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

20 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

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Human Herpesvirus 4
Replication Origin
Plasmids
Ligands
DNA
Pyrroles
Nylons
Viral Genes
Oncogenes
B-Lymphocytes
Virus Diseases
Blood Cells
Maintenance
Genome
Pharmacology
Cell Line
imidazole
Neoplasms

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

DNA ligand designed to antagonize EBNA1 represses Epstein-Barr virus-induced immortalization. / Yasuda, Ai; Noguchi, Kohji; Minoshima, Masafumi; Kashiwazaki, Gengo; Kanda, Teru; Katayama, Kazuhiro; Mitsuhashi, Junko; Bando, Toshikazu; Sugiyama, Hiroshi; Sugimoto, Yoshikazu.

In: Cancer Science, Vol. 102, No. 12, 12.2011, p. 2221-2230.

Research output: Contribution to journalArticle

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, vol. 102, no. 12, pp. 2221-2230. https://doi.org/10.1111/j.1349-7006.2011.02098.x
Yasuda A, Noguchi K, Minoshima M, Kashiwazaki G, Kanda T, Katayama K et al. DNA ligand designed to antagonize EBNA1 represses Epstein-Barr virus-induced immortalization. Cancer Science. 2011 Dec;102(12):2221-2230. https://doi.org/10.1111/j.1349-7006.2011.02098.x
Yasuda, Ai ; Noguchi, Kohji ; Minoshima, Masafumi ; Kashiwazaki, Gengo ; Kanda, Teru ; Katayama, Kazuhiro ; Mitsuhashi, Junko ; Bando, Toshikazu ; Sugiyama, Hiroshi ; Sugimoto, Yoshikazu. / DNA ligand designed to antagonize EBNA1 represses Epstein-Barr virus-induced immortalization. In: Cancer Science. 2011 ; Vol. 102, No. 12. pp. 2221-2230.
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