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.
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Authors | Renata Kowalczyk, Margaret A Brimble, Yusuke Tomabechi, Antony J Fairbanks, Madeleine Fletcher, Debbie L Hay |
Journal | Organic & biomolecular chemistry
(Org Biomol Chem)
Vol. 12
Issue 41
Pg. 8142-51
(Nov 07 2014)
ISSN: 1477-0539 [Electronic] England |
PMID | 25030939
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Chemical References |
- Amylin Receptor Agonists
- Islet Amyloid Polypeptide
- Receptors, Islet Amyloid Polypeptide
- pramlintide
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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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