Development of Cell-Active N6-Methyladenosine RNA Demethylase FTO Inhibitor
Development of Cell-Active N6-Methyladenosine RNA Demethylase FTO Inhibitor
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细胞活性 N6-甲基腺苷 RNA 去甲基酶 FTO 抑制剂的开发。
DOI：
10.1021/ja3064149
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发表时间：
2012-10-31
影响因子：
15
通讯作者：
Yang, Cai-Guang
中科院分区：
文献类型：
--
作者：
Chen, Baoen;Ye, Fei;Yang, Cai-Guang
直接核酸修复双加氧酶（FTO）是一种在体外和细胞内对mRNA中n -6-甲基腺苷（m(6)A）残基进行去甲基化的酶。FTO是第一个在哺乳动物中也起主要调节作用的RNA去甲基酶。结合基于结构的虚拟筛选和生化分析，我们首次发现了几种人类FTO去甲基化酶的小分子抑制剂。最有效的化合物是天然产物大黄酸，它既不是2-氧戊二酸的结构模拟物，也不是金属离子的螯合剂，在体外竞争性地结合到FTO活性位点。莱茵对细胞内m(6)A去甲基化也表现出良好的抑制活性。这些研究揭示了在RNA生物学和药物发现中使用的强大探针和新疗法的发展。
The direct nucleic acid repair dioxygenase FTO is an enzyme that demethylates N-6-methyladenosine (m(6)A) residues in mRNA in vitro and inside cells. FTO is the first RNA demethylase discovered that also serves a major regulatory function in mammals. Together with structure-based virtual screening and biochemical analyses, we report the first identification of several small-molecule inhibitors of human FTO demethylase. The most potent compound, the natural product rhein, which is neither a structural mimic of 2-oxoglutarate nor a chelator of metal ion, competitively binds to the FTO active site in vitro. Rhein also exhibits good inhibitory activity on m(6)A demethylation inside cells. These studies shed light on the development of powerful probes and new therapies for use in RNA biology and drug discovery.