetic properties of pramlintide and so deliver improved therapeutic agents for the treatment of diabetes and obesity.
AuthorsRenata Kowalczyk, Margaret A Brimble, Yusuke Tomabechi, Antony J Fairbanks, Madeleine Fletcher, Debbie L Hay
JournalOrganic & biomolecular chemistry (Org Biomol Chem) Vol. 12 Issue 41 Pg. 8142-51 (Nov 07 2014) ISSN: 1477-0539 [Electronic] England
PMID25030939 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Amylin Receptor Agonists
  • Islet Amyloid Polypeptide
  • Receptors, Islet Amyloid Polypeptide
  • pramlintide
Topics
  • Amylin Receptor Agonists (chemical synthesis, chemistry, pharmacology)
  • Dose-Response Relationship, Drug
  • Glycosylation
  • Humans
  • Islet Amyloid Polypeptide (chemical synthesis, chemistry, pharmacology)
  • Molecular Structure
  • Receptors, Islet Amyloid Polypeptide (metabolism)
  • Structure-Activity Relationship

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