Assembly of high-affinity insulin receptor agonists and antagonists from peptide building blocks.
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.
Schäffer
Lauge
L
Novo Nordisk AS, DK-2800 Bagsvaerd, Denmark. lsc@novonordisk.com
Brissette
Renee E
RE
Spetzler
Jane C
JC
Pillutla
Renuka C
RC
Østergaard
Søren
S
Lennick
Michael
M
Brandt
Jakob
J
Fletcher
Paul W
PW
Danielsen
Gillian M
GM
Hsiao
Ku-Chuan
KC
Andersen
Asser S
AS
Dedova
Olga
O
Ribel
Ulla
U
Hoeg-Jensen
Thomas
T
Hansen
Per Hertz
PH
Blume
Arthur J
AJ
Markussen
Jan
J
Goldstein
Neil I
NI
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
D007328:Insulin; D008055:Lipids; D010455:Peptides; D021122:Protein Subunits; D011994:Recombinant Proteins; D011972:Receptor, Insulin