Summary of probe development efforts to identify inhibitors of the Epstein-Barr virus nuclear antigen 1 (EBNA-1).
Name: Summary of probe development efforts to identify inhibitors of the Epstein-Barr virus nuclear antigen 1 (EBNA-1). ..more
Depositor Specified Assays
Source (MLPCN Center Name): The Scripps Research Institute Molecular Screening Center (SRIMSC)
Center Affiliation: The Scripps Research Institute (TSRI)
Assay Provider: Paul Lieberman, Wistar Institute
Network: Molecular Libraries Probe Production Centers Network (MLPCN)
Grant Proposal Number: I R21 NS063906-01
Grant Proposal PI: Paul Lieberman, Wistar Institute
External Assay ID: EBNA1_INH_POST-PRUN_SUMMARY
Name: Summary of probe development efforts to identify inhibitors of the Epstein-Barr virus nuclear antigen 1 (EBNA-1).
During each cell cycle in eukaryotes, the genome must be completely replicated and this replication must begin at the correct time and site (initiation site or origin) (1). Pathogenic viruses often take advantage of this cellular precision to maintain replication of their own genome. The Epstein-Barr virus (EBV) is an orally-transmitted herpesvirus associated with numerous human neoplasms (2) that infects over 90% of the world's population (3). Latent EBV infection stimulates B cell proliferation in vitro, and can lead to B cell transformation (4). Following infection, the EBV genome is maintained in the host cell as a plasmid that is replicated by machinery comprised of several host proteins and a sole EBV protein, the EBV nuclear antigen 1 (EBNA-1). This EBNA-1 protein is required for replication of the EBV DNA genome. EBNA-1 is a DNA-binding protein that binds to an EBV sequence called the viral origin of replication plasmid, OriP (5). Studies demonstrating a role for EBV in Burkitt's lymphoma and Hodgkin's disease (6), multiple sclerosis (7), lupus (8), infectious mononucleosis (9), and nasopharyngeal carcinoma (10), combined with the recent discovery that EBNA-1 induces DNA double strand breaks (11), suggest that inhibitors of EBNA-1 may serve useful for understanding virus-cell interactions, virus-mediated cellular transformation, and as therapies for EBV-associated pathologies.
Summary of Probe Development Effort:
Following primary HTS in singlicate to identify EBNA1 inhibitors (AID 1950), certain compounds were identified as candidates for probe development. Additional HTS assays and probe development efforts are currently underway.
1. Norseen, J, Thomae, A, Sridharan, V, Aiyar, A, Schepers, A and Lieberman, PM, RNA-dependent recruitment of the origin recognition complex. EMBO J, 2008. 27(22): p. 3024-35.
2. Carbone, A, Gloghini, A and Dotti, G, EBV-associated lymphoproliferative disorders: classification and treatment. Oncologist, 2008. 13(5): p. 577-85.
3. Schulz, TF and Cordes, S, Is the Epstein-Barr virus EBNA-1 protein an oncogene? Proc Natl Acad Sci U S A, 2009. 106(7): p. 2091-2.
4. Thorley-Lawson, DA and Babcock, GJ, A model for persistent infection with Epstein-Barr virus: the stealth virus of human B cells. Life Sci, 1999. 65(14): p. 1433-53.
5. Kirchmaier, AL and Sugden, B, Dominant-negative inhibitors of EBNA-1 of Epstein-Barr virus. J Virol, 1997. 71(3): p. 1766-75.
6. Hammerschmidt, W and Sugden, B, Epstein-Barr virus sustains Burkitt's lymphomas and Hodgkin's disease. Trends Mol Med, 2004. 10(7): p. 331-6.
7. Lunemann, JD, Kamradt, T, Martin, R and Munz, C, Epstein-barr virus: environmental trigger of multiple sclerosis? J Virol, 2007. 81(13): p. 6777-84.
8. Harley, JB, Harley, IT, Guthridge, JM and James, JA, The curiously suspicious: a role for Epstein-Barr virus in lupus. Lupus, 2006. 15(11): p. 768-77.
9. Vetsika, EK and Callan, M, Infectious mononucleosis and Epstein-Barr virus. Expert Rev Mol Med, 2004. 6(23): p. 1-16.
10. Raab-Traub, N, Epstein-Barr virus in the pathogenesis of NPC. Semin Cancer Biol, 2002. 12(6): p. 431-41.
11. Gruhne, B, Sompallae, R, Marescotti, D, Kamranvar, SA, Gastaldello, S and Masucci, MG, The Epstein-Barr virus nuclear antigen-1 promotes genomic instability via induction of reactive oxygen species. Proc Natl Acad Sci U S A, 2009. 106(7): p. 2313-8.
Summary AID, EBNA-1, EBNA1, EBNA, Epstein-Barr virus, EBV, herpesvirus, DNA virus, human herpesvirus 4, HHV4, lymphoma, cancers, inhibitors, inhibition, antagonists, fluorescence polarization, FP, primary, primary screen, HTS, high throughput screen, 1536, Scripps, Scripps Florida, The Scripps Research Institute Molecular Screening Center, SRIMSC, Molecular Libraries Probe Production Centers Network, MLPCN.
Details of protocols, compound structures, and results from the original assays can be found in PubChem at the respective AIDs. Please see AID 1950 for all protocols performed in this probe development effort.