Treatment of arthritis with a selective inhibitor of c-Fos/activator protein-1
| Autor: | Tetsuya Yamamoto, Kimiko Morimoto, Hisaaki Chaki, Shuichi Hirono, Akira Hashiramoto, Hirokazu Narita, Yukihiko Aikawa, Shunichi Shiozawa |
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| Rok vydání: | 2008 |
| Předmět: |
Male
medicine.medical_specialty Necrosis medicine.medical_treatment Biomedical Engineering Arthritis Bioengineering Matrix metalloproteinase Pharmacology Applied Microbiology and Biotechnology Proinflammatory cytokine Mice In vivo Internal medicine medicine Animals Disulfides Chemistry Activator (genetics) Genes fos medicine.disease In vitro Transcription Factor AP-1 Treatment Outcome Cytokine Endocrinology Mice Inbred DBA Cytokines Molecular Medicine medicine.symptom Biotechnology |
| Zdroj: | Nature Biotechnology. 26:817-823 |
| ISSN: | 1546-1696 1087-0156 |
| DOI: | 10.1038/nbt1412 |
| Popis: | To inhibit arthritis upstream of inflammatory cytokine release and matrix metalloproteinase (MMP) action, we designed de novo a small-molecule inhibitor of c-Fos/activator protein-1 (AP-1) using three-dimensional (3D) pharmacophore modeling. This model was based on the 3D structure of the basic region-leucine zipper domain of AP-1-DNA complex. Administration of this inhibitor prevented type II collagen-induced arthritis from day 21, before the onset of arthritis, or from day 27, resolved arthritis after its onset. Suppression of disease was accomplished by reducing the amounts of inflammatory cytokines and MMPs in vivo in sera and joints and in vitro in synovial cell and chondrocyte cultures. The primary action of this molecule was the inhibition of matrix-degrading MMPs and inflammatory cytokines including interleukin 1beta; this molecule also synergized with anti-tumor necrosis factor alpha to inhibit arthritis. Thus, selective inhibition of c-Fos/AP-1 resolves arthritis in a preclinical model of the disease. |
| Databáze: | OpenAIRE |
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