title: A sesquiterpene lactone from a medicinal herb inhibits proinflammatory activity of TNF-α by inhibiting ubiquitin-conjugating enzyme UbcH5.
abstract: UbcH5 is the key ubiquitin-conjugating enzyme catalyzing ubiquitination during TNF-α-triggered NF-κB activation. Here, we identified an herb-derived sesquiterpene lactone compound IJ-5 as a preferential inhibitor of UbcH5 and explored its therapeutic value in inflammatory and autoimmune disease models. IJ-5 suppresses TNF-α-induced NF-κB activation and inflammatory gene transcription by inhibiting the ubiquitination of receptor-interacting protein 1 and NF-κB essential modifier, which is essential to IκB kinase activation. Mechanistic investigations revealed that IJ-5 preferentially binds to and inactivates UbcH5 by forming a covalent adduct with its active site cysteine and thereby preventing ubiquitin conjugation to UbcH5. In preclinical models, pretreatment of IJ-5 exhibited potent anti-inflammatory activity against TNF-α- and D-galactosamine-induced hepatitis and collagen-induced arthritis. These findings highlight the potential of UbcH5 as a therapeutic target for anti-TNF-α interventions and provide an interesting lead compound for the development of new anti-inflammation agents.
authors.affiliation: Department of Phytochemistry, School of Pharmacy, Second Military Medical University, Shanghai 200433, China.
authors.forename: Li
authors.initials: L
authors.lastname: Liu
authors.affiliation: Department of Natural Medicinal Chemistry, School of Pharmacy, Shanghai JiaoTong University, Shanghai 200240, China.
authors.forename: Yaping
authors.initials: Y
authors.lastname: Hua
authors.affiliation: Department of Phytochemistry, School of Pharmacy, Second Military Medical University, Shanghai 200433, China.
authors.forename: Dan
authors.initials: D
authors.lastname: Wang
authors.affiliation: Department of Phytochemistry, School of Pharmacy, Second Military Medical University, Shanghai 200433, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Shan
authors.affiliation: Shanghai Key Laboratory of New Drug Design, State Key Laboratory of Bioreactor Engineering, School of Pharmacy, East China University of Science and Technology, Shanghai 200237, China.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Shanghai Key Laboratory of New Drug Design, State Key Laboratory of Bioreactor Engineering, School of Pharmacy, East China University of Science and Technology, Shanghai 200237, China.
authors.forename: Junsheng
authors.initials: J
authors.lastname: Zhu
authors.affiliation: Department of Natural Medicinal Chemistry, School of Pharmacy, Shanghai JiaoTong University, Shanghai 200240, China.
authors.forename: Huizi
authors.initials: H
authors.lastname: Jin
authors.affiliation: Shanghai Key Laboratory of New Drug Design, State Key Laboratory of Bioreactor Engineering, School of Pharmacy, East China University of Science and Technology, Shanghai 200237, China.
authors.forename: Honglin
authors.initials: H
authors.lastname: Li
authors.affiliation: Department of Biochemical Pharmacy, School of Pharmacy, Second Military Medical University, Shanghai 200433, China. Electronic address: zhenlinhu@hotmail.com.
authors.forename: Zhenlin
authors.initials: Z
authors.lastname: Hu
authors.affiliation: Department of Phytochemistry, School of Pharmacy, Second Military Medical University, Shanghai 200433, China. Electronic address: wdzhangy@hotmail.com.
authors.forename: Weidong
authors.initials: W
authors.lastname: Zhang
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D001665:Binding Sites; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D005260:Female; D057809:HEK293 Cells; D006505:Hepatitis / Q000188:drug therapy / Q000473:pathology; D006801:Humans; D051550:I-kappa B Kinase / Q000378:metabolism; D007783:Lactones / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008811:Mice, Inbred DBA; D062105:Molecular Docking Simulation; D016328:NF-kappa B / Q000378:metabolism; D010946:Plants, Medicinal / Q000737:chemistry* / Q000378:metabolism; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D012717:Sesquiterpenes / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use; D015398:Signal Transduction / Q000187:drug effects*; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000378:metabolism*; D044763:Ubiquitin-Conjugating Enzymes / Q000037:antagonists & inhibitors* / Q000378:metabolism; D054875:Ubiquitination / Q000187:drug effects
chemical_list: C000599362:1-hydroxyalantolactone; D000893:Anti-Inflammatory Agents; D007783:Lactones; D016328:NF-kappa B; D012717:Sesquiterpenes; D014409:Tumor Necrosis Factor-alpha; D044763:Ubiquitin-Conjugating Enzymes; D051550:I-kappa B Kinase