Potent inhibition of Epstein-Barr virus by phosphorothioate oligodeoxynucleotides without sequence specification

Yao, Gang‐Qing; Grill, Susan P.; Egan, William; Cheng, Yung‐Chi

doi:10.1128/aac.37.7.1420

Cited by 27 publications

(15 citation statements)

References 25 publications

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“…While L-I-OddU at 20 M has activity that is slightly better than that of DHPG at 20 M, with an anti-HHV8 activity of 60% compared to 41% (data not shown), it shows no advantage over ACV in our varicellazoster virus system, with EC 50 s of 17 M for L-I-OddU and of 4 M for ACV (data not shown). Only EBV showed significant increased selectivity, with an L-I-OddU EC 50 that was Ͼ1,000-fold lower than the EC 50 of 50 M for ACV. Our previous studies indicated that the action(s) responsible for the anti-EBV activity of L-I-OddU could be dependent on EBV-specific proteins (28).…”

Section: Epstein-barr Virus (Ebv) Is An Important Human Pathogenmentioning

confidence: 99%

“…Several compounds have shown anti-EBV activity in cell culture systems, including acyclovir (ACV), ganciclovir (DHPG), 2Ј-fluoro-5-methyl-␤-D-arabinofuranosyl uracil (D-FMAU), and (S)-1-(3-hydroxy-2-phosphonyl-methoxypropyl)cytosine (cidofivir) (6,9,26,27,36,50,52). However, the clinical application of many of these compounds is restricted by severe side effects (52).…”

Section: Epstein-barr Virus (Ebv) Is An Important Human Pathogenmentioning

confidence: 99%

“…It is hoped that a better understanding of EBV persistence and the part played by EBV in the oncogenic process will permit the development of new approaches aimed at the prevention and treatment of EBV-associated tumors. Therefore, it would be ultimately useful to have anti-EBV compounds that do not have serious side effects.Several compounds have shown anti-EBV activity in cell culture systems, including acyclovir (ACV), ganciclovir (DHPG), 2Ј-fluoro-5-methyl-␤-D-arabinofuranosyl uracil (D-FMAU), and (S)-1-(3-hydroxy-2-phosphonyl-methoxypropyl)cytosine (cidofivir) (6,9,26,27,36,50,52). However, the clinical application of many of these compounds is restricted by severe side effects (52).…”

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

Kira

Grill

Dutschman

et al. 2000

Antimicrob Agents Chemother

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␤-L-5-Iododioxolane uracil was shown to have potent anti-Epstein-Barr virus (EBV) activity (50% effective concentration ‫؍‬ 0.03 M) with low cytotoxicity (50% cytotoxic concentration ‫؍‬ 1,000 M). 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 ␤-L-5-iododioxolane uracil to the monophosphate metabolite. The K m of ␤-L-5-iododioxolane uracil with EBV thymidine kinase was estimated to be 5.5 M, which is similar to that obtained with thymidine but about fivefold higher than that obtained with 2 fluoro-5-methyl-␤-L-arabinofuranosyl uracil, the first L-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 ␤-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 ␤-L-5-iododioxolane uracil exerts its action after phosphorylation; therefore, EBV thymidine kinase is critical for the antiviral action of this drug. Epstein-Barr virus (EBV) is an important human pathogen.This virus has been determined to cause infectious mononucleosis, fatal acute infectious mononucleosis-X-linked lymphoproliferative syndrome, and oral hairy leukoplakia (16,17,48). EBV also has a close association with several types of malignancies, including Burkitt's lymphoma, nasopharyngeal carcinoma (NPC), Hodgkin's disease, (2, 13, 21), some T-cell lymphomas (1,26,32,35,40,58), smooth muscle cell leiomyosarcoma (23), and certain cases of gastric adenocarcinomas (38,46,53). EBV infection can enhance human immunodeficiency virus type 1 (HIV-1) replication in T cells (56), and EBV is also related to the development of lymphoma induced in AIDS patients (55). It was also reported that almost all posttransplant lymphomas appeared to be EBV genome positive, irrespective of histological appearance or clonability of the lesion (18,44,49,59). A more complex picture of EBV-associated malignancies is emerging, particularly with regard to virus-positive tumors of non-B-cell origin. It is hoped that a better understanding of EBV persistence and the part played by EBV in the oncogenic process will permit the development of new approaches aimed at the prevention and treatment of EBV-associated tumors. Therefore, it would be ultimately useful to have anti-EBV compounds that do not have serious side effects.Several compounds have shown anti-EBV activity in cell culture systems, including acyclovir (ACV), ganciclovir (DHPG), 2Ј-fluoro-5-methyl-␤-D-arabinofuranosyl uracil (D-FMAU), and (S)-1-(3-hydroxy-2-phosphonyl-methoxypropyl)cytosine (cidofivir) (6,9,26,27,36,50,52). However, the clinical application of many of these compounds is restricted by severe side effects (52). Recently, our laboratory found a new anti-EBV L-dioxolane nucleoside analogue, ␤...

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Section: Epstein-barr Virus (Ebv) Is An Important Human Pathogenmentioning

confidence: 99%

Section: Epstein-barr Virus (Ebv) Is An Important Human Pathogenmentioning

confidence: 99%

mentioning

confidence: 99%

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

Kira

Grill

Dutschman

et al. 2000

Antimicrob Agents Chemother

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“…For determination of Epstein-Barr virus (EBV)-inhibitory effects, H1 cells, a subclone of human P 3 HR-1 cells, were used (12,28). H1 cells were maintained in log-phase growth for 2 days prior to the initiation of treatment.…”

mentioning

confidence: 99%

Use of 2'-fluoro-5-methyl-beta-L-arabinofuranosyluracil as a novel antiviral agent for hepatitis B virus and Epstein-Barr virus

Chu

Shanmuganathan

et al. 1995

Antimicrob Agents Chemother

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239

133

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A novel anti-hepatitis B virus (anti-HBV) agent, 2-fluoro-5-methyl-␤-L-arabinofuranosyluracil (L-FMAU), was synthesized and found to be a potent anti-HBV and anti-Epstein-Barr virus agent. Its in vitro potency was evaluated in 2.2.15 and H1 cells for anti-HBV and anti-Epstein-Barr virus activities, respectively. In vitro cytotoxicity in MT2, CEM, 2.2.15, and H1 cells was also assessed, and the results indicated high antiviral selectivities of L-FMAU in these cells.A number of nucleosides have been reported to be antihepatitis B virus (anti-HBV) agents, although none of them have yet been proven to be clinically useful. As a part of our antiviral drug discovery program for HBV, we recently have reported the syntheses and anti-HBV activities of dioxolane (14, 15) and oxathiolane (1,8,13) nucleosides. (Ϫ)-␤-L-Dioxolane-cytosine has been found to be the most potent anti-HBV agent (50% effective concentration ϭ 0.0005 M in 2.2.15 cells), although the compound was the most toxic (50% inhibitory concentration ϭ 0.26 M in CEM cells) among those tested (15). Among the oxathiolane cytosine nucleosides we evaluated, (Ϫ)-␤-L-oxathiolane-cytosine has the most potent anti-HBV activity (50% effective concentration ϭ 0.01 M) and a favorable cytotoxicity (Ͼ50 M in CEM cells) (1). Interestingly, the (Ϫ)-␤-L isomer of this compound resisted deoxycytidine deaminase, while the (ϩ)-␤-D isomer was deaminated under similar conditions (3).Recently, an increasing number of L nucleosides have been reported to be antiherpesvirus (23), anti-human immunodeficiency virus (anti-HIV) (2,6,13,14,16,19), and anti-HBV (1,7,8,10,11,15,16) agents. Furthermore, some of the L nucleosides have been found to be more potent than the corresponding D nucleosides (6,13,14). Previously, 2Ј-fluoro-5-methyl-␤-D-arabinofuranosyluracil (FMAU) and 2Ј-fluoro-5-ethyl-␤-Darabinofuranosyluracil (FEAU) were reported (5, 24, 27) to be extremely potent antiviral agents against herpesvirus and HBV, respectively. However, the myelosuppression and neurotoxicity of FMAU limit its usefulness as a clinically effective antiviral agent. In view of the discovery that several nucleosides with the unnatural L configuration are selective antiviral agents, it was of interest to synthesize several 2Ј-fluoro-substituted (arabino configuration) nucleosides with the L configuration as potential antiviral agents, anticipating that these nucleosides will give lower toxicities than the corresponding D isomers. Thus, we report here the preliminary syntheses and antiviral activities of several pyrimidine nucleosides for which the corresponding D isomers have been known to exhibit potent antiviral activities.Synthesis. 1-O-Acetyl-2,3,5-tri-O-benzoyl-␤-L-ribofuranose (compound 1) was prepared from L-ribose (Fig. 1). The fully protected L-ribose compound 1 was selectively debenzoylated at the C-2 position and then was converted to the 2-fluorinated sugar (compound 3) according to the method described for the corresponding D isomer (25). The 2-fluorosugar (arabino configuration) compound 3 was c...

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“…Various oncogenes have been targeted with antisense oligonucleotides resulting in suppression of cell growth and differentiation [6]. The antisense strategy has been successfully explored in vitro for the treatment of several viral infections, for example, Rous sarcoma virus [39], human immunodeficiency virus [40], influenza virus [16], herpes simplex virus [25], human papilloma virus [9], EpsteinBarr virus [38], and human cytomegalovirus [3].…”

Section: Block Of Gene Expression At the Posttranscriptional Levelmentioning

confidence: 99%

Molecular therapeutic strategies in hepatitis B virus infection

Offensperger

Blum²,

Gerok

1994

Clin Investig

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Chronic infection with the hepatitis B virus is a major health problem worldwide. The only established therapy is interferon-alpha, with an efficacy of only 30-40% in highly selected patients. Nucleoside analogues do not show a significant clinical benefit. Molecular therapeutic strategies aimed at blocking gene expression include antisense DNA/RNA and ribozymes acting at the posttranscriptional level and triple helix formation blocking at the transcriptional level. In vitro, antisense oligodeoxynucleotides inhibit viral replication and gene expression in human hepatoma cell lines. In vivo, an antisense oligodeoxynucleotide directed against the 5'-region of the pre-S gene of the duck hepatitis B virus inhibited viral replication and gene expression in ducks. In vitro, ribozymes accurately cleave HBV substrate RNA. Triple helix formation is another very promising molecular approach. Results in hepadnaviral infection are not yet available, however.

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Potent inhibition of Epstein-Barr virus by phosphorothioate oligodeoxynucleotides without sequence specification

Cited by 27 publications

References 25 publications

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

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

Use of 2'-fluoro-5-methyl-beta-L-arabinofuranosyluracil as a novel antiviral agent for hepatitis B virus and Epstein-Barr virus

Molecular therapeutic strategies in hepatitis B virus infection

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