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Small molecule inhibition of Epstein-Barr virus nuclear antigen-1 DNA binding activity interferes with replication and persistence of the viral genome.
Antiviral Res. 2014 Apr; 104:73-83.AR

Abstract

The replication and persistence of extra chromosomal Epstein-Barr virus (EBV) episome in latently infected cells are primarily dependent on the binding of EBV-encoded nuclear antigen 1 (EBNA1) to the cognate EBV oriP element. In continuation of the previous study, herein we characterized EBNA1 small molecule inhibitors (H20, H31) and their underlying inhibitory mechanisms. In silico docking analyses predicted that H20 fits into a pocket in the EBNA1 DNA binding domain (DBD). However, H20 did not significantly affect EBNA1 binding to its cognate sequence. A limited structure-relationship study of H20 identified a hydrophobic compound H31, as an EBNA1 inhibitor. An in vitro EBNA1 EMSA and in vivo EGFP-EBNA1 confocal microscopy analysis showed that H31 inhibited EBNA1-dependent oriP sequence-specific DNA binding activity, but not sequence-nonspecific chromosomal association. Consistent with this, H31 repressed the EBNA1-dependent transcription, replication, and persistence of an EBV oriP plasmid. Furthermore, H31 induced progressive loss of EBV episome. In addition, H31 selectively retarded the growth of EBV-infected LCL or Burkitt's lymphoma cells. These data indicate that H31 inhibition of EBNA1-dependent DNA binding decreases transcription from and persistence of EBV episome in EBV-infected cells. These new compounds might be useful probes for dissecting EBNA1 functions in vitro and in vivo.

Authors+Show Affiliations

Samsung Advanced Institute for Health Sciences and Technology (SAIHST) and Samsung Biomedical Research Institute (SBRI), Samsung Medical Center, Sungkyunkwan University School of Medicine, 50 Irwon-dong, Gangnam-gu, Seoul Korea 135-710.Samsung Advanced Institute for Health Sciences and Technology (SAIHST) and Samsung Biomedical Research Institute (SBRI), Samsung Medical Center, Sungkyunkwan University School of Medicine, 50 Irwon-dong, Gangnam-gu, Seoul Korea 135-710.Samsung Advanced Institute for Health Sciences and Technology (SAIHST) and Samsung Biomedical Research Institute (SBRI), Samsung Medical Center, Sungkyunkwan University School of Medicine, 50 Irwon-dong, Gangnam-gu, Seoul Korea 135-710.Samsung Advanced Institute for Health Sciences and Technology (SAIHST) and Samsung Biomedical Research Institute (SBRI), Samsung Medical Center, Sungkyunkwan University School of Medicine, 50 Irwon-dong, Gangnam-gu, Seoul Korea 135-710.Infectious Diseases Division, Brigham and Women's Hospital, Department of Medicine and Department of Microbiology and Molecular Genetics, Harvard Medical School, Boston, MA 02115.Infectious Diseases Division, Brigham and Women's Hospital, Department of Medicine and Department of Microbiology and Molecular Genetics, Harvard Medical School, Boston, MA 02115.Samsung Advanced Institute for Health Sciences and Technology (SAIHST) and Samsung Biomedical Research Institute (SBRI), Samsung Medical Center, Sungkyunkwan University School of Medicine, 50 Irwon-dong, Gangnam-gu, Seoul Korea 135-710. Infectious Diseases Division, Brigham and Women's Hospital, Department of Medicine and Department of Microbiology and Molecular Genetics, Harvard Medical School, Boston, MA 02115.

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

24486954

Citation

Lee, Eun Kyung, et al. "Small Molecule Inhibition of Epstein-Barr Virus Nuclear Antigen-1 DNA Binding Activity Interferes With Replication and Persistence of the Viral Genome." Antiviral Research, vol. 104, 2014, pp. 73-83.
Lee EK, Kim SY, Noh KW, et al. Small molecule inhibition of Epstein-Barr virus nuclear antigen-1 DNA binding activity interferes with replication and persistence of the viral genome. Antiviral Res. 2014;104:73-83.
Lee, E. K., Kim, S. Y., Noh, K. W., Joo, E. H., Zhao, B., Kieff, E., & Kang, M. S. (2014). Small molecule inhibition of Epstein-Barr virus nuclear antigen-1 DNA binding activity interferes with replication and persistence of the viral genome. Antiviral Research, 104, 73-83. https://doi.org/10.1016/j.antiviral.2014.01.018
Lee EK, et al. Small Molecule Inhibition of Epstein-Barr Virus Nuclear Antigen-1 DNA Binding Activity Interferes With Replication and Persistence of the Viral Genome. Antiviral Res. 2014;104:73-83. PubMed PMID: 24486954.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Small molecule inhibition of Epstein-Barr virus nuclear antigen-1 DNA binding activity interferes with replication and persistence of the viral genome. AU - Lee,Eun Kyung, AU - Kim,Sun Young, AU - Noh,Ka-Won, AU - Joo,Eun Hye, AU - Zhao,Bo, AU - Kieff,Elliott, AU - Kang,Myung-Soo, Y1 - 2014/01/31/ PY - 2013/10/17/received PY - 2013/12/12/revised PY - 2014/01/06/accepted PY - 2014/2/4/entrez PY - 2014/2/4/pubmed PY - 2014/11/5/medline KW - EBNA1 KW - EBV KW - Inhibitor KW - Persistence KW - Small molecule KW - oriP SP - 73 EP - 83 JF - Antiviral research JO - Antiviral Res VL - 104 N2 - The replication and persistence of extra chromosomal Epstein-Barr virus (EBV) episome in latently infected cells are primarily dependent on the binding of EBV-encoded nuclear antigen 1 (EBNA1) to the cognate EBV oriP element. In continuation of the previous study, herein we characterized EBNA1 small molecule inhibitors (H20, H31) and their underlying inhibitory mechanisms. In silico docking analyses predicted that H20 fits into a pocket in the EBNA1 DNA binding domain (DBD). However, H20 did not significantly affect EBNA1 binding to its cognate sequence. A limited structure-relationship study of H20 identified a hydrophobic compound H31, as an EBNA1 inhibitor. An in vitro EBNA1 EMSA and in vivo EGFP-EBNA1 confocal microscopy analysis showed that H31 inhibited EBNA1-dependent oriP sequence-specific DNA binding activity, but not sequence-nonspecific chromosomal association. Consistent with this, H31 repressed the EBNA1-dependent transcription, replication, and persistence of an EBV oriP plasmid. Furthermore, H31 induced progressive loss of EBV episome. In addition, H31 selectively retarded the growth of EBV-infected LCL or Burkitt's lymphoma cells. These data indicate that H31 inhibition of EBNA1-dependent DNA binding decreases transcription from and persistence of EBV episome in EBV-infected cells. These new compounds might be useful probes for dissecting EBNA1 functions in vitro and in vivo. SN - 1872-9096 UR - https://www.unboundmedicine.com/medline/citation/24486954/Small_molecule_inhibition_of_Epstein_Barr_virus_nuclear_antigen_1_DNA_binding_activity_interferes_with_replication_and_persistence_of_the_viral_genome_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0166-3542(14)00030-8 DB - PRIME DP - Unbound Medicine ER -