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

Proc Natl Acad Sci U S A. 2003 Apr 15;100(8):4435-9. doi: 10.1073/pnas.0830026100. Epub 2003 Apr 8.

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.

MeSH terms

  • Adipocytes / drug effects
  • Adipocytes / metabolism
  • Amino Acid Sequence
  • Animals
  • Dimerization
  • Humans
  • In Vitro Techniques
  • Insulin / pharmacology
  • Kinetics
  • Lipids / biosynthesis
  • Male
  • Mice
  • Molecular Sequence Data
  • Peptides / chemistry
  • Peptides / genetics
  • Peptides / pharmacology*
  • Protein Subunits
  • Rats
  • Rats, Wistar
  • Receptor, Insulin / agonists*
  • Receptor, Insulin / antagonists & inhibitors*
  • Receptor, Insulin / genetics
  • Receptor, Insulin / metabolism
  • Recombinant Proteins / chemistry
  • Recombinant Proteins / genetics
  • Recombinant Proteins / pharmacology

Substances

  • Insulin
  • Lipids
  • Peptides
  • Protein Subunits
  • Recombinant Proteins
  • Receptor, Insulin