A Mechanism-Based Targeted Screen To Identify Epstein-Barr Virus-Directed Antiviral Agents.

Autor:	Li X; Division of Infectious Diseases, Department of Pediatrics, University of Florida, Gainesville, Florida, USA., Akinyemi IA; Child Health Research Institute, Department of Pediatrics, University of Florida, Gainesville, Florida, USA., You JK; Department of Microbiology and Immunology, Stony Brook University, Stony Brook, New York, USA., Rezaei MA; Department of Medicinal Chemistry, College of Pharmacy, University of Florida, Gainesville, Florida, USA., Li C; Department of Medicinal Chemistry, College of Pharmacy, University of Florida, Gainesville, Florida, USA., McIntosh MT; Child Health Research Institute, Department of Pediatrics, University of Florida, Gainesville, Florida, USA.; Department of Molecular Genetics and Microbiology, University of Florida, Gainesville, Florida, USA., Del Poeta M; Department of Microbiology and Immunology, Stony Brook University, Stony Brook, New York, USA.; Division of Infectious Diseases, Stony Brook University, Stony Brook, New York, USA.; Veterans Administration Medical Center, Northport, New York, USA., Bhaduri-McIntosh S; Division of Infectious Diseases, Department of Pediatrics, University of Florida, Gainesville, Florida, USA sbhadurimcintosh@ufl.edu.; Department of Molecular Genetics and Microbiology, University of Florida, Gainesville, Florida, USA.
Jazyk:	angličtina
Zdroj:	Journal of virology [J Virol] 2020 Oct 14; Vol. 94 (21). Date of Electronic Publication: 2020 Oct 14 (Print Publication: 2020).
DOI:	10.1128/JVI.01179-20
Abstrakt:	Epstein-Barr virus (EBV) is one of nine human herpesviruses that persist latently to establish permanent residence in their hosts. Periodic activation into the lytic/replicative phase allows such viruses to propagate and spread, but can also cause disease in the host. This lytic phase is also essential for EBV to cause infectious mononucleosis and cancers, including B lymphocyte-derived Burkitt lymphoma and immunocompromise-associated lymphoproliferative diseases/lymphomas as well as epithelial cell-derived nasopharyngeal cell carcinoma. In the absence of anti-EBV agents, however, therapeutic options for EBV-related diseases are limited. In earlier work, we discovered that through the activities of the viral protein kinase conserved across herpesviruses and two cellular proteins, ATM and KAP1, a lytic cycle amplification loop is established, and disruption of this loop disables the EBV lytic cascade. We therefore devised a high-throughput screening assay, screened a small-molecule-compound library, and identified 17 candidates that impair the release of lytically replicated EBV. The identified compounds will (i) serve as lead compounds or may be modified to inhibit EBV and potentially other herpesviruses, and (ii) be developed into anticancer agents, as functions of KAP1 and ATM are tightly linked to cancer. Importantly, our screening strategy may also be used to screen additional compound libraries for antiherpesviral and anticancer drugs. IMPORTANCE Epstein-Barr virus, which is nearly ubiquitous in humans, is causal to infectious mononucleosis, chronic active EBV infection, and lymphoid and epithelial cancers. However, EBV-specific antiviral agents are not yet available. To aid in the identification of compounds that may be developed as antivirals, we pursued a mechanism-based approach. Since many of these diseases rely on EBV's lytic phase, we developed a high-throughput assay that is able to measure a key step that is essential for successful completion of EBV's lytic cascade. We used this assay to screen a library of small-molecule compounds and identified inhibitors that may be pursued for their anti-EBV and possibly even antiherpesviral potential, as this key mechanism appears to be common to several human herpesviruses. Given the prominent role of this mechanism in both herpesvirus biology and cancer, our screening assay may be used as a platform to identify both antiherpesviral and anticancer drugs. (Copyright © 2020 American Society for Microbiology.)
Databáze:	MEDLINE
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