期刊
JOURNAL OF BIOLOGICAL CHEMISTRY
卷 287, 期 39, 页码 33001-33013出版社
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M112.383430
关键词
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资金
- Swiss National Science Foundation [310030_132884/1, CRSI33_130576/1]
- Promedica Foundation, Chur, Switzerland
- C.E.R.I.E.S. award
- Studienstiftung des Deutschen Volkes
- EMBO
- Swiss National Science Foundation (SNF) [CRSI33_130576] Funding Source: Swiss National Science Foundation (SNF)
Nuclear factor erythroid-derived 2-related factor 2 (Nrf2) is a master regulator of cellular antioxidant defense systems, and activation of this transcription factor is a promising strategy for protection of skin and other organs from environmental insults. To identify efficient Nrf2 activators in keratinocytes, we combined a chemical library screen with computer-based virtual screening. Among 14 novel Nrf2 activators, the most potent compound, a nitrophenyl derivative of 2-chloro-5-nitro-N-phenyl-benzamide, was characterized with regard to its molecular mechanism of action. This compound induced the expression of cytoprotective genes in keratinocytes isolated from wild-type but not from Nrf2-deficient mice. Most importantly, it showed low toxicity and protected primary human keratinocytes from UVB-induced cell death. Therefore, it represents a potential lead compound for the development of drugs for skin protection under stress conditions. Our study demonstrates that chemical library screening combined with advanced computational similarity searching is a powerful strategy for identification of bioactive compounds, and it points toward an innovative therapeutic approach against UVB-induced skin damage.
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