Issue 41, 2014

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.

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

Supplementary files

Article information

Article type
Paper
Submitted
11 Jun 2014
Accepted
10 Jul 2014
First published
10 Jul 2014

Org. Biomol. Chem., 2014,12, 8142-8151

Author version available

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

R. Kowalczyk, M. A. Brimble, Y. Tomabechi, A. J. Fairbanks, M. Fletcher and D. L. Hay, Org. Biomol. Chem., 2014, 12, 8142 DOI: 10.1039/C4OB01208A

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