Identification of compounds with anti-human cytomegalovirus activity that inhibit production of IE2 proteins.
Identification of compounds with anti-human cytomegalovirus activity that inhibit production of IE2 proteins.
复制标题
鉴定具有抗人巨细胞病毒活性、抑制 IE2 蛋白产生的化合物。
DOI：
10.1016/j.antiviral.2016.12.006
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发表时间：
2017-02
影响因子：
7.6
通讯作者：
Strang BL
中科院分区：
文献类型：
--
作者：
Beelontally R;Wilkie GS;Lau B;Goodmaker CJ;Ho CMK;Swanson CM;Deng X;Wang J;Gray NS;Davison AJ;Strang BL
使用高通量筛选方法，我们调查了一个集合，主要是未经表征的验证或怀疑激酶抑制剂的抗人巨细胞病毒（HCMV）的活动。从该筛选中，我们鉴定了三种结构相关的5-氨基吡嗪化合物（XMD 7 -1、XMD 7 - 2和XMD 7 - 27），其在低微摩尔浓度下在病毒产量降低测定中抑制HCMV复制。激酶选择性测定表明，每种化合物都是能够抑制一系列细胞蛋白激酶的激酶抑制剂。Western印迹和RNA测序证明，用XMD 7化合物处理感染的细胞导致主要HCMV转录反式激活因子IE 2蛋白（IE 2 -86、IE 2 -60和IE 2 -40）的产生缺陷，以及病毒基因组转录的总体减少。然而，某些病毒蛋白质的产生不受用XMD 7化合物处理的损害。因此，这些新的抗HCMV化合物可能抑制病毒基因组的转录，并通过抑制IE 2蛋白的产生来抑制病毒蛋白亚类的产生。高通量筛选鉴定了抑制HCMV蛋白产生的新型激酶抑制剂。5-氨基吡嗪化合物（XMD 7 -1、XMD 7 - 2和XMD 7 - 27）具有抗HCMV活性。XMD 7化合物抑制HCMV IE 2蛋白的产生。
Using a high throughput screening methodology we surveyed a collection of largely uncharacterized validated or suspected kinase inhibitors for anti-human cytomegalovirus (HCMV) activity. From this screen we identified three structurally related 5-aminopyrazine compounds (XMD7-1, -2 and -27) that inhibited HCMV replication in virus yield reduction assays at low micromolar concentrations. Kinase selectivity assays indicated that each compound was a kinase inhibitor capable of inhibiting a range of cellular protein kinases. Western blotting and RNA sequencing demonstrated that treatment of infected cells with XMD7 compounds resulted in a defect in the production of the major HCMV transcriptional transactivator IE2 proteins (IE2-86, IE2-60 and IE2-40) and an overall reduction in transcription from the viral genome. However, production of certain viral proteins was not compromised by treatment with XMD7 compounds. Thus, these novel anti-HCMV compounds likely inhibited transcription from the viral genome and suppressed production of a subset of viral proteins by inhibiting IE2 protein production. High throughput screening identified novel kinase inhibitors that inhibit HCMV protein production. 5-aminopyrazine compounds (XMD7-1, -2 and -27) have anti-HCMV activity. XMD7 compounds inhibited production of HCMV IE2 proteins.