Identification of UV-protective Activators of Nuclear Factor Erythroid-derived 2-Related Factor 2 (Nrf2) by Combining a Chemical Library Screen with Computer-based Virtual Screening
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Date
2012-09-21
Publication Type
Journal Article
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yes
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Abstract
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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published
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Journal / series
Volume
287 (39)
Pages / Article No.
33001 - 33013
Publisher
American Society for Biochemistry and Molecular Biology
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Subject
Chemical Biology; Chemoprevention; Nrf2; Oxidative Stress; Transcription Factors; UV; Chemical Library; Virtual Screening
Organisational unit
03683 - Detmar, Michael (emeritus) / Detmar, Michael (emeritus)
03520 - Werner, Sabine / Werner, Sabine
03852 - Schneider, Gisbert / Schneider, Gisbert
Notes
Funding
132884 - Fibroblast growth factor signaling in skin barrier function, wound repair and inflammatory skin disease (SNF)
130576 - miRNAs as integrative determinants of the keratino (SNF)
130576 - miRNAs as integrative determinants of the keratino (SNF)