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

Journal of Medicinal Chemistry
Zhehong ChengPu Wang

Abstract

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. EBNA1 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 EBNA1-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.

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Citations

Dec 12, 2019·Proceedings of the National Academy of Sciences of the United States of America·Lijun JiangKa-Leung Wong
Nov 6, 2018·International Journal of Molecular Sciences·Xing-Xian GuoJing Li
Mar 15, 2020·The Journal of Immunology : Official Journal of the American Association of Immunologists·Xiaozhen HeQingguo Ruan
May 1, 2021·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Tao ZhangJian-Hua Ran
Jul 31, 2021·Biochemical and Biophysical Research Communications·Meiqing LiWu Su
Feb 12, 2019·Advanced Drug Delivery Reviews·Zutao YuHiroshi Sugiyama

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