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Sci Transl Med. 2019 Mar 6;11(482). pii: eaau5612. doi: 10.1126/scitranslmed.aau5612.

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

Author information

1
The Wistar Institute, 3601 Spruce Street, Philadelphia, PA 19104, USA. lieberman@wistar.org troymessick@gmail.com.
2
Fox Chase Chemical Diversity Center Inc., 3805 Old Easton Road, Doylestown, PA 18902, USA.
3
The Wistar Institute, 3601 Spruce Street, Philadelphia, PA 19104, USA.
4
Vironika LLC, 3624 Market Street, Ste 5E, Philadelphia, PA 19104, USA.
5
Quantum Tessera Consulting LLC, 508 Tawnyberry Lane, Collegeville, PA 19426, USA.
6
Institut Gustave Roussy, 114 Rue Edouard Vaillant, 84800 Villejuif, France.

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-β (TGF-β) 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.

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