title: Insulins with built-in glucose sensors for glucose responsive insulin release.
abstract: Derivatization of insulin with phenylboronic acids is described, thereby equipping insulin with novel glucose sensing ability. It is furthermore demonstrated that such insulins are useful in glucose-responsive polymer-based release systems. The preferred phenylboronic acids are sulfonamide derivatives, which, contrary to naïve boronic acids, ensure glucose binding at physiological pH, and simultaneously operate as handles for insulin derivatization at LysB29. The glucose affinities of the novel insulins were evaluated by glucose titration in a competitive assay with alizarin. The affinities were in the range 15-31 mM (K(d)), which match physiological glucose fluctuations. The dose-responsive glucose-mediated release of the novel insulins was demonstrated using glucamine-derived polyethylene glycol polyacrylamide (PEGA) as a model, and it was shown that Zn(II) hexamer formulation of the boronated insulins resulted in steeper glucose sensitivity relative to monomeric insulin formulation. Notably, two of the boronated insulins displayed enhanced insulin receptor affinity relative to native insulin (113%-122%) which is unusual for insulin LysB29 derivatives.
authors.affiliation: Novo Nordisk A/S, DK-2880 Bagsvaerd, Denmark. tshj@novonordisk.com
authors.forename: Thomas
authors.initials: T
authors.lastname: Hoeg-Jensen
authors.forename: Signe
authors.initials: S
authors.lastname: Ridderberg
authors.forename: Svend
authors.initials: S
authors.lastname: Havelund
authors.forename: Lauge
authors.initials: L
authors.lastname: Schäffer
authors.forename: Per
authors.initials: P
authors.lastname: Balschmidt
authors.forename: Ib
authors.initials: I
authors.lastname: Jonassen
authors.forename: Per
authors.initials: P
authors.lastname: Vedsø
authors.forename: Preben H
authors.initials: PH
authors.lastname: Olesen
authors.forename: Jan
authors.initials: J
authors.lastname: Markussen
mesh_terms: D000595:Amino Acid Sequence; D015374:Biosensing Techniques; D005947:Glucose / Q000494:pharmacology*; D006801:Humans; D007202:Indicators and Reagents; D007328:Insulin / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism*; D000078790:Insulin Secretion; D008969:Molecular Sequence Data; D010456:Peptides, Cyclic / Q000138:chemical synthesis / Q000737:chemistry; D011972:Receptor, Insulin / Q000235:genetics / Q000378:metabolism; D017384:Sequence Deletion
chemical_list: D007202:Indicators and Reagents; D007328:Insulin; D010456:Peptides, Cyclic; D011972:Receptor, Insulin; D005947:Glucose