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 α-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 discr...

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Published in:Proceedings of the National Academy of Sciences - PNAS 2003-04, Vol.100 (8), p.4435-4439
Main Authors: Schäffer, Lauge, Brissette, Renee E., Spetzler, Jane C., Pillutla, Renuka C., Østergaard, Søren, Lennick, Michael, Brandt, Jakob, Fletcher, Paul W., Danielsen, Gillian M., Hsiao, Ku-Chuan, Andersen, Asser S., Dedova, Olga, Ribel, Ulla, Hoeg-Jensen, Thomas, Hansen, Per Hertz, Blume, Arthur J., Markussen, Jan, Goldstein, Neil I.
Format: Article
Language:English
Subjects:
Adipocytes
Adipocytes - drug effects
Adipocytes - metabolism
Agonists
Amino Acid Sequence
Animals
Biological Sciences
Dimerization
Dimers
Enzymes
Glycols
Humans
In Vitro Techniques
Insulin
Insulin - pharmacology
Insulin resistance
Kinetics
Lipids - biosynthesis
Lipogenesis
Male
Mice
Molecular Sequence Data
Monomers
Peptides
Peptides - chemistry
Peptides - genetics
Peptides - pharmacology
Protein Subunits
Proteins
Rats
Rats, Wistar
Receptor, Insulin - agonists
Receptor, Insulin - antagonists & inhibitors
Receptor, Insulin - genetics
Receptor, Insulin - metabolism
Receptors
Recombinant Proteins - chemistry
Recombinant Proteins - genetics
Recombinant Proteins - pharmacology
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Summary:Insulin is thought to elicit its effects by crosslinking the two extracellular α-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.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.0830026100