title: Pterisolic Acid B is a Nrf2 Activator by Targeting C171 within Keap1-BTB Domain.
abstract: The use of chemoprotective agents to minimize the side effects of the chemotherapy, primarily via activation of the Nrf2 pathway, is an emerging research field, which has attracted broad attention from both academia and pharmaceutical industry. Through high-throughput chemical screens we have disclosed that pterisolic acid B (J19), a naturally occuring diterpenoid, is an effective Nrf2 activator. We have also identified a more potent natural product analogue J19-1 by semisynthesis and the subsequent biochemical evaluations revealed that J19-1 activates the Nrf2 pathway by covalently modifying Cys171 of keap1, which inhibits Nrf2 degradation mediated by Keap1-Cul3 complexes. Ultimately, we have demonstrated that J19-1 shows significant cytoprotective effect against cisplatin-induced cytotoxicity in HKC cells.
authors.affiliation: Beijing National Laboratory for Molecular Sciences, Key Laboratory of Bioorganic Chemistry and Molecular Engineering of Ministry of Education, Department of Chemical Biology, College of Chemistry and Molecular Engineering, Synthetic and Functional Biomolecules Center, and Peking-Tsinghua Center for Life Sciences, Peking University, Beijing 100871 (China).|National Institute of Biological Sciences (NIBS), Changping District, Beijing 102206 (China).
authors.forename: Ting
authors.initials: T
authors.lastname: Dong
authors.affiliation: Beijing National Laboratory for Molecular Sciences, Key Laboratory of Bioorganic Chemistry and Molecular Engineering of Ministry of Education, Department of Chemical Biology, College of Chemistry and Molecular Engineering, Synthetic and Functional Biomolecules Center, and Peking-Tsinghua Center for Life Sciences, Peking University, Beijing 100871 (China).|National Institute of Biological Sciences (NIBS), Changping District, Beijing 102206 (China).
authors.forename: Weilong
authors.initials: W
authors.lastname: Liu
authors.affiliation: National Institute of Biological Sciences (NIBS), Changping District, Beijing 102206 (China).
authors.forename: Zhirong
authors.initials: Z
authors.lastname: Shen
authors.affiliation: National Institute of Biological Sciences (NIBS), Changping District, Beijing 102206 (China).
authors.forename: Lin
authors.initials: L
authors.lastname: Li
authors.affiliation: National Institute of Biological Sciences (NIBS), Changping District, Beijing 102206 (China).
authors.forename: She
authors.initials: S
authors.lastname: Chen
authors.affiliation: Beijing National Laboratory for Molecular Sciences, Key Laboratory of Bioorganic Chemistry and Molecular Engineering of Ministry of Education, Department of Chemical Biology, College of Chemistry and Molecular Engineering, Synthetic and Functional Biomolecules Center, and Peking-Tsinghua Center for Life Sciences, Peking University, Beijing 100871 (China).|National Institute of Biological Sciences (NIBS), Changping District, Beijing 102206 (China).
authors.forename: Xiaoguang
authors.initials: X
authors.lastname: Lei
mesh_terms: D002460:Cell Line; D004224:Diterpenes / Q000494:pharmacology*; D006801:Humans; D000072019:Kelch-Like ECH-Associated Protein 1 / Q000737:chemistry / Q000378:metabolism*; D051267:NF-E2-Related Factor 2 / Q000819:agonists* / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects; D054730:Protein Interaction Domains and Motifs; D021381:Protein Transport; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction; D054875:Ubiquitination
chemical_list: D004224:Diterpenes; C431364:KEAP1 protein, human; D000072019:Kelch-Like ECH-Associated Protein 1; D051267:NF-E2-Related Factor 2; D017382:Reactive Oxygen Species