DNA ligand designed to antagonize EBNA1 represses Epstein-Barr virus-induced immortalization

Ai Yasuda, Kohji Noguchi, Masafumi Minoshima, Gengo Kashiwazaki, Teru Kanda, Kazuhiro Katayama, Junko Mitsuhashi, Toshikazu Bando, Hiroshi Sugiyama, Yoshikazu Sugimoto

Research output: Contribution to journalArticle

22 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)2221-2230
Number of pages10
JournalCancer science
Volume102
Issue number12
DOIs
Publication statusPublished - 2011 Dec 1

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Yasuda, A., Noguchi, K., Minoshima, M., Kashiwazaki, G., Kanda, T., Katayama, K., Mitsuhashi, J., Bando, T., Sugiyama, H., & Sugimoto, Y. (2011). DNA ligand designed to antagonize EBNA1 represses Epstein-Barr virus-induced immortalization. Cancer science, 102(12), 2221-2230. https://doi.org/10.1111/j.1349-7006.2011.02098.x