Small molecule inhibition of Epstein-Barr virus nuclear antigen-1 DNA binding activity interferes with replication and persistence of the viral genome.
Small molecule inhibition of Epstein-Barr virus nuclear antigen-1 DNA binding activity interferes with replication and persistence of the viral genome.
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DOI：
10.1016/j.antiviral.2014.01.018
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发表时间：
2014-04
影响因子：
7.6
通讯作者：
Kang, Myung-Soo
中科院分区：
文献类型：
--
作者：
Lee, Eun Kyung;Kim, Sun Young;Noh, Ka-Won;Joo, Eun Hye;Zhao, Bo;Kieff, Elliott;Kang, Myung-Soo
染色体外EB病毒（EBV）附加体在潜伏感染细胞中的复制和持久性主要取决于EBV编码的核抗原1（EBNA 1）与同源EBV oriP元件的结合。在先前研究的继续中，本文中我们表征EBNA 1小分子抑制剂（H20、H31）及其潜在的抑制机制。计算机对接分析预测，H20适合EBNA 1 DNA结合结构域（DBD）中的口袋。然而，H20并不显著影响EBNA 1与其同源序列的结合。H20的有限结构关系研究鉴定了疏水化合物H31作为EBNA 1抑制剂。体外EBNA 1 EMSA和体内EGFP-EBNA 1共聚焦显微镜分析表明，H31抑制EBNA 1依赖性oriP序列特异性DNA结合活性，但不抑制序列非特异性染色体结合。与此相一致，H31抑制了EBV oriP质粒的EBNA 1依赖性转录、复制和持久性。此外，H31诱导EBV附加体的进行性丢失。此外，H31选择性地延缓EBV感染的LCL或伯基特淋巴瘤细胞的生长。这些数据表明，H31抑制EBNA 1依赖性DNA结合降低了EBV感染细胞中EBV附加体的转录和持久性。这些新化合物可能是有用的探针解剖EBNA 1功能在体外和体内。
The replication and persistence of extra chromosomal Epstein-Barr virus (EBV) episome in latently infected cells are primarily dependent on the binding of EBV-encoded nuclear antigen 1 (EBNA1) to the cognate EBV oriP element. In continuation of the previous study, herein we characterized EBNA1 small molecule inhibitors (H20, H31) and their underlying inhibitory mechanisms. In silico docking analyses predicted that H20 fits into a pocket in the EBNA1 DNA binding domain (DBD). However, H20 did not significantly affect EBNA1 binding to its cognate sequence. A limited structure-relationship study of H20 identified a hydrophobic compound H31, as an EBNA1 inhibitor. An in vitro EBNA1 EMSA and in vivo EGFP-EBNA1 confocal microscopy analysis showed that H31 inhibited EBNA1-dependent oriP sequence-specific DNA binding activity, but not sequence-nonspecific chromosomal association. Consistent with this, H31 repressed the EBNA1-dependent transcription, replication, and persistence of an EBV oriP plasmid. Furthermore, H31 induced progressive loss of EBV episome. In addition, H31 selectively retarded the growth of EBV-infected LCL or Burkitt’s lymphoma cells. These data indicate that H31 inhibition of EBNA1-dependent DNA binding decreases transcription from and persistence of EBV episome in EBV-infected cells. These new compounds might be useful probes for dissecting EBNA1 functions in vitro and in vivo.
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影响因子：
64.5
作者：
Bochkarev, A;Barwell, JA;Edwards, AM
通讯作者：
Edwards, AM
影响因子：
6.7
作者：
Aras S;Singh G;Johnston K;Foster T;Aiyar A
通讯作者：
Aiyar A
影响因子：
6.4
作者：
GESER, A;DETHE, G;WILLIAMS, EH
通讯作者：
WILLIAMS, EH
DOI：
10.1073/pnas.72.4.1477
发表时间：
1975-01-01
影响因子：
11.1
作者：
ADAMS, A;LINDAHL, T
通讯作者：
LINDAHL, T
DOI：
10.1007/s00432-005-0036-x
发表时间：
2006-01-01
影响因子：
3.6
作者：
Hong, M;Murai, Y;Takano, Y
通讯作者：
Takano, Y