title: DNA ligand designed to antagonize EBNA1 represses Epstein-Barr virus-induced immortalization.
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.affiliation: Division of Chemotherapy, Keio University, Tokyo, Japan.
authors.forename: Ai
authors.initials: A
authors.lastname: Yasuda
authors.forename: Kohji
authors.initials: K
authors.lastname: Noguchi
authors.forename: Masafumi
authors.initials: M
authors.lastname: Minoshima
authors.forename: Gengo
authors.initials: G
authors.lastname: Kashiwazaki
authors.forename: Teru
authors.initials: T
authors.lastname: Kanda
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Katayama
authors.forename: Junko
authors.initials: J
authors.lastname: Mitsuhashi
authors.forename: Toshikazu
authors.initials: T
authors.lastname: Bando
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Sugiyama
authors.forename: Yoshikazu
authors.initials: Y
authors.lastname: Sugimoto
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000502:physiology / Q000821:virology*; D001483:Base Sequence; D001665:Binding Sites; D002144:Callithrix; D002460:Cell Line; D002472:Cell Transformation, Viral / Q000187:drug effects*; D004261:DNA Replication; D004279:DNA, Viral / Q000235:genetics / Q000378:metabolism*; D019309:Epstein-Barr Virus Nuclear Antigens / Q000378:metabolism*; D004854:Herpesvirus 4, Human / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007093:Imidazoles / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology*; D007963:Leukocytes, Mononuclear / Q000502:physiology / Q000821:virology; D009757:Nylons / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology*; D011758:Pyrroles / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology*; D018741:Replication Origin / Q000187:drug effects; D014779:Virus Replication
chemical_list: D004279:DNA, Viral; C569393:DSE-3 compound; D019309:Epstein-Barr Virus Nuclear Antigens; D007093:Imidazoles; D009757:Nylons; D011758:Pyrroles; C417029:EBV-encoded nuclear antigen 1