Therapeutic Approaches to Targeting EBV Related Disease

Epstein-Barr virus infection is associated with several lymphoid and epithelial malignancies. The replication and persistence of the EBV genome in latently infected cells is dependent on the homodimer formation of EBV nuclear antigen 1 (EBNA1) and it’s binding to the cognate EBV OriP element. Current chemotherapeutic treatments of EBV-positive malignancies are not specific to the EBV status of the disease. EBNA1 has been considered as a driver for oncogenesis and is consistently detected in all EBVV-associated tumours. However, EBNA1 is able to regulate it’s own expression, both at transcriptional and translational levels. Our work focuses on controlling EBV-associated disease through the inhibition of EBNA1 expression or function. In order to inhibit function, the aim is to disrupt EBNA1 homodimer formation. To do this, we have designed and synthesised small peptides aimed to prevent EBNA1 homodimer formation and destabilise existing homodimers. These putative dimer inhibitory peptides (DIP), designed to mimic the proline-rich loop of the protein (which is thought to stabilise the dimer) are attached to the cell penetrating peptide TAT, to act as competitive inhibitors in the nucleus of infected cells. Data will be presented on the effect of these peptides in multiple EBV dependent and independent tumour B cell lines, with respect to cell penetration, cell viability and protein dimerisation. We have also been investigating agents that interfere with the unique self-regulatory mechanism of EBNA1 expression, and their potential as therapeutic drugs. These data will be presented. These studies may underpin novel approaches to treating EBV positive and dependent disease by inhibiting viral persistence, and possibly the cell survival properties of EBNA1