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Structure-based design of small-molecule inhibitors of EBNA1 DNA binding blocks Epstein-Barr virus latent infection and tumor growth.

ABSTRACT: Epstein-Barr virus (EBV) is a DNA tumor virus responsible for 1 to 2% of human cancers including subtypes of Burkitt's lymphoma, Hodgkin's lymphoma, gastric carcinoma, and nasopharyngeal carcinoma (NPC). Persistent latent infection drives EBV-associated tumorigenesis. Epstein-Barr nuclear antigen 1 (EBNA1) is the only viral protein consistently expressed in all EBV-associated tumors and is therefore an attractive target for therapeutic intervention. It is a multifunctional DNA binding protein critical for viral replication, genome maintenance, viral gene expression, and host cell survival. Using a fragment-based approach and x-ray crystallography, we identify a 2,3-disubstituted benzoic acid series that selectively inhibits the DNA binding activity of EBNA1. We characterize these inhibitors biochemically and in cell-based assays, including chromatin immunoprecipitation and DNA replication assays. In addition, we demonstrate the potency of EBNA1 inhibitors to suppress tumor growth in several EBV-dependent xenograft models, including patient-derived xenografts for NPC. These inhibitors selectively block EBV gene transcription and alter the cellular transforming growth factor-? (TGF-?) signaling pathway in NPC tumor xenografts. These EBNA1-specific inhibitors show favorable pharmacological properties and have the potential to be further developed for the treatment of EBV-associated malignancies.

SUBMITTER: Messick TE

PROVIDER: S-EPMC6936217 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature

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Structure-based design of small-molecule inhibitors of EBNA1 DNA binding blocks Epstein-Barr virus latent infection and tumor growth.

Messick Troy E TE Smith Garry R GR Soldan Samantha S SS McDonnell Mark E ME Deakyne Julianna S JS Malecka Kimberly A KA Tolvinski Lois L van den Heuvel A Pieter J APJ Gu Bai-Wei BW Cassel Joel A JA Tran Donna H DH Wassermann Benjamin R BR Zhang Yan Y Velvadapu Venkata V Zartler Edward R ER Busson Pierre P Reitz Allen B AB Lieberman Paul M PM

Science translational medicine 20190301 482

Epstein-Barr virus (EBV) is a DNA tumor virus responsible for 1 to 2% of human cancers including subtypes of Burkitt's lymphoma, Hodgkin's lymphoma, gastric carcinoma, and nasopharyngeal carcinoma (NPC). Persistent latent infection drives EBV-associated tumorigenesis. Epstein-Barr nuclear antigen 1 (EBNA1) is the only viral protein consistently expressed in all EBV-associated tumors and is therefore an attractive target for therapeutic intervention. It is a multifunctional DNA binding protein cr ...[more]

PMID: 30842315

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Project description:As the second leading cause of death in the United States, cancer has a considerable impact on society, and one cellular process that is commonly dysregulated in many cancers is the post-translational modification of proteins by the Small Ubiquitin-like Modifier (SUMO; sumoylation). We documented that sumoylation processes are up-regulated in lymphoma tissues in the presence of Latent Membrane Protein-1 (LMP1), the principal oncoprotein of Epstein-Barr virus (EBV). LMP1-mediated dysregulation of cellular sumoylation processes contributes to oncogenesis, modulates innate immune responses, and aids the maintenance of viral latency. Manipulation of protein sumoylation has been proposed for anti-cancer and anti-viral therapies; however, known inhibitors of sumoylation do not only target sumoylation processes. Recently, a specific and selective small-molecule inhibitor of sumoylation (ML-792) was identified; however, nothing is known about the effect of ML-792 on LMP1-mediated dysregulation of cellular sumoylation or the EBV life-cycle. We hypothesized that ML-792 modulates viral replication and the oncogenic potential of EBV LMP1 by inhibiting protein sumoylation. Results showed that ML-792 inhibited sumoylation processes in multiple EBV-positive B cell lines and EBV-positive nasopharyngeal carcinoma cell lines but not in their EBV-negative counterparts. Focusing on its effect on B cells, ML-792 inhibited B-cell growth and promoted cell death at very low doses. ML-792 also modulated LMP1-induced cell migration and cell adhesion, which suggests the abrogation of the oncogenic potential of LMP1. Finally, while higher concentrations of ML-792 were sufficient to induce low levels EBV spontaneous reactivation, they decreased the production of new infectious virus following an induced reactivation and the infection of new cells, suggesting that ML-792 has anti-viral potential. Together, these findings suggest that ML-792 may be a potential therapeutic drug to treat EBV-associated lymphoid malignancies by targeting oncogenesis and the EBV life-cycle.

Project description:Epstein-Barr virus (EBV) is associated with multiple human malignancies. EBV latent membrane protein 1 (LMP1) is required for the efficient transformation of primary B lymphocytes in vitro and possibly in vivo The tumor suppressor p53 plays a seminal role in cancer development. In some EBV-associated cancers, p53 tends to be wild type and overly expressed; however, the effects of p53 on LMP1 expression is not clear. We find LMP1 expression to be associated with p53 expression in EBV-transformed cells under physiological and DNA damaging conditions. DNA damage stimulates LMP1 expression, and p53 is required for the stimulation. Ectopic p53 stimulates endogenous LMP1 expression. Moreover, endogenous LMP1 blocks DNA damage-mediated apoptosis. Regarding the mechanism of p53-mediated LMP1 expression, we find that interferon regulatory factor 5 (IRF5), a direct target of p53, is associated with both p53 and LMP1. IRF5 binds to and activates a LMP1 promoter reporter construct. Ectopic IRF5 increases the expression of LMP1, while knockdown of IRF5 leads to reduction of LMP1. Furthermore, LMP1 blocks IRF5-mediated apoptosis in EBV-infected cells. All of the data suggest that cellular p53 stimulates viral LMP1 expression, and IRF5 may be one of the factors for p53-mediated LMP1 stimulation. LMP1 may subsequently block DNA damage- and IRF5-mediated apoptosis for the benefits of EBV. The mutual regulation between p53 and LMP1 may play an important role in EBV infection and latency and its related cancers.IMPORTANCE The tumor suppressor p53 is a critical cellular protein in response to various stresses and dictates cells for various responses, including apoptosis. This work suggests that an Epstein-Bar virus (EBV) principal viral oncogene is activated by cellular p53. The viral oncogene blocks p53-mediated adverse effects during viral infection and transformation. Therefore, the induction of the viral oncogene by p53 provides a means for the virus to cope with infection and DNA damage-mediated cellular stresses. This seems to be the first report that p53 activates a viral oncogene; therefore, the discovery would be interesting to a broad readership from the fields of oncology to virology.

Dataset Information

Structure-based design of small-molecule inhibitors of EBNA1 DNA binding blocks Epstein-Barr virus latent infection and tumor growth.

Publications

Structure-based design of small-molecule inhibitors of EBNA1 DNA binding blocks Epstein-Barr virus latent infection and tumor growth.

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