Molecular validation of novel Epstein-Barr virus (EBV) targets towards a lytic phase-directed antiviral drug development

• Applicant: Professor Dr. Manfred Marschall
• Subject Area: Virology
• Term: since 2025
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 566760749

Members of the family Herpesviridae represent major human pathogens that vary widely in their symptomatic features of infection. The clinically most complex and dominant species, Epstein-Barr virus (EBV) and human cytomegalovirus (HCMV), have continuously been considered as two herpesviruses of concern. While EBV is associated with malignant tumors and, as currently recognized, also with multiple sclerosis (MS), HCMV causes problematic infections during pregnancy and under immunodeficient situations. Vaccines are not licensed against both infections, while a crucial difference is given by the situation of therapy options. Although five anti-HCMV drugs have been clinically approved over the years, not a single effective EBV-specific treatment is available until today. Challenging factors in herpesviral pathogenesis are seen, on the one side, in the high viral load and productivity (typically HCMV), as well as, on the other side, in the long-term viral persistence based on non-productive, latent phases, including tumor association and immune-related symptoms (typically EBV). The latter situations may behave refractory to conventional antiviral treatment. Concerning EBV, it should be emphasized, however, that in addition to latency, distinct phases of high productivity are regularly occurring in permissive tissues, which are considered accessible to specific targeting by novel antiviral drugs. This distinct goal, which focuses on situations of lytic-type clinical problems of EBV infection, requires novel drug targeting strategies. Recently, we provided mechanistically new antiviral concepts and drug candidates for HCMV and other human herpesviruses. Such transfer of knowledge shall now likewise lead to the validation of novel EBV-specific antiviral target proteins. To this end, the project will aim at four promising targeting approaches, namely (i) the EBV-encoded protein kinase (BGLF4), (ii) the viral core nuclear egress complex (BFRF1–BFLF2), (iii) the host bridging factor (p32/gC1qR) that recruits BGLF4 to this egress complex, and (iv) associated host kinases that comprise a herpesvirus-supportive function (CDKs 2, 4/6, 7, 8, 9). Ultimately, this project shall answer the questions about favorable targeting options for putative inhibitory agents. The achievement of a positive target validation may open up so far unexploited ways of candidate strategies and the development of anti-EBV treatment in lytic replication-associated disease.

• DFG Programme: Research Grants