Maribavir: A Novel Antiviral Agent with Activity Against Cytomegalovirus

Trofe, Jennifer; Pote, Lindsey; Wade, Erin L; Blumberg, Emily A.; Bloom, Roy D.

doi:10.1345/aph.1l065

Cited by 50 publications

(22 citation statements)

References 36 publications

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“…Maribavir, a specific inhibitor of UL97 kinase activity, is currently being evaluated for approval as an antiviral agent against HCMV disease (10,11,47,48). Thus, the results presented here help establish a likely mechanism by which inhibition of UL97 may provide its therapeutic efficacy in patients (11,48).…”

Section: Discussionmentioning

confidence: 76%

Human papillomavirus 16 E7 inactivator of retinoblastoma family proteins complements human cytomegalovirus lacking UL97 protein kinase

Kamil¹,

Hume

Jurak³

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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Several different families of DNA viruses encode proteins that inactivate the cellular retinoblastoma tumor suppressor protein (pRb), which normally functions to bind E2F transcription factors and restrict expression of genes necessary for cellular processes including DNA replication. Human cytomegalovirus (HCMV) UL97, a protein kinase functionally orthologous to cellular cyclin-dependent kinases, phosphorylates pRb on inactivating residues during HCMV infection. To assess if such phosphorylation is biologically relevant, we tested whether the human papillomavirus type 16 E7 protein, which inactivates pRb family proteins by direct binding and destabilization, could substitute for UL97 during HCMV infection. In the absence of UL97, expression of wild-type E7 protein, but not a mutant E7 unable to bind pRb family proteins, restored E2F-responsive cellular gene expression, late viral gene expression, and viral DNA synthesis to levels normally observed during wildtype virus infection of quiescent cells. UL97-null mutants exhibited more pronounced defects in virus production and DNA synthesis in quiescent cells as compared to serum-fed, cycling cells. E7 expression substantially enhanced infectious virus production in quiescent cells, but did not complement the defects observed during UL97-null virus infection of cycling cells. Thus, a primary role of UL97 is to inactivate pRb family proteins during infection of quiescent cells, and this inactivation likely abets virus replication by induction of cellular E2F-responsive genes. Our findings have implications for human cytomegalovirus disease and for drugs that target UL97.E2F ͉ cyclin-dependent kinase ͉ cell cycle ͉ antiviral drugs ͉ retinoblastoma protein

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Section: Discussionmentioning

confidence: 76%

Human papillomavirus 16 E7 inactivator of retinoblastoma family proteins complements human cytomegalovirus lacking UL97 protein kinase

Kamil¹,

Hume

Jurak³

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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“…The drugs used in the present study were obtained from various sources: the CDK inhibitors R25 (also known as Alsterpaullone) (Rechter et al, 2009) and R22 were provided by GPC Biotech AG (Martinsried, Germany), the CDK7-specific inhibitor LDC4297 was provided by Lead Discovery Centre GmbH (Dortmund, Germany), and maribavir (MBV), a specific inhibitor of the HCMV protein kinase pUL97 (Trofe et al, 2008;Chou et al, 2012), was purchased from Shanghai PI Chemicals Ltd (China). The compounds were dissolved in dimethyl sulfoxide (DMSO) and stored at À20 C according to the manufacturer's instructions.…”

Section: Methodsmentioning

confidence: 99%

Cytomegalovirus pUL50 is the multi-interacting determinant of the core nuclear egress complex (NEC) that recruits cellular accessory NEC components

Sonntag

Hamilton

Hanife

et al. 2016

Journal of General Virology

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Nuclear egress of herpesvirus capsids through the nuclear envelope is mediated by the multimeric nuclear egress complex (NEC). The human cytomegalovirus (HCMV) core NEC is defined by an interaction between the membrane-anchored pUL50 and its nuclear co-factor pUL53, tightly associated through heterodimeric corecruitment to the nuclear envelope. Cellular proteins, such as p32/gC1qR, emerin and protein kinase C (PKC), are recruited by direct interaction with pUL50 for the multimeric extension of the NEC. As a functionally important event, the recruitment of both viral and cellular protein kinases leads to site-specific lamin phosphorylation and nuclear lamina disassembly. In this study, interaction domains within pUL50 for its binding partners were defined by co-immunoprecipitation. The interaction domain for pUL53 is located within the pUL50 N-terminus (residues 10-169), interaction domains for p32/gC1qR (100-358) and PKC (100-280) overlap in the central part of pUL50, and the interaction domain for emerin is located in the C-terminus (265-397). Moreover, expression and formation of core NEC proteins at the nuclear rim were consistently detected in cells permissive for productive HCMV replication, including two trophoblast-cell lines. Importantly, regular nuclear-rim formation of the core NEC was blocked by inhibition of cyclin-dependent kinase (CDK) activity. In relation to the recently published crystal structure of the HCMV core NEC, our findings result in a refined view of NEC assembly. In particular, we suggest that CDKs may play an important regulatory role in NEC formation during HCMV replication.

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“…MBV was developed in place of BDCRB, the development of which was abandoned since BDCRB is rapidly inactivated metabolically (61). MBV inhibits the replication of EBV and HCMV; the effects on HCMV involve the inhibition of enzymatic activity of the HCMV PK UL97, discovered initially through drug resistance caused by a mutation of the gene.…”

Section: Discussionmentioning

confidence: 99%

Maribavir Inhibits Epstein-Barr Virus Transcription in Addition to Viral DNA Replication

Wang

Roy

Gershburg

et al. 2009

J Virol

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Maribavir: A Novel Antiviral Agent with Activity Against Cytomegalovirus

Cited by 50 publications

References 36 publications

Human papillomavirus 16 E7 inactivator of retinoblastoma family proteins complements human cytomegalovirus lacking UL97 protein kinase

Human papillomavirus 16 E7 inactivator of retinoblastoma family proteins complements human cytomegalovirus lacking UL97 protein kinase

Cytomegalovirus pUL50 is the multi-interacting determinant of the core nuclear egress complex (NEC) that recruits cellular accessory NEC components

Maribavir Inhibits Epstein-Barr Virus Transcription in Addition to Viral DNA Replication

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