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 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.
Tsuchida
Keiichi
K
Discovery Laboratories, Toyama Chemical Co., Ltd., 4-1 Shimookui 2-chome, Toyama 930-8508, Japan. KEIICHI_TUCHIDA@toyama-chemical.co.jp
Chaki
Hisaaki
H
Takakura
Tadakazu
T
Yokotani
Junichi
J
Aikawa
Yukihiko
Y
Shiozawa
Shunichi
S
Gouda
Hiroaki
H
Hirono
Shuichi
S
D003198:Computer Simulation; D018360:Crystallography, X-Ray; D004247:DNA / Q000737:chemistry*; D004220:Disulfides / Q000138:chemical synthesis* / Q000737:chemistry; D015195:Drug Design; D016350:Leucine Zippers; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D009842:Oligopeptides / Q000138:chemical synthesis* / Q000737:chemistry; D010456:Peptides, Cyclic / Q000138:chemical synthesis* / Q000737:chemistry; D011485:Protein Binding / Q000187:drug effects; D011487:Protein Conformation; D018808:Transcription Factor AP-1 / Q000737:chemistry*
C488790:Ac-c(Cys-Gly-Gln-Leu-Asp-:Leu-Ala-Asp-Gly-Cys)-NH2; D004220:Disulfides; D009842:Oligopeptides; D010456:Peptides, Cyclic; D018808:Transcription Factor AP-1; D004247:DNA