Flaviviral methyltransferase/RNA interaction: structural basis for enzyme inhibition.
Flaviviral methyltransferase/RNA interaction: structural basis for enzyme inhibition.
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DOI：
10.1016/j.antiviral.2009.03.001
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发表时间：
2009-07
影响因子：
7.6
通讯作者：
Bolognesi M
中科院分区：
文献类型：
--
作者：
Milani M;Mastrangelo E;Bollati M;Selisko B;Decroly E;Bouvet M;Canard B;Bolognesi M
黄病毒是登革热或黄热病等严重疾病的病原体。该病毒使用的复制机制基于几种酶，包括位于 NS5 蛋白 N 末端结构域的甲基转移酶。黄病毒甲基转移酶参与 mRNA 加帽过程的最后两个步骤，将甲基从 S-腺苷-l-甲硫氨酸转移到帽鸟嘌呤的 N7 位置（鸟嘌呤-N7 甲基转移酶）以及帽鸟嘌呤之后的第一个核苷酸的核糖 2'O 位置（核苷-2'O 甲基转移酶）。 RNA 加帽过程对于 mRNA 稳定性、蛋白质合成和病毒复制至关重要。这种重要的功能使甲基转移酶成为抗病毒药物设计的有吸引力的靶标。在此背景下，我们从Wesselsbron黄病毒甲基转移酶的晶体结构出发，详细阐述了描述N7甲基转移过程中蛋白质/RNA相互作用的机制模型。接下来，我们使用计算机对接程序来识别对甲基转移酶活性位点表现出高亲和力的市售化合物。所选的最佳候选物经过体外测试，以测定它们对韦塞尔斯布朗和登革热病毒 (Dv) 甲基转移酶的 2'O 和 N7 甲基转移酶活性的有效抑制。这种结合计算和实验筛选方法的结果导致了高效抑制剂的鉴定。
Flaviviruses are the causative agents of severe diseases such as Dengue or Yellow fever. The replicative machinery used by the virus is based on few enzymes including a methyltransferase, located in the N-terminal domain of the NS5 protein. Flaviviral methyltransferases are involved in the last two steps of the mRNA capping process, transferring a methyl group from S-adenosyl-l-methionine onto the N7 position of the cap guanine (guanine-N7 methyltransferase) and the ribose 2′O position of the first nucleotide following the cap guanine (nucleoside-2′O methyltransferase). The RNA capping process is crucial for mRNA stability, protein synthesis and virus replication. Such an essential function makes methyltransferases attractive targets for the design of antiviral drugs. In this context, starting from the crystal structure of Wesselsbron flavivirus methyltransferase, we elaborated a mechanistic model describing protein/RNA interaction during N7 methyl transfer. Next we used an in silico docking procedure to identify commercially available compounds that would display high affinity for the methyltransferase active site. The best candidates selected were tested in vitro to assay their effective inhibition on 2′O and N7 methyltransferase activities on Wesselsbron and Dengue virus (Dv) methyltransferases. The results of such combined computational and experimental screening approach led to the identification of a high-potency inhibitor.
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影响因子：
7.6
作者：
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作者：
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通讯作者：
GOODFORD, PJ