Design, synthesis, and biological evaluation of new cyclic disulfide decapeptides that inhibit the binding of AP-1 to DNA

J Med Chem. 2004 Aug 12;47(17):4239-46. doi: 10.1021/jm049890+.


The transcription factor activator protein-1 (AP-1) is an attractive target for the treatment of immunoinflammatory diseases, such as rheumatoid arthritis. Using the three-dimensional (3D) X-ray crystallographic structure of the DNA-bound basic region leucine zipper (bZIP) domains of AP-1, new cyclic disulfide decapeptides were designed and synthesized that demonstrated AP-1 inhibitory activities. The most potent inhibition was exhibited by Ac-c[Cys-Gly-Gln-Leu-Asp-Leu-Ala-Asp-Gly-Cys]-NH2 (peptide 2) (IC50 = 8 microM), which was largely due to the side chains of residues 3-6 and 8 of the peptide, as shown by an alanine scan. To provide structural information about the biologically active conformation of peptide 2, the structures of peptide 2 derived from molecular dynamics simulation of the bZIP-peptide 2 complex with explicit water molecules were superimposed on the solution structures derived from NMR measurements of peptide 2 in water. These showed a strong structural similarity in the backbones of residues 3-7 and enabled the construction of a 3D pharmacophore model of AP-1 binding compounds, based on the chemical and structural features of the amino acid side chains of residues 3-7 in peptide 2.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Computer Simulation
  • Crystallography, X-Ray
  • DNA / chemistry*
  • Disulfides / chemical synthesis*
  • Disulfides / chemistry
  • Drug Design
  • Leucine Zippers
  • Magnetic Resonance Spectroscopy
  • Models, Molecular
  • Oligopeptides / chemical synthesis*
  • Oligopeptides / chemistry
  • Peptides, Cyclic / chemical synthesis*
  • Peptides, Cyclic / chemistry
  • Protein Binding / drug effects
  • Protein Conformation
  • Transcription Factor AP-1 / chemistry*


  • Ac-c(Cys-Gly-Gln-Leu-Asp-:Leu-Ala-Asp-Gly-Cys)-NH2
  • Disulfides
  • Oligopeptides
  • Peptides, Cyclic
  • Transcription Factor AP-1
  • DNA