Document text
Principal Investigator: Christopher Benton Whitehurst
Organization: NEW YORK MEDICAL COLLEGE
Fiscal Year: 2024
Award: $247,500
Funding agency: National Institute of Allergy and Infectious Diseases
Project Summary/Abstract
Epstein-Barr Virus (EBV), a human tumor virus, is the causative agent of mononucleosis and immunoblastic
lymphomas. EBV is strongly associated with Burkitt’s lymphoma, Hodgkin’s lymphoma, and nasopharyngeal
carcinoma (NPC). Additionally, recent studies suggest that EBV has a pathogenic role with the onset of Multiple
Sclerosis (MS). Approximately 90% of the world’s population is infected with EBV, but most do not present
disease. However, for those that do develop EBV-related illness there remains no directed small molecule
therapy. EBV-triggered disease, causing debilitating illness and death, remains a world-wide problem.
Interestingly, EBV expresses a unique protein (BPLF1) that possesses deubiquitinating activity. BPFL1 is known
to regulate both cellular and viral target activities, yet it remains largely unstudied. Our work has implicated
BPLF1 in a wide range of viral and cellular processes including infectivity (90% reduction with knockout of
BPLF1), viral DNA replication, and DNA repair. Also we recently reported surprising new findings that knockout
of BPLF1 delays and reduces human B-cell immortalization and lymphoma formation in humanized mice. The
aim of this proposal is to discover and characterize the first-in-world small molecule inhibitors of BPLF1
deubiquitinating activity. The goals of this proposal are to 1) use high throughput screening to identify novel
chemotypes for a lead optimization effort and 2) produce further validation that small molecule inhibition of BPLF1
deubiquitinating activity is a promising avenue for treating diseases caused by EBV infection. This work will lay
the foundation for a chemical probe and drug discovery effort to combat EBV-associated disease.
Terms: <APF-1><ATP-Dependent Proteolysis Factor 1><Active Follow-up><Affect><Assay><B blood cells><B cell><B cell immortalization><B cells><B lymphocyte immortalization><B-Cells><B-Lymphocytes><B-cell><Bioassay><Biological Assay><Burkitt Herpesvirus><Burkitt Lymphoma><Burkitt Lymphoma Virus><Burkitt Tumor><Burkitt's Lymphoma/Leukemia><Burkitt's Type Small Non-Cleaved Cell Lymphoma><COVID infected patient><COVID patient><COVID positive patient><COVID-19 infected patient><COVID-19 patient><COVID-19 positive patient><COVID19 patient><COVID19 positive patient><Cell Body><Cell Culture Techniques><Cell Function><Cell Physiology><Cell Process><Cell Survival><Cell Viability><Cells><Cellular Assay><Cellular Function><Cellular Physiology><Cellular Process><Cessation of life><Chemicals><DNA Damage Repair><DNA Repair><DNA Replication><DNA Synthesis><DNA biosynthesis><Data><Death><Deubiquitinating Enzyme><Diffuse Immunoblastic Lymphosarcoma><Disease><Disorder><Disseminated Sclerosis><Dose><Down-Regulation><EB virus><EBV><EBV Infections><EBV malignancies><EBV(+) malignancy><EBV-Related Malignancy><EBV-associated cancers><EBV-associated disease><EBV-associated malignancy><EBV-positive cancer><EBV-positive malignancy><EBV-positive malignant tumor><EBV-related cancer><Effectiveness><Enzyme Gene><Enzymes><Epstein Barr Virus><Epstein Barr Virus Malignancy><Epstein Barr Virus associated cancers><Epstein Barr Virus positive cancer><Epstein-Barr Virus Infections><Epstein-Barr Virus associated disease><Epstein-Barr Virus associated malignancy><Epstein-Barr Virus-Related Malignancy><Epstein-Barr Virus-Related Malignant Neoplasm><Epstein-Barr viral infections><Fluorescence><Foundations><Future><GeneHomolog><Generations><Germinoblastic Sarcoma><Germinoblastoma><Glandular Fever><Goals><HHV-4><HHV4><HMG-20><Herpesviridae><Herpesviruses><High Mobility Protein 20><High Throughput Assay><Hodgkin Disease><Hodgkin Disorder><Hodgkin lymphoma><Hodgkin's><Hodgkin's Lymphoma><Hodgkin's disease><Hodgkins lymphoma><Homolog><Homologous Gene><Homologue><Human><Human Herpesvirus 4><IFN><Immune Diseases><Immune Disorders><Immune Dysfunction><Immune System Diseases><Immune System Disorder><Immune System Dysfunction><Immune System and Related Disorders><Immunoblastic Lymphoma><Immunoblastic Sarcoma><Immunoblastoma><Immunoblotting><Immunodeficiency and Immunosuppression Disorders><Immunologic Diseases><Immunological Diseases><Immunological Dysfunction><Immunological System Dysfunction><In Vitro><Individual><Infection><Infectious Agent><Infectious Mononucleosis><Infectious Mononucleosis Virus><Interferons><Knock-out><Knockout><Large-Cell Immunoblastic Lymphoma><Libraries><Long COVID><Long COVID-19><Long coronavirus disease><Long coronavirus disease 2019><Lymphoma><Lytic Cycle><Lytic Infection><Lytic Phase><Malignant Lymphogranuloma><Malignant Lymphoma><Measures><Medical><Modern Man><Monitor><Multiple Sclerosis><Nasopharyngeal Carcinoma><Nasopharynx Carcinoma><Oncogenic Viruses><Pathogenesis><Pathogenicity><Persons><Plasmablastic Lymphoma><Population><Process><Proteins><Reporting><Research><Reticulolymphosarcoma><Rhodamine><Role><Running><S Period><S phase><SARS-CoV-2 infected patient><SARS-CoV-2 patient><SARS-CoV-2 positive patient><Source><Subcellular Process><Synthesis Period><Synthesis Phase><Testing><Therapeutic><Toxic effect><Toxicities><Tumor Viruses><Ubiquitilation><Ubiquitin><Ubiquitination><Ubiquitinoylation><United States><Unscheduled DNA Synthesis><Validation><Viral><Viral Diseases><Viral Genome><Virus><Virus Diseases><Western Blotting><Western Immunoblotting><Work><active followup><analog><assay development><cell assay><cell culture><cell cultures><chronic COVID><chronic COVID-19><chronic infection><chronic novel coronavirus disease 2019><combat><coronavirus disease 2019 infected patient><coronavirus disease 2019 patient><coronavirus disease 2019 positive patient><coronavirus disease infected patient><coronavirus disease patient><coronavirus disease positive patient><coronavirus disease-19 patient><coronavirus patient><de-ubiquitinase><de-ubiquitinating enzyme><drug discovery><drug repositioning><drug repurposing><enzyme activity><follow up><follow-up><followed up><followup><gamma-herpesvirus><gammaherpesvirus><herpes virus><high throughput screening><humanized mice><humanized mouse><immunosuppressed><improved><infectious organism><inhibitor><innovate><innovation><innovative><insular sclerosis><lead optimization><life-threatening COVID><life-threatening COVID-19><life-threatening SARS-CoV-2><life-threatening coronavirus disease><life-threatening coronavirus disease 2019><life-threatening severe acute respiratory syndrome coronavirus 2><long haul COVID><long haul COVID-19><long haul coronavirus disease><long haul coronavirus disease 2019><long-hauler COVID><long-hauler COVID-19><long-hauler coronavirus disease 2019><long-hauler syndrome><long-term COVID><long-term COVID-19><long-term coronavirus disease><long-term coronavirus disease 2019><longterm COVID><longterm COVID-19><longterm coronavirus disease><longterm coronavirus disease 2019><member><meter><mononucleosis><new approaches><novel><novel approaches><novel strategies><novel strategy><oncogenic tumor virus><patient infected with COVID><patient infected with COVID-19><patient infected with SARS-CoV-2><patient infected with coronavirus disease><patient infected with coronavirus disease 2019><patient infected with severe acute respiratory syndrome coronavirus 2><patient with COVID><patient with COVID-19><patient with COVID19><patient with SARS-CoV-2><patient with coronavirus disease><patient with coronavirus disease 2019><patient with severe acute respiratory distress syndrome coronavirus 2><persistent COVID-19><persistent infection><post COVID syndrome><post COVID-19 syndrome><post acute COVID syndrome><post acute COVID-19><post acute COVID-19 syndrome><post acute SARS-CoV-2><post acute coronavirus disease 2019><post acute coronavirus disease 2019 syndrome><post acute coronavirus disease syndrome><post acute severe acute respiratory syndrome coronavirus 2><post coronavirus disease 2019 syndrome><post coronavirus disease syndrome><post-acute phases of COVID-19><prolonged COVID-19 symptoms><protein blotting><repurposing agent><repurposing medication><response><serious COVID><serious COVID-19><serious SARS-CoV-2><serious coronavirus disease><serious coronavirus disease 2019><serious severe acute respiratory syndrome coronavirus 2><severe COVID><severe COVID-19><severe COVID19><severe SARS-CoV-2><severe acute respiratory syndrome coronavirus 2 infected patient><severe acute respiratory syndrome coronavirus 2 patient><severe acute respiratory syndrome coronavirus 2 positive patient><severe coronavirus disease><severe coronavirus disease 19><severe coronavirus disease 2019><severe severe acute respiratory syndrome coronavirus 2><small molecular inhibitor><small molecule><small molecule inhibitor><social role><synergism><targeted drug therapy><targeted drug treatments><targeted therapeutic><targeted therapeutic agents><targeted therapy><targeted treatment><ubiquination><ubiquitin conjugation><ubiquitin isopeptidase><ubiquitin-specific isopeptidase><validations><viral DNA><viral infection><virology><virus DNA><virus genome><virus infection><virus-induced disease><γ-herpesvirus>