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DNA ligand designed to antagonize EBNA1 represses Epstein-Barr virus-induced immortalization.
Cancer Sci. 2011 Dec; 102(12):2221-30.CS

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.

Authors+Show Affiliations

Division of Chemotherapy, Keio University, Tokyo, Japan.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

21910783

Citation

Yasuda, Ai, et al. "DNA Ligand Designed to Antagonize EBNA1 Represses Epstein-Barr Virus-induced Immortalization." Cancer Science, vol. 102, no. 12, 2011, pp. 2221-30.
Yasuda A, Noguchi K, Minoshima M, et al. DNA ligand designed to antagonize EBNA1 represses Epstein-Barr virus-induced immortalization. Cancer Sci. 2011;102(12):2221-30.
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), 2221-30. https://doi.org/10.1111/j.1349-7006.2011.02098.x
Yasuda A, et al. DNA Ligand Designed to Antagonize EBNA1 Represses Epstein-Barr Virus-induced Immortalization. Cancer Sci. 2011;102(12):2221-30. PubMed PMID: 21910783.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - DNA ligand designed to antagonize EBNA1 represses Epstein-Barr virus-induced immortalization. AU - Yasuda,Ai, AU - Noguchi,Kohji, AU - Minoshima,Masafumi, AU - Kashiwazaki,Gengo, AU - Kanda,Teru, AU - Katayama,Kazuhiro, AU - Mitsuhashi,Junko, AU - Bando,Toshikazu, AU - Sugiyama,Hiroshi, AU - Sugimoto,Yoshikazu, Y1 - 2011/09/30/ PY - 2011/9/14/entrez PY - 2011/9/14/pubmed PY - 2012/1/21/medline SP - 2221 EP - 30 JF - Cancer science JO - Cancer Sci VL - 102 IS - 12 N2 - 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. SN - 1349-7006 UR - https://www.unboundmedicine.com/medline/citation/21910783/DNA_ligand_designed_to_antagonize_EBNA1_represses_Epstein_Barr_virus_induced_immortalization_ L2 - https://doi.org/10.1111/j.1349-7006.2011.02098.x DB - PRIME DP - Unbound Medicine ER -