The Cytomegalovirus Protein Kinase pUL97: Host Interactions, Regulatory Mechanisms and Antiviral Drug Targeting

Abstract

Human cytomegalovirus (HCMV) expresses a variety of viral regulatory proteins that undergo close interaction with host factors including viral-cellular multiprotein complexes. The HCMV protein kinase pUL97 represents a viral cyclin-dependent kinase ortholog (vCDK) that determines the efficiency of HCMV replication via phosphorylation of viral and cellular substrates. A hierarchy of functional importance of individual pUL97-mediated phosphorylation events has been discussed; however, the most pronounced pUL97-dependent phenotype could be assigned to viral nuclear egress, as illustrated by deletion of the UL97 gene or pharmacological pUL97 inhibition. Despite earlier data pointing to a cyclin-independent functionality, experimental evidence increasingly emphasized the role of pUL97-cyclin complexes. Consequently, the knowledge about pUL97 involvement in host interaction, viral nuclear egress and additional replicative steps led to the postulation of pUL97 as an antiviral target. Indeed, validation experiments in vitro and in vivo confirmed the sustainability of this approach. Consequently, current investigations of pUL97 in antiviral treatment go beyond the known pUL97-mediated ganciclovir prodrug activation and henceforward include pUL97-specific kinase inhibitors. Among a number of interesting small molecules analyzed in experimental and preclinical stages, maribavir is presently investigated in clinical studies and, in the near future, might represent a first kinase inhibitor applied in the field of antiviral therapy.

Combinatorial Drug Treatments Reveal Promising Anticytomegaloviral Profiles for Clinically Relevant Pharmaceutical Kinase Inhibitors (PKIs)

“…These were most intensely investigated for anti-HCMV effects but also against other viruses [ 23 , 24 , 25 , 37 , 38 , 39 , 40 , 41 ]. A broad spectrum of antiviral efficacy was revealed as a typical hallmark of HDAs, with PKIs repeatedly showing a promising profile of activity [ 30 , 31 , 42 , 43 , 44 , 45 , 46 , 47 ]. Building on this experience, we investigated several PKIs for antiviral activity here, focusing on a small number of drugs currently under preclinical (CDK7 inhibitor LDC4297) or clinical investigation (MBV) or approved for antitumoral therapy (ABE).…”

“…While a substantial characterization of the antiviral properties of MBV and LDC4297 in vitro and in vivo has been reported [ 30 , 31 , 42 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 ], any similar antiviral activity of ABE has not yet been assessed. To this end, the in vitro and in vivo inhibitory properties of ABE were determined against HCMV and MCMV, respectively.…”

The Artemisinin-Derived Autofluorescent Compound BG95 Exerts Strong Anticytomegaloviral Activity Based on a Mitochondrial Targeting Mechanism

“…Data indicate that HCMV infection in general has a stimulatory impact on ATP levels in HFFs. Importantly, BG95 showed an inhibitory effect on ATP-dependent reporter signals, which was distinct from the treatment with reference drugs, such as GCV, maribavir (MBV, an inhibitor of viral kinase activity; [ 66 ]) or SC88941 (a host-directed antiviral compound possessing a complex spectrum of target protein binding; [ 67 ]). Thus, the ATP-reducing activity of BG95 was found specific compared to other antiviral drugs and was similarly detectable for HCMV-infected and mock-infected cells.…”

Nuclear Egress Complexes of HCMV and Other Herpesviruses: Solving the Puzzle of Sequence Coevolution, Conserved Structures and Subfamily-Spanning Binding Properties

“…During recent years, the HCMV-encoded protein kinase pUL97 has been suggested as another highly interesting drug target, such that kinase inhibitors with pUL97 specificity, derived from independent chemical classes, have been profoundly characterized towards their clinical investigation [7]. Maribavir (MBV) is a benzimidazole riboside, structurally related to the terminase inhibitor LMV.…”

“…Thus, HCMV disease manifestations can range from self-limiting febrile periods to fatal end-organ disease. So far, no vaccine has been approved for the prevention of HCMV infections and although anti-HCMV drugs are available, problems of unwarranted side-effects or drug-induced viral resistance mutations interfere with the success of therapy and the mechanistic repertoire of approved drugs is still limited [5][6][7]. This underlines the need for novel anticytomegaloviral/antiherpesviral strategies and accessible target proteins.…”