کد مقاله کد نشریه سال انتشار مقاله انگلیسی نسخه تمام متن
2509889 1557839 2014 11 صفحه PDF دانلود رایگان
عنوان انگلیسی مقاله ISI
Small molecule inhibition of Epstein–Barr virus nuclear antigen-1 DNA binding activity interferes with replication and persistence of the viral genome
موضوعات مرتبط
علوم زیستی و بیوفناوری ایمنی شناسی و میکروب شناسی ویروس شناسی
پیش نمایش صفحه اول مقاله
Small molecule inhibition of Epstein–Barr virus nuclear antigen-1 DNA binding activity interferes with replication and persistence of the viral genome
چکیده انگلیسی


• Characterized mechanisms of small molecules for inhibiting Epstein–Barr virus nuclear antigen 1 (EBNA1).
• H31 inhibited EBNA1 functions of DNA binding, transactivation, replication and support of viral genome persistence.
• It selectively suppressed the proliferation of EBV-infected cells.

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.

ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Antiviral Research - Volume 104, April 2014, Pages 73–83
نویسندگان
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