title: 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.
authors.affiliation: The School of Chemical Sciences, University of Auckland, 23 Symonds St, Auckland 1010, New Zealand. m.brimble@auckland.ac.nz.
authors.forename: Renata
authors.initials: R
authors.lastname: Kowalczyk
authors.forename: Margaret A
authors.initials: MA
authors.lastname: Brimble
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Tomabechi
authors.forename: Antony J
authors.initials: AJ
authors.lastname: Fairbanks
authors.forename: Madeleine
authors.initials: M
authors.lastname: Fletcher
authors.forename: Debbie L
authors.initials: DL
authors.lastname: Hay
mesh_terms: D065091:Amylin Receptor Agonists / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D006031:Glycosylation; D006801:Humans; D058228:Islet Amyloid Polypeptide / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D015394:Molecular Structure; D058287:Receptors, Islet Amyloid Polypeptide / Q000378:metabolism*; D013329:Structure-Activity Relationship
chemical_list: D065091:Amylin Receptor Agonists; D058228:Islet Amyloid Polypeptide; D058287:Receptors, Islet Amyloid Polypeptide; C105254:pramlintide