Cargando…
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...
Autores principales: | , , , , , , |
---|---|
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 |
_version_ | 1782180049542184960 |
---|---|
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. |
format | Text |
id | pubmed-2853575 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2010 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
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 |
work_keys_str_mv | AT lining discoveryofselectiveinhibitorsagainstebna1viahighthroughputinsilicovirtualscreening AT thompsonscott discoveryofselectiveinhibitorsagainstebna1viahighthroughputinsilicovirtualscreening AT schultzdavidc discoveryofselectiveinhibitorsagainstebna1viahighthroughputinsilicovirtualscreening AT zhuweiliang discoveryofselectiveinhibitorsagainstebna1viahighthroughputinsilicovirtualscreening AT jianghualiang discoveryofselectiveinhibitorsagainstebna1viahighthroughputinsilicovirtualscreening AT luocheng discoveryofselectiveinhibitorsagainstebna1viahighthroughputinsilicovirtualscreening AT liebermanpaulm discoveryofselectiveinhibitorsagainstebna1viahighthroughputinsilicovirtualscreening |