Novel Pyrrole-Imidazole Polyamide Hoechst Conjugate Suppresses Epstein-Barr Virus Replication and Virus-Positive Tumor Growth

被引：9

作者：

Cheng, Zhehong ^{[1
,2
]}

Wang, Wei ^{[1
]}

Wu, Chunlei ^{[1
]}

Zou, Xiaohua ^{[3
]}

Fang, Lijing ^{[1
]}

Su, Wu ^{[1
]}

Wang, Pu ^{[3
]}

机构：

[1] Shenzhen Inst Adv Technol, Inst Biomed & Biotechnol, Guangdong Key Lab Nanomed, Shenzhen 518055, Guangdong, Peoples R China

[2] Univ Chinese Acad Sci, Shenzhen Coll Adv Technol, Shenzhen 518055, Guangdong, Peoples R China

[3] Chinese Acad Sci, Shenzhen Inst Adv Technol, Inst Biomed & Biotechnol, Shenzhen Lab Antibody Engn, Shenzhen 518055, Guangdong, Peoples R China

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2018年 / 61卷 / 15期

基金：

中国国家自然科学基金;

关键词：

DNA MINOR-GROOVE; INHIBITS PROLIFERATION; SEQUENCE RECOGNITION; EBNA1; CELLS; GENE; TRANSCRIPTION; PROMOTER; ORIGIN; EXPRESSION;

D O I：

10.1021/acs.jmedchem.8b00496

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Epstein Barr virus (EBV) establishes latent infection and is associated with several types of lymphomas and carcinomas. EBV nuclear antigen 1 (EBNA1) is expressed in all EBV-positive tumor cells. EBNAI binds to the origin of virus plasmid replication (OriP) on the EBV episome to initiate virus DNA replication and regulates virus gene expression as a transcriptional activator. In this study, we designed and synthesized a pyrrole imidazole polyamide Hoechst 33258 conjugate named EIP-2 (2), which specifically binds to the OriP region with high affinity, to interrupt EBNAI-OriP binding in vitro and in vivo. By eradicating the EBV episome in EBV-positive cells, compound 2 selectively inhibited EBV-positive cell proliferation. Moreover, the injection of 2 significantly suppressed tumor growth in the mice xenograft tumor model. These findings demonstrate that compound 2 is a potential therapeutic candidate for the treatment of EBV-associated tumors.

引用

页码：6674 / 6684

页数：11

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