Pseudosubstrate peptides inhibit Akt and induce cell growth inhibition

Biochemistry. 2004 Feb 10;43(5):1254-63. doi: 10.1021/bi034515p.

Abstract

We have designed peptide inhibitors that potently inhibit Akt both in vitro and inside cells. These peptide inhibitors are selective for Akt versus other closely related kinases. The peptides inhibit the in vitro phosphorylation of a biotinylated Bad peptide by Akt with potency up to 100 nM. We have shown that the binding between Akt1 and these peptide inhibitors requires MgATP. Mutating the two putative Akt phosphorylation sites to Ala (nonsubstrate) in these peptides increases the inhibitory potency while mutating the sites to aspartic acid (phosphorylation mimetic) reduces the potency. When delivered into cells, these peptide inhibitors can inhibit cellular Akt activity and cell growth. Thus, these Akt-specific peptide inhibitors provide prototypes for peptide mimetic drugs as well as very useful tools to dissect cellular functions of Akt.

MeSH terms

  • Adenosine Triphosphate / chemistry
  • Amino Acid Sequence
  • Aspartic Acid / genetics
  • Binding, Competitive / genetics
  • Cell Line, Tumor
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / chemistry*
  • Glycogen Synthase Kinase 3 / antagonists & inhibitors
  • Glycogen Synthase Kinase 3 / metabolism
  • Growth Inhibitors / chemical synthesis
  • Growth Inhibitors / chemistry*
  • Growth Inhibitors / genetics
  • HeLa Cells
  • Histidine / chemistry
  • Humans
  • Molecular Sequence Data
  • Peptides / chemical synthesis
  • Peptides / chemistry*
  • Peptides / genetics
  • Phosphorylation
  • Protein Binding / genetics
  • Protein-Serine-Threonine Kinases / antagonists & inhibitors*
  • Protein-Serine-Threonine Kinases / metabolism*
  • Protein-Serine-Threonine Kinases / physiology
  • Proto-Oncogene Proteins c-akt
  • Proto-Oncogene Proteins*
  • Serine / genetics
  • Substrate Specificity / genetics

Substances

  • Enzyme Inhibitors
  • Growth Inhibitors
  • Peptides
  • Proto-Oncogene Proteins
  • Aspartic Acid
  • Serine
  • Histidine
  • Adenosine Triphosphate
  • AKT1 protein, human
  • Protein-Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt
  • Glycogen Synthase Kinase 3