Antiviral Action and Cellular Toxicity of Four Thymidine Analogues: 5-Ethyl-, 5-Vinyl-, 5-Propyl-, and 5-Allyl-2′-Deoxyuridine

Cheng, Yung‐Chi; Domin, Barbara A.; Sharma, Ram A.; Bobek, M.

doi:10.1128/aac.10.1.119

Cited by 106 publications

(32 citation statements)

References 9 publications

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“…These results suggest that L-I-OddU could serve as a "selective alternate substrate" as described in our previous study (5) and can explain the good selective therapeutic index observed with this compound. While EBV TK appears to be responsible for the formation of L-I-OddUMP, further phosphorylation may occur by human dTMP kinase and NDP kinase to form L-I-OddUDP and L-I-OddUTP, respectively.…”

Section: Discussionsupporting

confidence: 82%

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: Discussionsupporting

confidence: 82%

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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“…A new approach has evolved from the discovery in 1963 of a virally specified enzyme, thymidine kinase (TK) in HSV-infected cells (7). The specificity of this enzyme allows it to selectively trap certain nucleoside analogs within HSV-infected cells and has been of use in developing effective antiviral drugs with low toxicity (3,6). It also offers the promise that a nucleoside analog labeled with a gamma-emitting isotope might be of value in detecting HSV infections and could be utilized in a selective brain scan for HSV encephalitis.…”

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confidence: 99%

Quantitative uptake studies of 131I-labeled (E)-5-(2-iodovinyl)-2'-deoxyuridine in herpes simplex virus-infected cells in vitro

Gill¹,

Samuel²,

Wiebe³

et al. 1984

Antimicrob Agents Chemother

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We have synthesized a 131I-radiolabeled antiviral compound (E)-5-(2-iodovinyl)-2'-deoxyuridine (IVdU) and shown that this agent was selectively trapped within rabbit kidney cells, infected in vitro by thymidine kinase-positive (TK+) herpes simplex virus (HSV). The uptake of 131I-labeled IVdU was specific, as it was not concentrated within either HSV (TK-) or mock-infected cells. In certain conditions, over 40% of the radiolabel was selectively trapped within HSV (TK+)-infected cells. This was a 20- to 30-fold increase over the uptake of 131I-labeled IVdU by HSV (TK-) or mock-infected cells. The uptake of 131I-labeled IVdU varied directly with (i) the dose of the virus used to infect the rabbit kidney cells; (ii) the concentration of radiolabeled IVdU added to the system; and (iii) the time of exposure of IVdU to infected cells. The ability of this agent to be trapped within HSV (TK+)-infected cells merits further evaluation in animal models as it has potential as a noninvasive, herpes-specific diagnostic test, in particular for HSV encephalitis.

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“…Virus-specific DNA polymerase (deoxynucleoside triphosphate:DNA nucleotidyltransferase, EC 2.7.7.7) is one of the target enzymes most suitable for this purpose (1)(2)(3). Several nucleoside analogs inhibit virus replication by affecting this enzyme (4)(5)(6)(7)(8)(9). Acyclovir [ACV; 9-(2-hydroxyethoxymethyl)guanine] is one of a class of antiviral compounds recently shown to be effective in a variety of herpesvirus infections in vitro and in animal models (10).…”

mentioning

confidence: 99%

Acyclovir inhibition of Epstein-Barr virus replication.

Datta¹,

Colby²,

Shaw³

et al. 1980

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

117

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Acyclovir [92-hydroxyethoxymethyl)guanineJ triphosphate inhibits Epstein-Barr virus (EBV)associated DNA polymerase (DNA nucleotidyltransferase; EC 2.7.7.7) to a greater extent than it inhibits host a and jB DNA polymerases. The affinity of the compound for viral polymerase is 100-fold higher than for a-polymerase. Selective prevention of virus replication can be attained by compounds that inactivate the novel enzymes necessary for virus growth. Virus-specific DNA polymerase (deoxynucleoside triphosphate:DNA nucleotidyltransferase, EC 2.7.7.7) is one of the target enzymes most suitable for this purpose (1-3). Several nucleoside analogs inhibit virus replication by affecting this enzyme (4-9). Acyclovir [ACV; 9-(2-hydroxyethoxymethyl)guanine] is one of a class of antiviral compounds recently shown to be effective in a variety of herpesvirus infections in vitro and in animal models (10). In both herpes simplex virus (HSV) type I and type II systems the drug is highly effective with an ED50 (effective dose required for 50% inhibition) of 0.1-0.2 AM without adverse effect on the host cells.Studies on the mechanism of action of this compound in HSV systems have shown that the drug is phosphorylated by the virus-specified thymidine kinase to its monophosphate form, which is subsequently converted to triphosphate by the host enzyme systems (11, 12). The triphosphorylated form of this compound inhibits viral DNA synthesis by inhibiting viral DNA polymerase by competing with dGTP (13). Results have been presented to suggest that the drug is incorporated into HSV DNA chains and thus terminates viral DNA synthesis (13). Recent genetic experiments also suggest that at least two virally coded functions, namely, virus-specific thymidine kinase and DNA polymerase, are responsible for the action of acyclovir in HSV-infected cells (14,15).The compound is also effective in inhibiting Epstein-Barr virus (EBV) replication at drug-dosage levels (6-7 ,uM) The present studies show that acyclovir triphosphate inhibits EBV-associated DNA polymerase to a much greater extent than it inhibits host a-and /3-polymerases. The triphosphorylated form of the drug behaves as a classical competitive inhibitor of EBV DNA polymerase with respect to dGTP. The concept that the action of this drug is reversible is further supported by the fact that the virus-producing cells (P3HR-1) exposed to the drug over a long period of time show lowered levels of viral capsid antigen (VCA) and viral genome numbers that return to control levels with the removal of the drug. These observations, coupled with the apparent inefficient phosphorylation of ACV in EBV-infected cells (unpublished results), in contrast to the striking and selective phosphorylation in HSV-infected cells (11,12), lead us to propose that the high sensitivity of EBVassociated DNA polymerase towards ACV triphosphate accounts for the inhibition of EBV replication. In this case a small amount of phosphorylated drug, phosphorylated perhaps by host thymidine or purine nucleoside kinases, is...

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Antiviral Action and Cellular Toxicity of Four Thymidine Analogues: 5-Ethyl-, 5-Vinyl-, 5-Propyl-, and 5-Allyl-2′-Deoxyuridine

Cited by 106 publications

References 9 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

Quantitative uptake studies of 131I-labeled (E)-5-(2-iodovinyl)-2'-deoxyuridine in herpes simplex virus-infected cells in vitro

Acyclovir inhibition of Epstein-Barr virus replication.

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