选择性阻断登革病毒甲基转移酶的小分子抑制剂。
Small molecule inhibitors that selectively block dengue virus methyltransferase.
机构信息
Novartis Institute for Tropical Diseases, 05-01 Chromos, Singapore.
出版信息
J Biol Chem. 2011 Feb 25;286(8):6233-40. doi: 10.1074/jbc.M110.179184. Epub 2010 Dec 8.
Abstract
Crystal structure analysis of Flavivirus methyltransferases uncovered a flavivirus-conserved cavity located next to the binding site for its cofactor, S-adenosyl-methionine (SAM). Chemical derivatization of S-adenosyl-homocysteine (SAH), the product inhibitor of the methylation reaction, with substituents that extend into the identified cavity, generated inhibitors that showed improved and selective activity against dengue virus methyltransferase (MTase), but not related human enzymes. Crystal structure of dengue virus MTase with a bound SAH derivative revealed that its N6-substituent bound in this cavity and induced conformation changes in residues lining the pocket. These findings demonstrate that one of the major hurdles for the development of methyltransferase-based therapeutics, namely selectivity for disease-related methyltransferases, can be overcome.
摘要
黄病毒甲基转移酶的晶体结构分析揭示了一个位于其辅助因子 S-腺苷甲硫氨酸（SAM）结合位点附近的黄病毒保守腔。对甲基化反应产物抑制剂 S-腺苷同型半胱氨酸（SAH）进行取代基化学衍生，这些取代基延伸到鉴定出的腔中，生成了对登革热病毒甲基转移酶（MTase）具有改善和选择性活性的抑制剂，但对相关的人类酶没有活性。与结合的 SAH 衍生物的登革热病毒 MTase 的晶体结构表明，其 N6-取代基结合在该腔中，并诱导口袋中残基的构象变化。这些发现表明，基于甲基转移酶的治疗方法的主要障碍之一，即对疾病相关甲基转移酶的选择性，可以被克服。
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J Biol Chem. 2010 Oct 15;285(42):32586-95. doi: 10.1074/jbc.M110.129197. Epub 2010 Aug 4.
2
Biochemical and genetic characterization of dengue virus methyltransferase.登革热病毒甲基转移酶的生化和遗传特征。
Virology. 2010 Sep 30;405(2):568-78. doi: 10.1016/j.virol.2010.06.039. Epub 2010 Jul 23.
3
Characterization of dengue virus resistance to brequinar in cell culture.在细胞培养中鉴定登革热病毒对布雷喹纳的抗性。
Antimicrob Agents Chemother. 2010 Sep;54(9):3686-95. doi: 10.1128/AAC.00561-10. Epub 2010 Jul 6.
4
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Virology. 2010 Jun 20;402(1):52-60. doi: 10.1016/j.virol.2010.03.011. Epub 2010 Mar 29.
5
Structure and functionality in flavivirus NS-proteins: perspectives for drug design.黄病毒NS蛋白的结构与功能：药物设计的前景
Antiviral Res. 2010 Aug;87(2):125-48. doi: 10.1016/j.antiviral.2009.11.009. Epub 2009 Nov 27.
6
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Nat Rev Drug Discov. 2009 Sep;8(9):724-32. doi: 10.1038/nrd2974.
7
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8
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J Mol Biol. 2009 Feb 6;385(5):1643-54. doi: 10.1016/j.jmb.2008.11.058. Epub 2008 Dec 11.
9
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10
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