scholarly journals Activity and Mechanism of Action of N-Methanocarbathymidine against Herpesvirus and Orthopoxvirus Infections

2006 ◽  
Vol 50 (4) ◽  
pp. 1336-1341 ◽  
Author(s):  
Mark N. Prichard ◽  
Kathy A. Keith ◽  
Debra C. Quenelle ◽  
Earl R. Kern
Keyword(s):  
Herpes Simplex Virus ◽  
Herpes Simplex ◽  
Mechanism Of Action ◽  
Type I ◽  
Viral Dna ◽  
Barr Virus ◽  
Epstein Barr ◽  
Simplex Virus

ABSTRACT N-Methanocarbathymidine [(N)-MCT] is a conformationally locked nucleoside analog that is active against some herpesviruses and orthopoxviruses in vitro. The antiviral activity of this molecule is dependent on the type I thymidine kinase (TK) in herpes simplex virus and also appears to be dependent on the type II TK expressed by cowpox and vaccinia viruses, suggesting that it is a substrate for both of these divergent forms of the enzyme. The drug is also a good inhibitor of viral DNA synthesis in both viruses and is consistent with inhibition of the viral DNA polymerase once it is activated by the viral TK homologs. This mechanism of action explains the rather unusual spectrum of activity, which is limited to orthopoxviruses, alphaherpesviruses, and Epstein-Barr virus, since these viruses express molecules with TK activity that can phosphorylate and thus activate the drug. The compound is also effective in vivo and reduces the mortality of mice infected with orthopoxviruses, as well as those infected with herpes simplex virus type 1 when treatment is initiated 24 h after infection. These results indicate that (N)-MCT is active in vitro and in vivo, and its mechanism of action suggests that the molecule may be an effective therapeutic for orthopoxvirus and herpesvirus infections, thus warranting further development.

scholarly journals HCF1 and OCT2 Cooperate with EBNA1 To Enhance OriP-Dependent Transcription and Episome Maintenance of Latent Epstein-Barr Virus

2016 ◽  
Vol 90 (11) ◽  
pp. 5353-5367 ◽  
Author(s):  
Jayaraju Dheekollu ◽  
Andreas Wiedmer ◽  
Daniel Sentana-Lledo ◽  
Joel Cassel ◽  
Troy Messick ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Herpes Simplex Virus ◽  
Herpes Simplex ◽  
Epstein Barr Virus ◽  
Histone H3 ◽  
Type I ◽  
Barr Virus ◽  
Cellular Factors ◽  
Epstein Barr ◽  
Simplex Virus

ABSTRACTEpstein-Barr virus (EBV) establishes latent infections as multicopy episomes with complex patterns of viral gene transcription and chromatin structure. The EBV origin of plasmid replication (OriP) has been implicated as a critical control element for viral transcription, as well as viral DNA replication and episome maintenance. Here, we examine cellular factors that bind OriP and regulate histone modification, transcription regulation, and episome maintenance. We found that OriP is enriched for histone H3 lysine 4 (H3K4) methylation in multiple cell types and latency types. Host cell factor 1 (HCF1), a component of the mixed-lineage leukemia (MLL) histone methyltransferase complex, and transcription factor OCT2 (octamer-binding transcription factor 2) bound cooperatively with EBNA1 (Epstein-Barr virus nuclear antigen 1) at OriP. Depletion of OCT2 or HCF1 deregulated latency transcription and histone modifications at OriP, as well as the OriP-regulated latency type-dependent C promoter (Cp) and Q promoter (Qp). HCF1 depletion led to a loss of histone H3K4me3 (trimethylation of histone H3 at lysine 4) and H3 acetylation at Cp in type III latency and Qp in type I latency, as well as an increase in heterochromatic H3K9me3 at these sites. HCF1 depletion resulted in the loss of EBV episomes from Burkitt's lymphoma cells with type I latency and reactivation from lymphoblastoid cells (LCLs) with type III latency. These findings indicate that HCF1 and OCT2 function at OriP to regulate viral transcription, histone modifications, and episome maintenance. As HCF1 is best known for its function in herpes simplex virus 1 (HSV-1) immediate early gene transcription, our findings suggest that EBV latency transcription shares unexpected features with HSV gene regulation.IMPORTANCEEBV latency is associated with several human cancers. Viral latent cycle gene expression is regulated by the epigenetic control of the OriP enhancer region. Here, we show that cellular factors OCT2 and HCF1 bind OriP in association with EBNA1 to maintain elevated histone H3K4me3 and transcriptional enhancer function. HCF1 is known as a transcriptional coactivator of herpes simplex virus (HSV) immediate early (IE) transcription, suggesting that OriP enhancer shares aspects of HSV IE transcription control.

The Essential in Vivo Function of the Herpes Simplex Virus UL42 Protein Correlates with Its Ability to Stimulate the Viral DNA Polymerase in Vitro

Virology ◽  
1994 ◽  
Vol 200 (2) ◽  
pp. 447-456 ◽  
Author(s):  
Peter J. Reddig ◽  
Lynn A. Grinstead ◽  
Steven J. Monahan ◽  
Paul A. Johnson ◽  
Deborah S. Parris
Keyword(s):  
Herpes Simplex Virus ◽  
Herpes Simplex ◽  
Dna Polymerase ◽  
Viral Dna ◽  
Simplex Virus

scholarly journals Antiviral Properties of R. tanguticum Nanoparticles on Herpes Simplex Virus Type I In Vitro and In Vivo

2019 ◽  
Vol 10 ◽  
Author(s):  
Meng-xin Shen ◽  
Nian Ma ◽  
Min-ke Li ◽  
Yuan-yuan Liu ◽  
Tian Chen ◽  
...  
Keyword(s):  
Herpes Simplex Virus ◽  
Herpes Simplex ◽  
Virus Type ◽  
Herpes Simplex Virus Type ◽  
Type I ◽  
Simplex Virus

scholarly journals In Vitro and In Vivo Activity, Tolerability, and Mechanism of Action of BX795 as an Antiviral against Herpes Simplex Virus 2 Genital Infection

2020 ◽  
Vol 64 (9) ◽  
Author(s):  
James Hopkins ◽  
Tejabhiram Yadavalli ◽  
Rahul Suryawanshi ◽  
Farreh Qatanani ◽  
Ipsita Volety ◽  
...  
Keyword(s):  
Herpes Simplex Virus ◽  
Herpes Simplex ◽  
Epithelial Cells ◽  
Mechanism Of Action ◽  
Nucleoside Analogs ◽  
Protein Translation ◽  
Vaginal Epithelial Cells ◽  
Simplex Virus

ABSTRACT Herpes simplex virus type 2 (HSV-2) causes recurrent lesions in the anogenital area that may be transmitted through sexual encounters. Nucleoside analogs, such as acyclovir (ACV), are currently prescribed clinically to curb this infection. However, in some cases, reduced efficacy has been observed due to the emergence of resistance against these drugs. In our previous study, we reported the discovery of a novel anti-HSV-1 small molecule, BX795, which was originally used as an inhibitor of TANK-binding kinase 1 (TBK1). In this study, we report the antiviral efficacy of BX795 on HSV-2 infection in vaginal epithelial cells in vitro at 10 μM and in vivo at 50 μM. Additionally, through biochemical assays in vitro and histopathology in vivo, we show the tolerability of BX795 in vaginal epithelial cells at concentrations as high as 80 μM. Our investigations also revealed that the mechanism of action of BX795 antiviral activity stems from the reduction of viral protein translation via inhibition of protein kinase B phosphorylation. Finally, using a murine model of vaginal infection, we show that topical therapy using 50 μM BX795 is well tolerated and efficacious in controlling HSV-2 replication.

scholarly journals Antiherpesvirus Activities of Two Novel 4′-Thiothymidine Derivatives, KAY-2-41 and KAH-39-149, Are Dependent on Viral and Cellular Thymidine Kinases

2014 ◽  
Vol 58 (8) ◽  
pp. 4328-4340 ◽  
Author(s):  
Natacha Coen ◽  
Sophie Duraffour ◽  
Kazuhiro Haraguchi ◽  
Jan Balzarini ◽  
Joost J. van den Oord ◽  
...  
Keyword(s):  
Herpes Simplex Virus ◽  
Herpes Simplex ◽  
Antiviral Activity ◽  
Epstein Barr Virus ◽  
Varicella Zoster ◽  
Barr Virus ◽  
Epstein Barr ◽  
Simplex Virus ◽  
Hsv 1

ABSTRACTThe emergence of drug-resistant herpesviruses represents a significant problem in clinical practice, primarily in immunocompromised patients. Furthermore, effective antiviral therapies against gammaherpesvirus-associated diseases are lacking. Here, we present two thiothymidine derivatives, KAY-2-41 and KAH-39-149, with different spectra of antiviral activity from those of the reference antiherpetic drugs, showing inhibitory activities against herpes simplex virus, varicella-zoster virus (VZV), and particularly against Epstein-Barr virus, with high selectivityin vitro. While KAY-2-41- and KAH-39-149-resistant herpesviruses were found to harbor mutations in the viral thymidine kinase (TK), these mutations conferred only low levels of resistance to these drugs but high levels to other TK-dependent drugs. Also, antiviral assays in HeLa TK-deficient cells showed a lack of KAY-2-41 and KAH-39-149 activities against herpes simplex virus 1 (HSV-1) and HSV-2 TK-deficient mutants. Furthermore, enzymatic TK assays showed the ability of HSV-1 TK, VZV TK, and cellular TK1 and TK2 to recognize and phosphorylate KAY-2-41 and KAH-39-149. These results demonstrate that the compounds depend on both viral and host TKs to exert antiviral activity. Additionally, the antiviral efficacy of KAH-39-149 proved to be superior to that of KAY-2-41 in a mouse model of gammaherpesvirus infection, highlighting the potential of this class of antiviral agents for further development as selective therapeutics against Epstein-Barr virus.

scholarly journals Structural Variability of the Herpes Simplex Virus 1 GenomeIn VitroandIn Vivo

2012 ◽  
Vol 86 (16) ◽  
pp. 8592-8601 ◽  
Author(s):  
Charlotte Mahiet ◽  
Ayla Ergani ◽  
Nicolas Huot ◽  
Nicolas Alende ◽  
Ahmed Azough ◽  
...  
Keyword(s):  
Herpes Simplex Virus ◽  
Herpes Simplex ◽  
Considerable Proportion ◽  
Inverted Repeats ◽  
Herpes Simplex Virus 1 ◽  
Cell Extracts ◽  
Simplex Virus ◽  
Hsv 1

Herpes simplex virus 1 (HSV-1) is a human pathogen that leads to recurrent facial-oral lesions. Its 152-kb genome is organized in two covalently linked segments, each composed of a unique sequence flanked by inverted repeats. Replication of the HSV-1 genome produces concatemeric molecules in which homologous recombination events occur between the inverted repeats. This mechanism leads to four genome isomers (termed P, IS, IL, and ILS) that differ in the relative orientations of their unique fragments. Molecular combing analysis was performed on DNA extracted from viral particles and BSR, Vero, COS-7, and Neuro-2a cells infected with either strain SC16 or KOS of HSV-1, as well as from tissues of experimentally infected mice. Using fluorescence hybridization, isomers were repeatedly detected and distinguished and were accompanied by a large proportion of noncanonical forms (40%). In both cell and viral-particle extracts, the distributions of the four isomers were statistically equivalent, except for strain KOS grown in Vero and Neuro-2a cells, in which P and IS isomers were significantly overrepresented. In infected cell extracts, concatemeric molecules as long as 10 genome equivalents were detected, among which, strikingly, the isomer distributions were equivalent, suggesting that any such imbalance may occur during encapsidation.In vivo, for strain KOS-infected trigeminal ganglia, an unbalanced distribution distinct from the onein vitrowas observed, along with a considerable proportion of noncanonical assortment.

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