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Biophysical Screens Identify Fragments That Bind to the Viral DNA-Binding Proteins EBNA1 and LANA
The human gamma-herpesviruses Epstein–Barr virus (EBV) (HHV-4) and Kaposi’s sarcoma-associated herpesvirus (KSHV) (HHV-8) are responsible for a number of diseases, including various types of cancer. Epstein–Barr nuclear antigen 1 (EBNA1) from EBV and latency-associated nuclear antigen (LANA) from KS...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7180839/ https://www.ncbi.nlm.nih.gov/pubmed/32290261 http://dx.doi.org/10.3390/molecules25071760 |
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author | Messick, Troy E. Tolvinski, Lois Zartler, Edward R. Moberg, Anna Frostell, Åsa Smith, Garry R. Reitz, Allen B. Lieberman, Paul M. |
author_facet | Messick, Troy E. Tolvinski, Lois Zartler, Edward R. Moberg, Anna Frostell, Åsa Smith, Garry R. Reitz, Allen B. Lieberman, Paul M. |
author_sort | Messick, Troy E. |
collection | PubMed |
description | The human gamma-herpesviruses Epstein–Barr virus (EBV) (HHV-4) and Kaposi’s sarcoma-associated herpesvirus (KSHV) (HHV-8) are responsible for a number of diseases, including various types of cancer. Epstein–Barr nuclear antigen 1 (EBNA1) from EBV and latency-associated nuclear antigen (LANA) from KSHV are viral-encoded DNA-binding proteins that are essential for the replication and maintenance of their respective viral genomes during latent, oncogenic infection. As such, EBNA1 and LANA are attractive targets for the development of small-molecule inhibitors. To this end, we performed a biophysical screen of EBNA1 and LANA using a fragment library by saturation transfer difference (STD)–NMR spectroscopy and surface plasmon resonance (SPR). We identified and validated a number of unique fragment hits that bind to EBNA1 or LANA. We also determined the high-resolution crystal structure of one fragment bound to EBNA1. Results from this screening cascade provide new chemical starting points for the further development of potent inhibitors for this class of viral proteins. |
format | Online Article Text |
id | pubmed-7180839 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-71808392020-05-01 Biophysical Screens Identify Fragments That Bind to the Viral DNA-Binding Proteins EBNA1 and LANA Messick, Troy E. Tolvinski, Lois Zartler, Edward R. Moberg, Anna Frostell, Åsa Smith, Garry R. Reitz, Allen B. Lieberman, Paul M. Molecules Article The human gamma-herpesviruses Epstein–Barr virus (EBV) (HHV-4) and Kaposi’s sarcoma-associated herpesvirus (KSHV) (HHV-8) are responsible for a number of diseases, including various types of cancer. Epstein–Barr nuclear antigen 1 (EBNA1) from EBV and latency-associated nuclear antigen (LANA) from KSHV are viral-encoded DNA-binding proteins that are essential for the replication and maintenance of their respective viral genomes during latent, oncogenic infection. As such, EBNA1 and LANA are attractive targets for the development of small-molecule inhibitors. To this end, we performed a biophysical screen of EBNA1 and LANA using a fragment library by saturation transfer difference (STD)–NMR spectroscopy and surface plasmon resonance (SPR). We identified and validated a number of unique fragment hits that bind to EBNA1 or LANA. We also determined the high-resolution crystal structure of one fragment bound to EBNA1. Results from this screening cascade provide new chemical starting points for the further development of potent inhibitors for this class of viral proteins. MDPI 2020-04-10 /pmc/articles/PMC7180839/ /pubmed/32290261 http://dx.doi.org/10.3390/molecules25071760 Text en © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Messick, Troy E. Tolvinski, Lois Zartler, Edward R. Moberg, Anna Frostell, Åsa Smith, Garry R. Reitz, Allen B. Lieberman, Paul M. Biophysical Screens Identify Fragments That Bind to the Viral DNA-Binding Proteins EBNA1 and LANA |
title | Biophysical Screens Identify Fragments That Bind to the Viral DNA-Binding Proteins EBNA1 and LANA |
title_full | Biophysical Screens Identify Fragments That Bind to the Viral DNA-Binding Proteins EBNA1 and LANA |
title_fullStr | Biophysical Screens Identify Fragments That Bind to the Viral DNA-Binding Proteins EBNA1 and LANA |
title_full_unstemmed | Biophysical Screens Identify Fragments That Bind to the Viral DNA-Binding Proteins EBNA1 and LANA |
title_short | Biophysical Screens Identify Fragments That Bind to the Viral DNA-Binding Proteins EBNA1 and LANA |
title_sort | biophysical screens identify fragments that bind to the viral dna-binding proteins ebna1 and lana |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7180839/ https://www.ncbi.nlm.nih.gov/pubmed/32290261 http://dx.doi.org/10.3390/molecules25071760 |
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