scholarly journals Unique Metabolism of a Novel Antivirall-Nucleoside Analog, 2′-Fluoro-5-Methyl-β-l-Arabinofuranosyluracil: a Substrate for Both Thymidine Kinase and Deoxycytidine Kinase

1998 ◽  
Vol 42 (4) ◽  
pp. 833-839 ◽  
Author(s):  
Shwu-Huey Liu ◽  
Kristie L. Grove ◽  
Yung-Chi Cheng
Keyword(s):  
Thymidine Kinase ◽  
Nucleoside Analogs ◽  
Nucleoside Analog ◽  
Nucleoside Transport ◽  
Deoxycytidine Kinase ◽  
Barr Virus ◽  
B Virus ◽  
Antiviral Activities ◽  
Epstein Barr ◽  
Low Cytotoxicity

ABSTRACT 2′-Fluoro-5-methyl-β-l-arabinofuranosyluracil (l-FMAU) is the first l-nucleoside analog with low cytotoxicity discovered to have potent antiviral activities against both hepatitis B virus and Epstein-Barr virus but not human immunodeficiency virus. This spectrum of activity is different from those of the other l-nucleoside analogs examined.l-FMAU enters cells through equilibrative-sensitive and -insensitive nucleoside transport as well as through nonfacilitated passive diffusion. l-FMAU is phosphorylated stepwise in cells to its mono-, di-, and triphosphate forms. In the present study the enzymes responsible for the first step of l-FMAU phosphorylation were identified. This is the first thymidine analog shown to be a substrate not only for cytosolic thymidine kinase and mitochondrial deoxypyrimidine kinase but also for deoxycytidine kinase. This finding suggests that the antiviral activity of l-FMAU will not be limited by the loss or alteration of any of these deoxynucleoside kinases.

scholarly journals Sensitivity of Monkey B Virus (Cercopithecine herpesvirus 1) to Antiviral Drugs: Role of Thymidine Kinase in Antiviral Activities of Substrate Analogs and Acyclonucleosides

2007 ◽  
Vol 51 (6) ◽  
pp. 2028-2034 ◽  
Author(s):  
Federico Focher ◽  
Andrea Lossani ◽  
Annalisa Verri ◽  
Silvio Spadari ◽  
Andrew Maioli ◽  
...  
Keyword(s):  
Vero Cell ◽  
Thymidine Kinase ◽  
Nucleoside Analogs ◽  
Modified Nucleosides ◽  
Experimental Conditions ◽  
Substrate Analogs ◽  
B Virus ◽  
Antiviral Activities ◽  
Simplex Virus ◽  
Hsv 1

ABSTRACT Herpes B virus (B virus [BV]) is a macaque herpesvirus that is occasionally transmitted to humans where it can cause rapidly ascending encephalitis that is often fatal. To understand the low susceptibility of BV to the acyclonucleosides, we have cloned, expressed, and characterized the BV thymidine kinase (TK), an enzyme that is expected to “activate” nucleoside analogs. This enzyme is similar in sequence and properties to the TK of herpes simplex virus (HSV), i.e., it has a broad substrate range and low enantioselectivity and is sensitive to inhibitors of HSV TKs. The BV enzyme phosphorylates some modified nucleosides and acyclonucleosides and l enantiomers of thymidine and related antiherpetic analogs. However, the potent anti-HSV drugs acyclovir (ACV), ganciclovir (GCV), and 5-bromovinyldeoxyuridine were poorly or not phosphorylated by the BV enzyme under the experimental conditions. The antiviral activities of a number of marketed antiherpes drugs and experimental compounds were compared against BV strains and, for comparison, HSV type 1 (HSV-1) in Vero cell cultures. For most compounds tested, BV was found to be about as sensitive as HSV-1 was. However, BV was less sensitive to ACV and GCV than HSV-1 was. The abilities of thymidine analogs and acyclonucleosides to inhibit replication of BV in Vero cell culture were not always proportional to their substrate properties for BV TK. Our studies characterize BV TK for the first time and suggest new lead compounds, e.g., 5-ethyldeoxyuridine and pencyclovir, which may be superior to ACV or GCV as treatment for this emerging infectious disease.

scholarly journals Spectrum of Activity and Mechanisms of Resistance of Various Nucleoside Derivatives against Gammaherpesviruses

2014 ◽  
Vol 58 (12) ◽  
pp. 7312-7323 ◽  
Author(s):  
Natacha Coen ◽  
Sophie Duraffour ◽  
Dimitri Topalis ◽  
Robert Snoeck ◽  
Graciela Andrei
Keyword(s):  
Protein Kinase ◽  
Thymidine Kinase ◽  
Nucleoside Analogs ◽  
Drug Susceptibility ◽  
Inhibitory Effect ◽  
Cross Resistance ◽  
Barr Virus ◽  
Resistance Patterns ◽  
Epstein Barr

ABSTRACTThe susceptibilities of gammaherpesviruses, including Epstein-Barr virus (EBV), Kaposi's sarcoma-associated herpesvirus (KSHV), and animal rhadinoviruses, to various nucleoside analogs was investigated in this work. Besides examining the antiviral activities and modes of action of antivirals currently marketed for the treatment of alpha- and/or betaherpesvirus infections (including acyclovir, ganciclovir, penciclovir, foscarnet, and brivudin), we also investigated the structure-activity relationship of various 5-substituted uridine and cytidine molecules. The antiviral efficacy of nucleoside derivatives bearing substitutions at the 5 position was decreased if the bromovinyl was replaced by chlorovinyl. 1-β-d-Arabinofuranosyl-(E)-5-(2-bromovinyl)uracil (BVaraU), a nucleoside with an arabinose configuration of the sugar ring, exhibited no inhibitory effect against rhadinoviruses but was active against EBV. On the other hand, the fluoroarabinose cytidine analog 2′-fluoro-5-iodo-aracytosine (FIAC) showed high selectivity indices against gammaherpesviruses that were comparable to those of brivudin. Additionally, we selected brivudin- and acyclovir-resistant rhadinovirusesin vitroand characterized them by phenotypic and genotypic (i.e., sequencing of the viral thymidine kinase, protein kinase, and DNA polymerase) analysis. Here, we reveal key amino acids in these enzymes that play an important role in substrate recognition. Our data on drug susceptibility profiles of the different animal gammaherpesvirus mutants highlighted cross-resistance patterns and indicated that pyrimidine nucleoside derivatives are phosphorylated by the viral thymidine kinase and purine nucleosides are preferentially activated by the gammaherpesvirus protein kinase.

scholarly journals Anti-Epstein-Barr Virus (EBV) Activity of β-l-5-Iododioxolane Uracil Is Dependent on EBV Thymidine Kinase

2000 ◽  
Vol 44 (12) ◽  
pp. 3278-3284 ◽  
Author(s):  
Toshihiko Kira ◽  
Susan P. Grill ◽  
Ginger E. Dutschman ◽  
Ju-Sheng Lin ◽  
Fucheng Qu ◽  
...  
Keyword(s):  
Thymidine Kinase ◽  
Epstein Barr Virus ◽  
Kinase Inhibitor ◽  
Effective Concentration ◽  
Viral Protein Synthesis ◽  
Barr Virus ◽  
Ebv Dna ◽  
Epstein Barr ◽  
Low Cytotoxicity ◽  
In Cells

ABSTRACT β-l-5-Iododioxolane uracil was shown to have potent anti-Epstein-Barr virus (EBV) activity (50% effective concentration = 0.03 μM) with low cytotoxicity (50% cytotoxic concentration = 1,000 μM). It exerts its antiviral activity by suppressing replicative EBV DNA and viral protein synthesis. This compound is phosphorylated in cells where the EBV is replicating but not in cells where the EBV is latent. EBV-specific thymidine kinase could phosphorylate β-l-5-iododioxolane uracil to the monophosphate metabolite. The Km of β-l-5-iododioxolane uracil with EBV thymidine kinase was estimated to be 5.5 μM, which is similar to that obtained with thymidine but about fivefold higher than that obtained with 2′ fluoro-5-methyl-β-l-arabinofuranosyl uracil, the firstl-nucleoside analogue discovered to have anti-EBV activity. The relative V max is seven times higher than that of thymidine. The anti-EBV activity of β-l-5-iododioxolane uracil and its intracellular phosphorylation could be inhibited by 5′-ethynylthymidine, a potent EBV thymidine kinase inhibitor. The present study suggests that β-l-5-iododioxolane uracil exerts its action after phosphorylation; therefore, EBV thymidine kinase is critical for the antiviral action of this drug.

Characterization of an Epstein-Barr virus-induced thymidine kinase.

1986 ◽  
Vol 57 (3) ◽  
pp. 1105-1112 ◽  
Author(s):  
M de Turenne-Tessier ◽  
T Ooka ◽  
G de The ◽  
J Daillie
Keyword(s):  
Thymidine Kinase ◽  
Epstein Barr Virus ◽  
Barr Virus ◽  
Epstein Barr

scholarly journals Immunotherapy and Gene Therapy for Oncoviruses Infections: A Review

Viruses ◽  
2021 ◽  
Vol 13 (5) ◽  
pp. 822
Author(s):  
Nathália Alves Araújo de Almeida ◽  
Camilla Rodrigues de Almeida Ribeiro ◽  
Jéssica Vasques Raposo ◽  
Vanessa Salete de Paula
Keyword(s):  
Gene Therapy ◽  
Checkpoint Inhibitors ◽  
Gene Replacement ◽  
Gene Products ◽  
Transcription Activator ◽  
Therapeutic Gene ◽  
T Lymphotropic Virus ◽  
Barr Virus ◽  
B Virus ◽  
Epstein Barr

Immunotherapy has been shown to be highly effective in some types of cancer caused by viruses. Gene therapy involves insertion or modification of a therapeutic gene, to correct for inappropriate gene products that cause/may cause diseases. Both these types of therapy have been used as alternative ways to avoid cancers caused by oncoviruses. In this review, we summarize recent studies on immunotherapy and gene therapy including the topics of oncolytic immunotherapy, immune checkpoint inhibitors, gene replacement, antisense oligonucleotides, RNA interference, clustered regularly interspaced short palindromic repeats Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)-based gene editing, transcription activator-like effector nucleases (TALENs) and custom treatment for Epstein–Barr virus, human T-lymphotropic virus 1, hepatitis B virus, human papillomavirus, hepatitis C virus, herpesvirus associated with Kaposi’s sarcoma, Merkel cell polyomavirus, and cytomegalovirus.

Diagnosis of Nasopharyngeal Carcinoma Using the Epstein-Barr Virus Coded Alkaline Dnase, Membrane Antigen and Thymidine Kinase

1991 ◽  
pp. 353-356
Author(s):  
Edward Littler ◽  
Sally A. Baylis ◽  
Yvonne Connolly ◽  
Margaret J. Conway ◽  
Michael Mackett ◽  
...  
Keyword(s):  
Nasopharyngeal Carcinoma ◽  
Thymidine Kinase ◽  
Epstein Barr Virus ◽  
Barr Virus ◽  
Epstein Barr

Prevention of Infection-Related Cancers

2017 ◽  
Author(s):  
Marc Bulterys ◽  
Julia Brotherton ◽  
Ding-Shinn Chen
Keyword(s):  
Randomized Clinical Trials ◽  
Viral Infections ◽  
Prevention Measures ◽  
Barr Virus ◽  
Non Hodgkin Lymphoma ◽  
B Virus ◽  
Immunodeficiency Virus ◽  
Epstein Barr ◽  
Liver Flukes

This chapter discusses primary prevention measures that disrupt transmission of oncogenic infections. It begins by discussing vaccination against hepatitis B virus (HBV) and human papillomavirus (HPV), two major causes of cancer for which safe and effective vaccines are currently available. It briefly discusses the importance of treatment and prophylaxis against human immunodeficiency virus type 1 (HIV-1), which potentiates the virulence of other viral infections as well as directly increasing the incidence of non-Hodgkin lymphoma. It does not discuss the treatment of HBV or hepatitis C virus (HCV) infection, since these are considered in Chapters 25 and 33. Also beyond the scope of this chapter are the randomized clinical trials currently underway to assess the efficacy and feasibility of eradication of Helicobacter pylori (Chapters 24, 31), vaccination against Epstein-Barr virus (EBV) (Chapters 24, 26, 39), or the prevention of schistosomiasis and liver flukes (Chapters 24, 33, and 52).

scholarly journals Metabolism in Human Cells of the d and l Enantiomers of the Carbocyclic Analog of 2′-Deoxyguanosine: Substrate Activity with Deoxycytidine Kinase, Mitochondrial Deoxyguanosine Kinase, and 5′-Nucleotidase

1998 ◽  
Vol 42 (5) ◽  
pp. 1045-1051 ◽  
Author(s):  
L. Lee Bennett ◽  
Paula W. Allan ◽  
Gussie Arnett ◽  
Y. Fulmer Shealy ◽  
Donna S. Shewach ◽  
...  
Keyword(s):  
Biological Activity ◽  
Nucleoside Analogs ◽  
Human Platelets ◽  
Biologically Active ◽  
Deoxycytidine Kinase ◽  
Link Type ◽  
Duck Hepatitis ◽  
B Virus ◽  
Deoxyguanosine Kinase ◽  
Infected Cells

ABSTRACT The carbocyclic analog of 2′-deoxyguanosine (CdG) has broad-spectrum antiviral activity. Because of recent observations with other nucleoside analogs that biological activity may be associated thel enantiomer rather than, as expected, with thed enantiomer, we have studied the metabolism of both enantiomers of CdG to identify the enzymes responsible for the phosphorylation of CdG in noninfected and virally infected human and duck cells. We have examined the enantiomers as substrates for each of the cellular enzymes known to catalyze phosphorylation of deoxyguanosine. Both enantiomers of CdG were substrates for deoxycytidine kinase (EC 2.7.1.74) from MOLT-4 cells, 5′-nucleotidase (EC 3.1.3.5) from HEp-2 cells, and mitochondrial deoxyguanosine kinase (EC 2.7.1.113) from human platelets and CEM cells. For both deoxycytidine kinase and mitochondrial deoxyguanosine kinase, thel enantiomer was the better substrate. Even though thed enantiomer was the preferred substrate with 5′-nucleotidase, the rate of phosphorylation of the lenantiomer was substantial. The phosphorylation of d-CdG in MRC-5 cells was greatly stimulated by infection with human cytomegalovirus. The fact that the phosphorylation of d-CdG was stimulated by mycophenolic acid and was not affected by deoxycytidine suggested that 5′-nucleotidase was the enzyme primarily responsible for its metabolism in virally infected cells.d-CdG was extensively phosphorylated in duck hepatocytes, and its phosphorylation was not affected by infection with duck hepatitis B virus. These results are of importance in understanding the mode of action of d-CdG and related analogs and in the design of new biologically active analogs.

Imaging and therapy for Epstein-Barr virus-associated gastric cancer

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 4644-4644
Author(s):  
D. Fu ◽  
J. Chong ◽  
C. Foss ◽  
J. Fox ◽  
S. Wang ◽  
...  
Keyword(s):  
Epstein Barr Virus ◽  
Tumor Regression ◽  
Human Cancer ◽  
Nucleoside Analogs ◽  
Scid Mice ◽  
Tumor Xenografts ◽  
Barr Virus ◽  
Bortezomib Treatment ◽  
Epstein Barr

4644 Background: Epstein-Barr virus (EBV) has been identified in a wide variety of malignancies, including gastric carcinomas. The virus encodes kinases that phosphorylate nucleoside analogs such as 2’-deoxy-2’-fluoro-5-iodo-1-beta-D- arabinofuranosyluracil (FIAU). We hypothesized that it might be possible to use the viral enzyme to specifically concentrate [125I]FIAU or [131I] FIAU in tumor cells harboring virus and thus deliver imaging and therapeutic radiation. Bortezomib is a potent stimulator of viral kinase expression in EBV tumor cell lines. Methods: We imaged lytic induction in vivo and evaluated the effect of [131I] FIAU on human cancer xenografts in SCID mice. These include a tumor line engineered to constitutively express the EBV thymide kinase (EBVTK), and a control engineered with a sham vector (SHAM), as well one EBV-associated human gastric tumor (KT tumor). Mice were treated with buffer, bortezomib (2μg/g), or radiolabeled FIAU or radiolabeled FIAU and bortezomib in combination. For imaging, mice, [125I]-FIAU and SPECT/CT were used. For therapy, 131I-FIAU was used and tumor dimensions were monitored with calipers. Results: SPECT/CT imaging with [125I]-FIAU of tumor-bearing SCID mice showed selective concentration of radiotracer in tumor tissue in EBVTK (3/3) and in EBV-associated KT tumors (3/3) when animals were pretreated with bortezomib. Treatment with buffer had no effect on 3 EBVTK tumors and 3 SHAM tumors all of which increased in volume. Treatment with 1.6 mCi of [131I]-FIAU alone led to tumor response in 3/3 mice with EBVTK tumors and 0/3 mice with SHAM tumors. Treatment with [131I]-FIAU alone had no effect on EBV KT tumor xenografts (0/3) and all tumors increased in volume. Treatment with bortezomib induced modest responses in all KT tumors. However, treatment with bortezomib and [131I]-FIAU led to marked tumor regression (>80%) in EBV-associated KT tumors (3/3). Conclusions: Treatment with bortezomib leads to selective concentration of radiolabeled FIAU in the EBV-associated tumor xenografts. In combination with [131I]-FIAU it leads to tumor regression. No significant financial relationships to disclose.

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