title: Assembly of high-affinity insulin receptor agonists and antagonists from peptide building blocks.
abstract: Insulin is thought to elicit its effects by crosslinking the two extracellular alpha-subunits of its receptor, thereby inducing a conformational change in the receptor, which activates the intracellular tyrosine kinase signaling cascade. Previously we identified a series of peptides binding to two discrete hotspots on the insulin receptor. Here we show that covalent linkage of such peptides into homodimers or heterodimers results in insulin agonists or antagonists, depending on how the peptides are linked. An optimized agonist has been shown, both in vitro and in vivo, to have a potency close to that of insulin itself. The ability to construct such peptide derivatives may offer a path for developing agonists or antagonists for treatment of a wide variety of diseases.
authors.affiliation: Novo Nordisk AS, DK-2800 Bagsvaerd, Denmark. lsc@novonordisk.com
authors.forename: Lauge
authors.initials: L
authors.lastname: Schäffer
authors.forename: Renee E
authors.initials: RE
authors.lastname: Brissette
authors.forename: Jane C
authors.initials: JC
authors.lastname: Spetzler
authors.forename: Renuka C
authors.initials: RC
authors.lastname: Pillutla
authors.forename: Søren
authors.initials: S
authors.lastname: Østergaard
authors.forename: Michael
authors.initials: M
authors.lastname: Lennick
authors.forename: Jakob
authors.initials: J
authors.lastname: Brandt
authors.forename: Paul W
authors.initials: PW
authors.lastname: Fletcher
authors.forename: Gillian M
authors.initials: GM
authors.lastname: Danielsen
authors.forename: Ku-Chuan
authors.initials: KC
authors.lastname: Hsiao
authors.forename: Asser S
authors.initials: AS
authors.lastname: Andersen
authors.forename: Olga
authors.initials: O
authors.lastname: Dedova
authors.forename: Ulla
authors.initials: U
authors.lastname: Ribel
authors.forename: Thomas
authors.initials: T
authors.lastname: Hoeg-Jensen
authors.forename: Per Hertz
authors.initials: PH
authors.lastname: Hansen
authors.forename: Arthur J
authors.initials: AJ
authors.lastname: Blume
authors.forename: Jan
authors.initials: J
authors.lastname: Markussen
authors.forename: Neil I
authors.initials: NI
authors.lastname: Goldstein
mesh_terms: D017667:Adipocytes / Q000187:drug effects / Q000378:metabolism; D000595:Amino Acid Sequence; D000818:Animals; D019281:Dimerization; D006801:Humans; D066298:In Vitro Techniques; D007328:Insulin / Q000494:pharmacology; D007700:Kinetics; D008055:Lipids / Q000096:biosynthesis; D008297:Male; D051379:Mice; D008969:Molecular Sequence Data; D010455:Peptides / Q000737:chemistry / Q000235:genetics / Q000494:pharmacology*; D021122:Protein Subunits; D051381:Rats; D017208:Rats, Wistar; D011972:Receptor, Insulin / Q000819:agonists* / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000494:pharmacology
chemical_list: D007328:Insulin; D008055:Lipids; D010455:Peptides; D021122:Protein Subunits; D011994:Recombinant Proteins; D011972:Receptor, Insulin