Article abstract
Nature Biotechnology 26, 817 - 823 (2008)
Published online: 29 June 2008 | doi:10.1038/nbt1412
Treatment of arthritis with a selective inhibitor of c-Fos/activator protein-1
Yukihiko Aikawa1, Kimiko Morimoto1, Tetsuya Yamamoto1, Hisaaki Chaki1, Akira Hashiramoto2, Hirokazu Narita1, Shuichi Hirono3 & Shunichi Shiozawa2,4
Abstract
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 1
; this molecule also synergized with anti-tumor necrosis factor 
to inhibit arthritis. Thus, selective inhibition of c-Fos/AP-1 resolves arthritis in a preclinical model of the disease.
- Research Laboratories, Toyama Chemical Co., Ltd., 4-1 Shimookui 2-chome, Toyama 930-8508, Japan.
- Division of Rheumatology, Kobe University Graduate School of Medicine and Health Science, 7-10-2 Tomogaoka Suma-ku, Kobe 654-0142 and the Center for Rheumatic Diseases, Kobe University Hospital, 7-5-2 Kusunokicho, Chuo-ku, Kobe 650-0017, Japan.
- Department of Pharmaceutical Sciences, School of Pharmacy, Kitasato University, 5-9-1 Shirokane, Minato-ku, Tokyo 108-8641, Japan.
- Global Center of Excellence (COE) Japan.
Correspondence to: Shunichi Shiozawa2,4 e-mail: shioz@kobe-u.ac.jp
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