Liu Li, Hua Yaping, Wang Dan, Shan Lei, Zhang Yuan, Zhu Junsheng, Jin Huizi, Li Honglin, Hu Zhenlin, Zhang Weidong
Department of Phytochemistry, School of Pharmacy, Second Military Medical University, Shanghai 200433, China.
Department of Natural Medicinal Chemistry, School of Pharmacy, Shanghai JiaoTong University, Shanghai 200240, China.
Chem Biol. 2014 Oct 23;21(10):1341-1350. doi: 10.1016/j.chembiol.2014.07.021. Epub 2014 Sep 4.
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.
UbcH5是在肿瘤坏死因子-α（TNF-α）触发的核因子-κB（NF-κB）激活过程中催化泛素化的关键泛素结合酶。在此，我们鉴定出一种源自草药的倍半萜内酯化合物IJ-5作为UbcH5的优先抑制剂，并在炎症和自身免疫性疾病模型中探索了其治疗价值。IJ-5通过抑制受体相互作用蛋白1和NF-κB必需调节因子的泛素化来抑制TNF-α诱导的NF-κB激活和炎症基因转录，而这对于IκB激酶激活至关重要。机制研究表明，IJ-5通过与其活性位点半胱氨酸形成共价加合物，优先结合并使UbcH5失活，从而阻止泛素与UbcH5结合。在临床前模型中，IJ-5预处理对TNF-α和D-半乳糖胺诱导的肝炎以及胶原诱导的关节炎表现出强大的抗炎活性。这些发现突出了UbcH5作为抗TNF-α干预治疗靶点的潜力，并为开发新型抗炎药物提供了一种有趣的先导化合物。
