DNA ligand designed to antagonize EBNA1 represses Epstein–Barr virus‐induced immortalization
DNA ligand designed to antagonize EBNA1 represses Epstein–Barr virus‐induced immortalization
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DOI：
10.1111/j.1349-7006.2011.02098.x
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发表时间：
2011-12
期刊：
影响因子：
5.7
通讯作者：
Ai Yasuda;K. Noguchi;Masafumi Minoshima;Gengo Kashiwazaki;T. Kanda;K. Katayama;J. Mitsuhashi;T. Bando;H. Sugiyama;Y. Sugimoto
中科院分区：
文献类型：
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作者：
Ai Yasuda;K. Noguchi;Masafumi Minoshima;Gengo Kashiwazaki;T. Kanda;K. Katayama;J. Mitsuhashi;T. Bando;H. Sugiyama;Y. Sugimoto
EB病毒（Epstein-Barr virus，EBV）在体外可将人B淋巴细胞转化为永生化细胞，在体内可引起多种恶性肿瘤。EBNA 1在大多数EBV感染的细胞中表达，识别EBV基因组顺式作用的潜在质粒复制起点（oriP）元件处的特异性DNA序列。EBNA 1在病毒附加体维持中起关键作用，并在潜伏感染的细胞中反式激活病毒转化基因。因此，能够破坏EBNA 1-oriP相互作用的DNA靶向剂将提供EBNA 1的新型功能性抑制剂。吡咯-咪唑聚酰胺，序列特异性DNA配体，可以被设计成干扰各种转录因子的结合。在这里，我们合成了靶向EBNA 1结合的DNA序列的吡咯-咪唑聚酰胺，并开发了EBNA 1-oriP相互作用的抑制剂。一种吡咯-咪唑聚酰胺，命名为DSE-3，与位于oriP的二分体对称元件中的EBNA 1识别序列相邻结合，并在体外和体内选择性抑制EBNA 1-oriP结合。DSE-3还通过从细胞中消除EBV附加体来抑制已建立的淋巴母细胞样细胞系的增殖。此外，在用EBV感染人外周血单核细胞后，DSE-3抑制病毒转化基因的表达，从而抑制EBV介导的B-细胞永生化。这些结果表明，EBNA 1功能将成为EBV相关疾病的一个有吸引力的药理学靶点。（Cancer Sci 2011; 102：2221-2230）
Epstein–Barr virus (EBV) transforms human B lymphocytes into immortalized cells in vitro and is associated with various malignancies in vivo. EBNA1, which is expressed in the majority of EBV‐infected cells, recognizes specific DNA sequences at the cis‐acting latent origin of plasmid replication (oriP) element of the EBV genome. EBNA1 plays a critical role in the viral episome maintenance and transactivates viral transforming genes in latently infected cells. Therefore, DNA‐targeting agents that can disrupt the EBNA1–oriP interaction will offer novel functional inhibitors of EBNA1. Pyrrole–imidazole polyamides, sequence‐specific DNA ligands, can be designed to interfere with the binding of various transcriptional factors. Here, we synthesized pyrrole–imidazole polyamides targeting EBNA1‐bound DNA sequences and developed an inhibitor for the EBNA1–oriP interaction. A pyrrole‐imidazole polyamide, designated as DSE‐3, bound adjacent to the EBNA1 recognition sequences located in the dyad symmetry element of oriP, and selectively inhibited EBNA1–oriP binding both in vitro and in vivo. DSE‐3 also inhibited the proliferation of established lymphoblastoid cell lines by eradicating EBV episomes from the cells. In addition, DSE‐3 repressed the expression of viral transforming genes after infecting human peripheral blood mononuclear cells with EBV and, as a consequence, inhibited EBV‐mediated B‐cell immortalization. These results suggest that EBNA1 functions will be an attractive pharmacological target for EBV‐associated diseases. (Cancer Sci 2011; 102: 2221–2230)