Abstract | BACKGROUND: METHODOLOGY: Here, we report the identification of a new class of small molecules that inhibit EBNA1 DNA binding activity. These compounds were identified by virtual screening of 90,000 low molecular mass compounds using computational docking programs with the solved crystal structure of EBNA1. Four structurally related compounds were found to inhibit EBNA1-DNA binding in biochemical assays with purified EBNA1 protein. Compounds had a range of 20-100 microM inhibition of EBNA1 in fluorescence polarization assays and were further validated for inhibition using electrophoresis mobility shift assays. These compounds exhibited no significant inhibition of an unrelated DNA binding protein. Three of these compounds inhibited EBNA1 transcription activation function in cell-based assays and reduced EBV genome copy number when incubated with a Burkitt lymphoma cell line. CONCLUSIONS: These experiments provide a proof-of-principle that virtual screening can be used to identify specific inhibitors of EBNA1 that may have potential for treatment of EBV latent infection.
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Authors | Ning Li, Scott Thompson, David C Schultz, Weiliang Zhu, Hualiang Jiang, Cheng Luo, Paul M Lieberman |
Journal | PloS one
(PLoS One)
Vol. 5
Issue 4
Pg. e10126
(Apr 12 2010)
ISSN: 1932-6203 [Electronic] United States |
PMID | 20405039
(Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
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Chemical References |
- Epstein-Barr Virus Nuclear Antigens
- Viral Proteins
- DNA
- EBV-encoded nuclear antigen 1
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Topics |
- Burkitt Lymphoma
- Cell Line, Tumor
- Computer Simulation
- DNA
(metabolism)
- Drug Discovery
(methods)
- Drug Evaluation, Preclinical
(methods)
- Epstein-Barr Virus Infections
(drug therapy)
- Epstein-Barr Virus Nuclear Antigens
(drug effects)
- Herpesvirus 4, Human
- Humans
- Protein Binding
(drug effects)
- Transcription, Genetic
(drug effects)
- Viral Proteins
(antagonists & inhibitors)
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