Natural product piperine alleviates experimental allergic encephalomyelitis in mice by targeting dihydroorotate dehydrogenase
Natural product piperine alleviates experimental allergic encephalomyelitis in mice by targeting dihydroorotate dehydrogenase
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天然产物胡椒碱通过靶向二氢乳清酸脱氢酶缓解小鼠实验性过敏性脑脊髓炎
DOI：
10.1016/j.bcp.2020.114000
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发表时间：
2020
影响因子：
5.8
通讯作者：
Huang Jin
中科院分区：
文献类型：
--
作者：
Liu Zehui;Hu Qian;Wang Wanyan;Lu Sisi;Wu Dang;Ze Shuyin;He Jiacheng;Huang Ying;Chen Wuyan;Xu Yechun;Lu Weiqiang;Huang Jin
多发性硬化症（MS）是中枢神经系统（CNS）最常见的慢性和衰弱性炎症性疾病，仍然无法治愈。二氢羟酸脱氢酶（DHODH）对T淋巴细胞的活性至关重要，是ms的潜在治疗靶点。我们发现黑胡椒中的一种生物活性成分胡椒碱是DHODH的有效抑制剂，ic50值为0.88 μM。等温滴定量热法和热荧光法证实了胡椒碱与DHODH之间的直接相互作用。DHODH与胡椒碱在1.98 Å分辨率下的共络合物晶体结构进一步揭示了DHODH的Tyr356残基对胡椒碱的结合至关重要。重要的是，我们在豆豆蛋白a触发的T细胞实验和混合淋巴细胞反应实验中发现，胡椒碱可以以dhodh依赖的方式抑制T细胞的过度激活。最后，胡椒碱在mog诱导的实验性过敏性脑脊髓炎（EAE）中表现出强大的预防和治疗作用，通过限制炎症细胞向中枢神经系统的浸润，防止髓磷脂破坏和血脑屏障（BBB）破坏，这是研究MS潜在治疗方法的有用模型。综上所述，这些发现突出了DHODH作为神经系统自身免疫性疾病的治疗靶点，并证明了胡椒碱在治疗多发性硬化症中的新作用。
Multiple sclerosis (MS) is the most popular chronic and debilitating inflammatory disease of the central nervous system (CNS) that remains incurable. Dihydroorotate dehydrogenase (DHODH) is critical to the activity of T lymphocytes and represents a potential therapeutic target for MS. Here we identify piperine, a bioactive constituent of black pepper, as a potent inhibitor of DHODH with an IC50value of 0.88 μM. Isothermal titration calorimetry and thermofluor assay demonstrate the directly interaction between piperine and DHODH. The co-complex crystal structure of DHODH and piperine at 1.98 Å resolution further reveal that Tyr356 residue of DHODH is crucial for piperine binding. Importantly, we show that piperine can inhibit T cell overactivation in a DHODH-dependent manner in concanavalin A-triggered T-cell assay and mixed lymphocyte reaction assay. Finally, piperine exhibits strong preventive and therapeutic effect in the MOG-induced experimental allergic encephalomyelitis (EAE), a useful model for studying potential treatments for MS, by restricting inflammatory cells infiltration into the CNS and preventing myelin destruction and blood–brain barrier (BBB) disruption. Taken together, these findings highlight DHODH as a therapeutic target for autoimmune disease of the nervous system, and demonstrate a novel role for piperine in the treatment of MS.