title: 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.
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.
authors.affiliation: Department of Biology, Swiss Federal Institute of Technology (ETH) Zurich, 8093 Zurich, Switzerland.
authors.forename: Franziska
authors.initials: F
authors.lastname: Lieder
authors.forename: Felix
authors.initials: F
authors.lastname: Reisen
authors.forename: Tim
authors.initials: T
authors.lastname: Geppert
authors.forename: Gabriel
authors.initials: G
authors.lastname: Sollberger
authors.forename: Hans-Dietmar
authors.initials: HD
authors.lastname: Beer
authors.forename: Ulrich
authors.initials: U
authors.lastname: auf dem Keller
authors.forename: Matthias
authors.initials: M
authors.lastname: Schäfer
authors.forename: Michael
authors.initials: M
authors.lastname: Detmar
authors.forename: Gisbert
authors.initials: G
authors.lastname: Schneider
authors.forename: Sabine
authors.initials: S
authors.lastname: Werner
mesh_terms: D000818:Animals; D001549:Benzamides / Q000494:pharmacology*; D016923:Cell Death / Q000187:drug effects / Q000235:genetics / Q000528:radiation effects; D002461:Cell Line, Transformed; D019610:Cytoprotection / Q000187:drug effects* / Q000235:genetics / Q000528:radiation effects; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics / Q000528:radiation effects; D006801:Humans; D015603:Keratinocytes / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D051267:NF-E2-Related Factor 2 / Q000235:genetics / Q000378:metabolism*; D012867:Skin / Q000293:injuries / Q000378:metabolism / Q000473:pathology; D014466:Ultraviolet Rays / Q000009:adverse effects*
chemical_list: C549132:2-chloro-N-(4-chlorophenyl)-5-nitrobenzamide; D001549:Benzamides; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; C495636:Nfe2l2 protein, mouse