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Proc Natl Acad Sci U S A. 2003 Apr 15;100(8):4435-9. Epub 2003 Apr 8.

Assembly of high-affinity insulin receptor agonists and antagonists from peptide building blocks.

Author information

1
Novo Nordisk AS, DK-2800 Bagsvaerd, Denmark. lsc@novonordisk.com

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.

PMID:
12684539
PMCID:
PMC153573
DOI:
10.1073/pnas.0830026100
[Indexed for MEDLINE]
Free PMC Article

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