Electrophile Modulation of Inflammation: A Two-Hit Approach.
Electrophile Modulation of Inflammation: A Two-Hit Approach.
复制标题
DOI：
10.3390/metabo10110453
复制
发表时间：
2020-11-10
期刊：
影响因子：
4.1
通讯作者：
Wendell SG
中科院分区：
文献类型：
--
作者：
O'Brien J;Wendell SG
亲电小分子在过去十年中在共价药物发现领域获得了显著的关注。长期以来被认为是炎症过程的介质，最近的证据表明，亲电体可以通过调节代谢网络来调节免疫反应。这些分子充当多效性信号传导介质，能够与亲核生物分子可逆地反应，最显著地在反应性半胱氨酸处。更具体地说，亲电体靶向氧化还原调节蛋白中的关键半胱氨酸，以激活保护性途径，如核因子红细胞2相关因子2-Kelch样ECH相关蛋白1（Nrf 2-Keap 1）抗氧化剂信号传导途径，同时还抑制核因子κB（NF-κB）。在炎症状态期间，活性物质通过脂质、氨基酸和核酸的氧化广泛地改变细胞信号传导，有效地传播炎症序列。代谢信号传导的后续变化告知免疫细胞成熟和效应器功能。靶向炎性病理的治疗策略利用亲电药物化合物，部分原因是它们对细胞氧化还原平衡的作用。随着越来越多的证据表明氧化还原信号传导和代谢之间的联系，亲电体代表了治疗炎症性疾病的理想治疗候选物。通过它们的多效性信号传导活性，亲电体可以策略性地用于直接和间接靶向免疫细胞代谢。
Electrophilic small molecules have gained significant attention over the last decade in the field of covalent drug discovery. Long recognized as mediators of the inflammatory process, recent evidence suggests that electrophiles may modulate the immune response through the regulation of metabolic networks. These molecules function as pleiotropic signaling mediators capable of reversibly reacting with nucleophilic biomolecules, most notably at reactive cysteines. More specifically, electrophiles target critical cysteines in redox regulatory proteins to activate protective pathways such as the nuclear factor erythroid 2-related factor 2-Kelch-like ECH-associated protein 1 (Nrf2-Keap1) antioxidant signaling pathway while also inhibiting Nuclear Factor κB (NF-κB). During inflammatory states, reactive species broadly alter cell signaling through the oxidation of lipids, amino acids, and nucleic acids, effectively propagating the inflammatory sequence. Subsequent changes in metabolic signaling inform immune cell maturation and effector function. Therapeutic strategies targeting inflammatory pathologies leverage electrophilic drug compounds, in part, because of their documented effect on the redox balance of the cell. With mounting evidence demonstrating the link between redox signaling and metabolism, electrophiles represent ideal therapeutic candidates for the treatment of inflammatory conditions. Through their pleiotropic signaling activity, electrophiles may be used strategically to both directly and indirectly target immune cell metabolism.
登录
查看更多内容
DOI：
10.1126/science.1211485
发表时间：
2011-12-02
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Anastasiou D;Poulogiannis G;Asara JM;Boxer MB;Jiang JK;Shen M;Bellinger G;Sasaki AT;Locasale JW;Auld DS;Thomas CJ;Vander Heiden MG;Cantley LC
通讯作者：
Cantley LC
影响因子：
5.3
作者：
Bhargava, Pavan;Fitzgerald, Kathryn C.;Calabresi, Peter A.
通讯作者：
Calabresi, Peter A.
影响因子：
32.4
作者：
Buckley, Christopher D.;Gilroy, Derek W.;Serhan, Charles N.
通讯作者：
Serhan, Charles N.
影响因子：
7.3
作者：
Blewett MM;Xie J;Zaro BW;Backus KM;Altman A;Teijaro JR;Cravatt BF
通讯作者：
Cravatt BF
影响因子：
4.6
作者：
Ball, Michael S.;Bhandari, Rajan;Pioli, Patricia A.
通讯作者：
Pioli, Patricia A.