The phospho-dynamics of cytomegalovirus capsid interaction, with its protein kinase and nuclear egress complex, provide an antiviral targeting concept

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Human cytomegalovirus (HCMV) is a major pathogen with worldwide distribution. Improved insight into antiviral targeting is urgently needed for drug development. Viral nuclear capsid egress is a validated target for new small molecules, including the approved viral kinase inhibitor maribavir (MBV). A detailed understanding of the regulatory interplay between HCMV kinase activity (pUL97), the nuclear egress complex (NEC), and viral capsids is pertinent in this regard. Specifically, the egress-based protein–protein interactions represent a virus rate-limiting determinant. The conserved process of nuclear capsid egress is defined by the interaction between the capsid and NEC, as well as an essential regulatory impact of pUL97 phosphorylation. Using recombinant virus analysis systems, we demonstrated the proteins responsible for NEC–capsid binding. The data indicated that the core NEC component pUL53 acts as the primary capsid interactor. Importantly, MBV revealed a dependence on phosphorylation for individual steps in these interactive processes. Of particular note, we used the highly selective mode of MBV in the study to identify pUL97 as a key factor in the regulation of NEC–capsid interaction. The findings also included the direct pUL97–capsid association, as supported by data from protein assembly assays, in vitro kinase reactions, comprehensive microscopy, and bioinformatic modeling of available structures. Finally, the determination of phosphorylated versus nonphosphorylated states of involved proteins led to a more refined understanding of the mechanistic concept of HCMV nuclear capsid egress. Combined, the study may improve our understanding of viral replication efficacy and mechanisms of antiviral drug activity. • Maribavir, the latest approved anti-HCMV drug, is the first antiviral kinase inhibitor • Current data support that the antiviral activity of maribavir targets the viral nuclear egress • Identification of direct viral kinase interaction with the nuclear egress complex (NEC) • Phosphorylation-specific dynamics of capsid interaction with NEC and viral kinase • Mechanistics of maribavir reveal insights into newly defined antiviral targeting options

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