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Discovery of Selective Inhibitors Against EBNA1 via High Throughput In Silico Virtual Screening

BACKGROUND: Epstein-Barr Virus (EBV) latent infection is associated with several human malignancies and is a causal agent of lymphoproliferative diseases during immunosuppression. While inhibitors of herpesvirus DNA polymerases, like gancyclovir, reduce EBV lytic cycle infection, these treatments ha...

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Detalles Bibliográficos
Autores principales: Li, Ning, Thompson, Scott, Schultz, David C., Zhu, Weiliang, Jiang, Hualiang, Luo, Cheng, Lieberman, Paul M.
Formato: Texto
Lenguaje:English
Publicado: Public Library of Science 2010
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2853575/
https://www.ncbi.nlm.nih.gov/pubmed/20405039
http://dx.doi.org/10.1371/journal.pone.0010126
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author Li, Ning
Thompson, Scott
Schultz, David C.
Zhu, Weiliang
Jiang, Hualiang
Luo, Cheng
Lieberman, Paul M.
author_facet Li, Ning
Thompson, Scott
Schultz, David C.
Zhu, Weiliang
Jiang, Hualiang
Luo, Cheng
Lieberman, Paul M.
author_sort Li, Ning
collection PubMed
description BACKGROUND: Epstein-Barr Virus (EBV) latent infection is associated with several human malignancies and is a causal agent of lymphoproliferative diseases during immunosuppression. While inhibitors of herpesvirus DNA polymerases, like gancyclovir, reduce EBV lytic cycle infection, these treatments have limited efficacy for treating latent infection. EBNA1 is an EBV-encoded DNA-binding protein required for viral genome maintenance during latent infection. 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 µM 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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spelling pubmed-28535752010-04-19 Discovery of Selective Inhibitors Against EBNA1 via High Throughput In Silico Virtual Screening Li, Ning Thompson, Scott Schultz, David C. Zhu, Weiliang Jiang, Hualiang Luo, Cheng Lieberman, Paul M. PLoS One Research Article BACKGROUND: Epstein-Barr Virus (EBV) latent infection is associated with several human malignancies and is a causal agent of lymphoproliferative diseases during immunosuppression. While inhibitors of herpesvirus DNA polymerases, like gancyclovir, reduce EBV lytic cycle infection, these treatments have limited efficacy for treating latent infection. EBNA1 is an EBV-encoded DNA-binding protein required for viral genome maintenance during latent infection. 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 µM 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. Public Library of Science 2010-04-12 /pmc/articles/PMC2853575/ /pubmed/20405039 http://dx.doi.org/10.1371/journal.pone.0010126 Text en Li et al. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Li, Ning
Thompson, Scott
Schultz, David C.
Zhu, Weiliang
Jiang, Hualiang
Luo, Cheng
Lieberman, Paul M.
Discovery of Selective Inhibitors Against EBNA1 via High Throughput In Silico Virtual Screening
title Discovery of Selective Inhibitors Against EBNA1 via High Throughput In Silico Virtual Screening
title_full Discovery of Selective Inhibitors Against EBNA1 via High Throughput In Silico Virtual Screening
title_fullStr Discovery of Selective Inhibitors Against EBNA1 via High Throughput In Silico Virtual Screening
title_full_unstemmed Discovery of Selective Inhibitors Against EBNA1 via High Throughput In Silico Virtual Screening
title_short Discovery of Selective Inhibitors Against EBNA1 via High Throughput In Silico Virtual Screening
title_sort discovery of selective inhibitors against ebna1 via high throughput in silico virtual screening
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2853575/
https://www.ncbi.nlm.nih.gov/pubmed/20405039
http://dx.doi.org/10.1371/journal.pone.0010126
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