核苷类似物对西尼罗河病毒甲基转移酶的选择性抑制。
Selective inhibition of the West Nile virus methyltransferase by nucleoside analogs.
机构信息
Wadsworth Center, New York State Department of Health, 120 New Scotland Ave., Albany, NY 12208, USA.
出版信息
Antiviral Res. 2013 Mar;97(3):232-9. doi: 10.1016/j.antiviral.2012.12.012. Epub 2012 Dec 22.
Abstract
The flavivirus methyltransferase (MTase) sequentially methylates the N-7 and 2'-O positions of the viral RNA cap (GpppA-RNA→m(7)GpppA-RNA→m(7)GpppAm-RNA), using S-adenosyl-l-methionine (SAM) as a methyl donor. We report here the synthesis and biological evaluation of a series of novel nucleoside analogs. Two of these compounds can effectively and competitively inhibit the WNV MTase with IC50 values in micromolar range and, more importantly, do not inhibit human MTase. The compounds can also suppress the WNV replication in cell culture.
摘要
黄病毒甲基转移酶（MTase）依次对病毒 RNA 帽的 N-7 和 2'-O 位进行甲基化（GpppA-RNA→m(7)GpppA-RNA→m(7)GpppAm-RNA），使用 S-腺苷甲硫氨酸（SAM）作为甲基供体。我们在此报告了一系列新型核苷类似物的合成和生物学评价。其中两种化合物可以有效且竞争性地抑制 WNV MTase，IC50 值为微摩尔级，更重要的是，它们不抑制人 MTase。这些化合物还可以抑制细胞培养中的 WNV 复制。
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本文引用的文献
1
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J Chem Theory Comput. 2011 Dec 13;7(12):4026-37. doi: 10.1021/ct200196m. Epub 2011 Nov 15.
2
Flavivirus RNA cap methyltransferase: structure, function, and inhibition.黄病毒RNA帽甲基转移酶：结构、功能及抑制作用
Front Biol (Beijing). 2010 Aug 1;5(4):286-303. doi: 10.1007/s11515-010-0660-y.
3
Small molecule inhibitors that selectively block dengue virus methyltransferase.选择性阻断登革病毒甲基转移酶的小分子抑制剂。
J Biol Chem. 2011 Feb 25;286(8):6233-40. doi: 10.1074/jbc.M110.179184. Epub 2010 Dec 8.
4
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PLoS One. 2010 Sep 17;5(9):e12836. doi: 10.1371/journal.pone.0012836.
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Chem Commun (Camb). 2010 Feb 28;46(8):1218-20. doi: 10.1039/b924807b. Epub 2010 Jan 25.
7
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9
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J Med Chem. 2010 Feb 25;53(4):1483-95. doi: 10.1021/jm900776m.
10
Hill coefficients, dose-response curves and allosteric mechanisms.希尔系数、剂量反应曲线与别构机制
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