Development of a Small Molecule Inhibitor for EBV Lytic Reactivation

Period of Performance: 08/19/2016 - 07/31/2017

$300K

Phase 1 SBIR

Recipient Firm

Vironika, LLC
Philadelphia, PA 19104
Principal Investigator

Abstract

Abstract:The goal of this SBIR research program is to develop a novel small molecule inhibitor of lytic Epstein-BarrVirus (EBV) infection. EBV is a ubiquitous gamma-herpesvirus that has been classified by the World HealthOrganization as a human carcinogen. Vironika, with its consortium partners the Wistar Institute and Fox ChaseChemical Diversity Center, Inc., will develop a highly specific and potent inhibitor of EBV lytic (re)activation thatwill provide an important therapeutic strategy to treat EBV-associated diseases. EBV infection is associatedwith multiple human malignancies, including Burkitt's lymphoma, nasopharyngeal carcinomas, Hodgkin'slymphoma, gastric carcinomas, and immunoblastic B-cell lymphoma's during immunosuppression. Currently,no EBV-specific therapies exist that target lytic (re)activation, and therefore it remains impossible to effectivelytreat or prevent EBV-associated disease. The lytic infection depends on a viral encoded protein, ZTA, whichfunctions in the (re)activation of the lytic virus cycle. The binding domain of this protein has been characterizedstructurally and biochemically, and serves as an ideal molecule for targeted small molecule inhibition of EBVinfection. We have screened over 420,000 compounds in our primary HTS screen. Preliminary hits werefiltered by counterscreen, and cherry picked and validated in triplicate single concentration assay formats.Among the 42 hits that passed these criteria, three chemotypes were identified. In this Phase 1 proposal, wewill further validate these hits and generate focused libraries to advance a lead compound using medicinalchemistry methods and extensive biochemical and biological analysis to validate mechanism of drug action. InPhase 2, we will develop our advanced leads into a pre-clinical lead candidate. The ultimate goal of this SBIRprogram is to develop a novel small molecule therapeutic agent to treat lytic EBV infection and its associatedmalignancies.