Small molecule inhibition of Epstein-Barr virus nuclear antigen-1 DNA binding activity interferes with replication and persistence of the viral genome.
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.
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.
Eun Kyung
EK
Lee
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.
Sun Young
SY
Kim
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.
Ka-Won
KW
Noh
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.
Eun Hye
EH
Joo
Infectious Diseases Division, Brigham and Women's Hospital, Department of Medicine and Department of Microbiology and Molecular Genetics, Harvard Medical School, Boston, MA 02115.
Bo
B
Zhao
Infectious Diseases Division, Brigham and Women's Hospital, Department of Medicine and Department of Microbiology and Molecular Genetics, Harvard Medical School, Boston, MA 02115.
Elliott
E
Kieff
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.
Myung-Soo
MS
Kang
D000998:Antiviral Agents / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D001665:Binding Sites; D002460:Cell Line; D004261:DNA Replication / Q000187:drug effects*; D019309:Epstein-Barr Virus Nuclear Antigens / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D015967:Gene Expression Regulation, Viral / Q000187:drug effects; D016679:Genome, Viral; D004854:Herpesvirus 4, Human / Q000187:drug effects* / Q000502:physiology*; D006801:Humans; D008958:Models, Molecular; D008968:Molecular Conformation; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D013329:Structure-Activity Relationship; D014158:Transcription, Genetic / Q000187:drug effects; D014779:Virus Replication / Q000187:drug effects*
D000998:Antiviral Agents; D019309:Epstein-Barr Virus Nuclear Antigens; C417029:EBV-encoded nuclear antigen 1
EBNA1; EBV; Inhibitor; Persistence; Small molecule; oriP