Targeting the terminase: An important step forward in the treatment and prophylaxis of human cytomegalovirus infections.

@article{Gentry2019TargetingTT,
  title={Targeting the terminase: An important step forward in the treatment and prophylaxis of human cytomegalovirus infections.},
  author={Brian Gentry and Elke Bogner and John C. Drach},
  journal={Antiviral research},
  year={2019},
  volume={161},
  pages={
          116-124
        }
}

Terminase Large Subunit Provides a New Drug Target for Herpesvirus Treatment

The genetic characteristics, protein structure, and function of the herpesvirus terminase large subunit, as well as the antiviral drugs that target the terminaseLarge subunit are reviewed.

Bright and Early: Inhibiting Human Cytomegalovirus by Targeting Major Immediate-Early Gene Expression or Protein Function

An update is provided on the regulation of major IE gene expression and the functions of IE1 and IE2 proteins believed to control all subsequent early and late events in HCMV replication, including reactivation from latency, in part by antagonizing intrinsic and innate immune responses.

DNA Encapsidation and Capsid Assembly Are Underexploited Antiviral Targets for the Treatment of Herpesviruses

Targeting DNA encapsidation or capsid assembly provide additional options for the development of non-nucleoside, small molecule anti-herpesviral drugs.

Small Molecules—Prospective Novel HCMV Inhibitors

There is an urgent need to find new well-tolerated compounds supporting different modes of action of HCMV, and a selection of compounds in clinical trials and novel inhibitors targeting host-cell factors or viral proteins is presented.

Computational modeling of protracted HCMV replication using genome substrates and protein temporal profiles.

The utility of a data-driven and expandable computational model simulating lytic HCMV infection simulating vDNA kinetics and late lytic replication based on in-house experimental data is demonstrated.

Letermovir Resistance Analysis in a Clinical Trial of Cytomegalovirus Prophylaxis for Hematopoietic Stem Cell Transplant Recipients.

The detected incidence of CMV resistance among subjects who received LET as prophylaxis in this Phase 3 trial was low and the LET RAVs that were detected mapped to the CMV UL56 gene at positions associated with reduced susceptibility to LET based on resistance selections in cell culture.

Positive HCMV DNAemia in stem cell recipients undergoing letermovir prophylaxis is expression of abortive infection

  • I. CassanitiA. Colombo F. Baldanti
  • Biology, Medicine
    American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons
  • 2020
This report provides the first evidence that during LMV prophylaxis the clinical relevance of HCMV DNAemia should be critically considered.

References

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Human cytomegalovirus packaging: an update on structure–function relationships

DNA packaging of human cytomegalovirus is a key step in viral replication and the necessary nuclease activity to process the concatemers into unit-length genomes is mediated by the terminase subunit pUL89.

Interaction of the Putative Human Cytomegalovirus Portal Protein pUL104 with the Large Terminase Subunit pUL56 and Its Inhibition by Benzimidazole-d-Ribonucleosides

Electron microscopy revealed that in the presence of Cl4RB DNA is not packaged into capsids and these capsids failed to egress from the nucleus, thus indicating that these HCMV inhibitors block the insertion of the DNA into the capsid by preventing a necessary interaction of pUL56 with the portal.

Identification of a short sequence in the HCMV terminase pUL56 essential for interaction with pUL89 subunit

The results show that this motif is essential for HCMV replication and could be a target for development of new small antiviral drugs or peptidomimetics.

The Human Cytomegalovirus UL51 Protein Is Essential for Viral Genome Cleavage-Packaging and Interacts with the Terminase Subunits pUL56 and pUL89

Evidence is provided that pUL51 is crucial for HCMV genome cleavage-packaging and may represent a third component of the viral terminase complex, and interference with the interactions between the terminase subunits by antiviral drugs could be a strategy to disrupt the H CMV replication cycle.

ATPase Activity of the Terminase Subunit pUL56 of Human Cytomegalovirus*

It is demonstrated that both terminase subunits interact with each other and the subunit pUL56 has an ATPase activity, and the characterization of the ATP hydrolysis showed that the enzymatic reaction is a fast process, whereas the spontaneous ATP decay followed slow kinetics.

The C-terminal part of the human cytomegalovirus terminase subunit pUL51 is central for terminase complex assembly.

Insight is provided into the interaction of pUL51 with the other two terminase components, and the basis for unravelling the mode of action of novel antiviral drugs targeting the HCMV terminase is provided.

Structure and inhibition of herpesvirus DNA packaging terminase nuclease domain

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It is demonstrated that UL89-C has the capacity to process the DNA and that the nuclease function can be inactivated by raltegravir, a recently approved anti-AIDS drug that targets the HIV integrase.

Mutual Interplay between the Human Cytomegalovirus Terminase Subunits pUL51, pUL56, and pUL89 Promotes Terminase Complex Formation

A model of the HCMV terminase as a multiprotein complex in which the three players regulate each other concerning stability, subcellular localization, and assembly into the functional tripartite holoenzyme is described.

The terminase subunits pUL56 and pUL89 of human cytomegalovirus are DNA-metabolizing proteins with toroidal structure.

A first characterization of the terminase subunits pUL56 and pUL89 of human cytomegalovirus (HCMV) is reported, providing the first insights into theterminase-dependent viral DNA-packaging mechanism of HCMV.

Identification of the interaction domain of the small terminase subunit pUL89 with the large subunit pUL56 of human cytomegalovirus.

Immunoprecipitations with a UL89-specific antibody and immunofluorescence demonstrated that both terminase subunits co-localized in viral replication centers of infected cells, and Cotransfection assays demonstrated that the 20 aa sequence GRDKALAVEQFISRFNSGYIK is sufficient for the interaction with pUL56 and in conclusion required for DNA packaging.
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