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

Org Biomol Chem. 2014 Nov 7;12(41):8142-51. doi: 10.1039/c4ob01208a. Epub 2014 Jul 17.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amylin Receptor Agonists / chemical synthesis
  • Amylin Receptor Agonists / chemistry*
  • Amylin Receptor Agonists / pharmacology*
  • Dose-Response Relationship, Drug
  • Glycosylation
  • Humans
  • Islet Amyloid Polypeptide / chemical synthesis*
  • Islet Amyloid Polypeptide / chemistry
  • Islet Amyloid Polypeptide / pharmacology*
  • Molecular Structure
  • Receptors, Islet Amyloid Polypeptide / metabolism*
  • Structure-Activity Relationship


  • Amylin Receptor Agonists
  • Islet Amyloid Polypeptide
  • Receptors, Islet Amyloid Polypeptide
  • pramlintide