Project Details
Projekt
Exploring the cytomegalovirus-specific nuclear egress complex as a central determinant of viral replication efficiency and host interaction
Subject Area
Virology
Biochemistry
Biochemistry
Term
since 2018
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 396049570
The human cytomegalovirus (HCMV) and other herpesviruses evolved elaborate mechanisms of the nucleocytoplasmic egress of viral particles. The two conserved viral nuclear egress proteins, pUL50 and pUL53, play a central role in this process. The heterodimeric assembly of pUL50 and pUL53 forms the core of the HCMV-specific nuclear egress complex (NEC), which is anchored to the inner nuclear membrane, and provides a scaffold for the assembly of viral and cellular NEC-associated components. Crystal structures of the globular domains of the pUL50-pUL53 heterodimer, as well as of related herpesviral NECs, revealed unique structural and functional properties. Research in the previous funding period was focused on refining our knowledge of the effector mechanism of viral nuclear egress, as well as on exploring the herpesviral NEC as a target to generate virus-specific or broad-spectrum active NEC-directed drugs. Indeed, our most recent results provided a validation of this concept and demonstrated that small molecules can serve as powerful NEC-blocking agents, consequently exerting pronounced antiviral activity. With this continuation proposal, we intend to further expand this understanding by an interdisciplinary molecular analysis of the HCMV-specific and related herpesviral core NECs. The NEC functions will be addressed using several scientific approaches, including virology, medicinal chemistry, structural biology, as well as bioinformatics, to further explore the role of the NEC as a central determinant of viral replication efficiency. In essence, modern techniques of virus recombination and protein/peptide design will be applied to gain improved insight into NEC fine-regulatory properties. This may open up so far untapped opportunities to highlight herpesviral mechanisms of host cell interaction and virulence. Eventually the project should contribute to develop interfering strategies against these medically very relevant human infections.
DFG Programme
Research Grants
