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Design, Synthesis, and Biological Evaluation of New Cyclic Disulfide Decapeptides That Inhibit the Binding of AP-1 to DNA

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 cycli...

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Bibliographic Details
Published in:Journal of medicinal chemistry 2004-08, Vol.47 (17), p.4239-4246
Main Authors: Tsuchida, Keiichi, Chaki, Hisaaki, Takakura, Tadakazu, Yokotani, Junichi, Aikawa, Yukihiko, Shiozawa, Shunichi, Gouda, Hiroaki, Hirono, Shuichi
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Language:English
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Summary: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 μM), 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.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm049890+