Design, Synthesis, and Biological Evaluation of New Cyclic Disulfide Decapeptides That Inhibit the Binding of AP-1 to DNA
| Autor: | Yukihiko Aikawa, Tadakazu Takakura, Keiichi Tsuchida, Shuichi Hirono, Hisaaki Chaki, Hiroaki Gouda, Shunichi Shiozawa, Junichi Yokotani |
|---|---|
| Rok vydání: | 2004 |
| Předmět: | |
| Zdroj: | Journal of Medicinal Chemistry. 47:4239-4246 |
| ISSN: | 1520-4804 0022-2623 |
| DOI: | 10.1021/jm049890+ |
| Popis: | 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|