A sesquiterpene lactone from a medicinal herb inhibits proinflammatory activity of TNF-α by inhibiting ubiquitin-conjugating enzyme UbcH5

Li Liu; Yaping Hua; Dan Wang; Lei Shan; Yuan Zhang; Junsheng Zhu; Huizi Jin; Honglin Li; Zhenlin Hu; Weidong Zhang

doi:10.1016/j.chembiol.2014.07.021

A sesquiterpene lactone from a medicinal herb inhibits proinflammatory activity of TNF-α by inhibiting ubiquitin-conjugating enzyme UbcH5

Chem Biol. 2014 Oct 23;21(10):1341-1350. doi: 10.1016/j.chembiol.2014.07.021. Epub 2014 Sep 4.

Authors

Li Liu¹, Yaping Hua², Dan Wang¹, Lei Shan¹, Yuan Zhang³, Junsheng Zhu³, Huizi Jin², Honglin Li³, Zhenlin Hu⁴, Weidong Zhang⁵

Affiliations

¹ Department of Phytochemistry, School of Pharmacy, Second Military Medical University, Shanghai 200433, China.
² Department of Natural Medicinal Chemistry, School of Pharmacy, Shanghai JiaoTong University, Shanghai 200240, China.
³ 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.
⁴ Department of Biochemical Pharmacy, School of Pharmacy, Second Military Medical University, Shanghai 200433, China. Electronic address: [email protected].
⁵ Department of Phytochemistry, School of Pharmacy, Second Military Medical University, Shanghai 200433, China. Electronic address: [email protected].

PMID: 25200604
DOI: 10.1016/j.chembiol.2014.07.021

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Anti-Inflammatory Agents / chemistry
Anti-Inflammatory Agents / pharmacology
Anti-Inflammatory Agents / therapeutic use
Binding Sites
Cell Line
Cell Survival / drug effects
Female
HEK293 Cells
Hepatitis / drug therapy
Hepatitis / pathology
Humans
I-kappa B Kinase / metabolism
Lactones / chemistry
Lactones / pharmacology*
Lactones / therapeutic use
Male
Mice
Mice, Inbred BALB C
Mice, Inbred DBA
Molecular Docking Simulation
NF-kappa B / metabolism
Plants, Medicinal / chemistry*
Plants, Medicinal / metabolism
Protein Binding
Protein Structure, Tertiary
Sesquiterpenes / chemistry*
Sesquiterpenes / pharmacology
Sesquiterpenes / therapeutic use
Signal Transduction / drug effects*
Tumor Necrosis Factor-alpha / antagonists & inhibitors
Tumor Necrosis Factor-alpha / metabolism*
Ubiquitin-Conjugating Enzymes / antagonists & inhibitors*
Ubiquitin-Conjugating Enzymes / metabolism
Ubiquitination / drug effects

Substances

1-hydroxyalantolactone
Anti-Inflammatory Agents
Lactones
NF-kappa B
Sesquiterpenes
Tumor Necrosis Factor-alpha
Ubiquitin-Conjugating Enzymes
I-kappa B Kinase