Regulatory effects of deoxyribonucleosides on the activity of 5-methoxymethyl-2′-deoxycytidine: Modulation of antiherpes activity by deoxyguanosine and tetrahydrodeoxyuridine

Aduma, P. J.; Gupta, Sagar V.; Tourigny, Guy

doi:10.1016/0166-3542(91)90011-f

Antiviral Research

1991

DOI: 10.1016/0166-3542(91)90011-f

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Regulatory effects of deoxyribonucleosides on the activity of 5-methoxymethyl-2′-deoxycytidine: Modulation of antiherpes activity by deoxyguanosine and tetrahydrodeoxyuridine

P. J. Aduma¹,

Sagar V. Gupta²,

Guy Tourigny³

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Cited by 7 publications

(3 citation statements)

References 15 publications

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“…The significance of the dCMP deaminase pathway in HSV-1-infected cells has since been analysed by means of halogenated analogues of deoxycytidine and deaminase inhibitors. The results of these studies indicate that during virus replication the bulk of TTP for viral DNA synthesis is derived mainly from this pathway (Aduma et al, 1990(Aduma et al, , 1991. In the present study, we have shown that the cellular content of the dCMP deaminase protein is upregulated following HCMV infection of quiescent fibroblasts.…”

supporting

confidence: 54%

Human cytomegalovirus requires cellular deoxycytidylate deaminase for replication in quiescent cells

Gribaudo¹,

Riera²,

Caposio³

et al. 2003

Journal of General Virology

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We have previously observed that the expression of two thymidylate biosynthesis enzymes, dihydrofolate reductase and thymidylate synthase (TS), is upregulated in quiescent human fibroblasts infected with human cytomegalovirus (HCMV). Here, we have demonstrated that HCMV increases expression of the cellular deoxycytidylate deaminase (dCMP deaminase), which provides the substrate for TS by converting dCMP to dUMP. We observed an increase in dCMP deaminase protein levels, whereas deoxyuridine triphosphatase (dUTPase), another cellular enzyme that may provide dUMP by hydrolysing dUTP, was undetectable. The essential requirement of cellular dCMP deaminase for productive HCMV replication was further emphasized by showing that a precursor of a potent dCMP deaminase inhibitor, zebularine, suppressed virus replication and DNA synthesis. These results suggest that HCMV exploits the host's dCMP deaminase activity to replicate in quiescent cells.Human cytomegalovirus (HCMV) is a ubiquitous herpesvirus which generally causes asymptomatic infections in healthy individuals but may lead to severe diseases in immunologically immature or immunocompromised hosts (Mocarski & Courcelle, 2001;Landolfo et al., 2002). Its success as an opportunist largely depends on its ability to establish latent life-long infections, counteract host antiviral defence mechanisms and replicate in a wide variety of cells and tissues, including differentiated post-mitotic cells such as mesenchymal cells, endothelial cells, epithelial cells, smooth muscle cells and monocytes/macrophages (Hengel et al., 1998;Fortunato et al., 2000;Bissinger et al., 2002).Unlike other herpesviruses, HCMV does not encode specific dNTP biosynthetic enzymes, such as thymidine kinase (TK), dihydrofolate reductase (DHFR), thymidylate synthase (TS) or an active form of ribonucleotide reductase (Chee et al., 1990). It thus depends mainly on host cell metabolism for a sufficient concentration of dNTPs for the replication of its DNA. However, the biochemical pathways needed for such replication are expressed at very low levels in non-dividing cells. To explain this apparent paradox, it has been hypothesized that in these cells HCMV infection stimulates the relevant host dNTP-synthesizing enzymes. We have indeed demonstrated that this occurs for some of the enzymes involved in thymidylate biosynthesis, since infection of quiescent fibroblasts with both murine and human CMV increases cellular DHFR and TS content, and inhibition of these activities abrogates virus replication (Lembo et al., 1998(Lembo et al., , 1999Gribaudo et al., 2000Gribaudo et al., , 2002. TS catalyses the de novo biosynthesis of thymidylic acid (dTMP) by reductive transfer of the methylene group from 5,10-methylenetetrahydrofolate to the 5-position of the substrate, deoxyuridylic acid (dUMP), to form dTMP and dihydrofolate (Maley & Maley, 1990;Johnson, 1994). Therefore, the intracellular availability of dUMP may be the rate-limiting step in dTMP biosynthesis and hence critical for efficient CMV replication in quie...

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supporting

confidence: 54%

Human cytomegalovirus requires cellular deoxycytidylate deaminase for replication in quiescent cells

Gribaudo¹,

Riera²,

Caposio³

et al. 2003

Journal of General Virology

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“…Reduced nucleoside analogs are of great interest as tools for understanding the chemistry and biology of nucleic acids, for probing proteins to which they bind, and for their medicinal properties 1–5. Tetrahydrouridines (THUs) and dihydrouridines (DHUs) (Figure 1) have been used in various studies, including as transition-state analogs of cytidine deaminase inhibitors (CDA) 6, 7.…”

mentioning

confidence: 99%

“…Reduced nucleoside analogues are of great interest as tools for understanding the chemistry and biology of nucleic acids, for probing proteins to which they bind, and for their medicinal properties. − Tetrahydrouridines (THUs) and dihydrouridines (DHUs) (Figure ) have been used in various studies, including as transition-state analogues of cytidine deaminase inhibitors (CDA). , Our own interest in the deoxynucleoside of THU relates to ongoing studies of the human APOBEC3G cytidine deaminase domain, which plays a defensive role in HIV infection. , In studies of CDA substrate analogue inhibitors, a tetrahedral transition state is proposed, such as that involving in situ generation of zebularine hydrate 2 from zebularine 1 (Scheme ) . Reduced pyrimidine analogues enabled the study of the hydrate as a discreet chemical entity .…”

mentioning

confidence: 99%

Synthesis of Deoxytetrahydrouridine

2009

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The α-hydroxyamido functionality of 2′-deoxytetrahydrouridine (dTHU) makes this seemingly simple and generally useful compound difficult to obtain. Reported synthetic strategies produce extremely poor yields and multiple products, and full characterization data is not available. Described herein is a two-step approach for synthesizing dTHU in increased yields and purity; stability concerns are also addressed. Catalytic reduction (5% Rh/alumina) of 2′-deoxyuridine, followed by reduction with sodium borohydride as a limiting reagent produces dTHU and limits formation of side products. Evidence was obtained for formation of a methoxy-substituted analog during purification. By this strategy, dTHU of >95% purity can be obtained in 40% yield on a 150mg scale.Reduced nucleoside analogs are of great interest as tools for understanding the chemistry and biology of nucleic acids, for probing proteins to which they bind, and for their medicinal properties. [1][2][3][4][5] Tetrahydrouridines (THUs) and dihydrouridines (DHUs) (Figure 1) have been used in various studies, including as transition-state analogs of cytidine deaminase inhibitors (CDA). 6,7 Our own interest in the deoxynucleoside of THU relates to ongoing studies of the human APOBEC3G cytidine deaminase domain, which plays a defensive role in HIV infection. 8,9 In studies of CDA substrate analog inhibitors, a tetrahedral transition state is proposed, such as that involving in situ generation of zebularine hydrate 2 from zebularine 1 (Scheme 1). 10 Reduced pyrimidine analogs enabled the study of the hydrate as a discreet chemical entity. 11 Thus,3,4,5, and the deoxy-analog dTHU have been subjects of research for over forty years. 1, 12 However, we were surprised to find that reported methods to prepare the compound are notably inefficient, and no diagnostic spectroscopic data are available in the literature. This report addresses a long-standing need for a reliable method to synthesize dTHU and provides its full chemical characterization. Photoreduction, catalytic hydrogenation, and borohydride reduction have been used to transform pyrimidine nucleosides to their hydropyrimidinone analogues. 1,13 Typically referenced for the synthesis of dTHU is a 1967 study by Hanze and co-workers detailing the synthesis of THU. 1 The procedure involves Rh/alumina-catalyzed hydrogenation of cytidine, to yield 3,4,5,6-tetrahydrocytidine. Acetic acid-mediated hydrolysis of this intermediate is reported to provide THU after multiple purification steps. While this general procedure can be used to synthesize the deoxy-analog dTHU from deoxycytidine (Scheme 2), in our experience, yields are poor (<1%) for a >95% purity sample of dTHU. The major drawback in application of Hanze's route is the difficult separation of dTHU from multiple impurities generated during the synthesis. Our experiences with dTHU preparation are consistent with Hanze's observations for the synthesis of THU. On the basis of MS and 1 H NMR analysis of the resulting mixture, major contaminants result from inco...

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Relationship Between Conformation and Antiviral Activity -IV. 5-Ethyl-2′-Deoxyurldine and 5-Ethyl-2′-Deoxycytidine⁺

Kumar

Gupta

Zoghaib

et al. 1997

Nucleosides and Nucleotides

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Regulatory effects of deoxyribonucleosides on the activity of 5-methoxymethyl-2′-deoxycytidine: Modulation of antiherpes activity by deoxyguanosine and tetrahydrodeoxyuridine

Cited by 7 publications

References 15 publications

Human cytomegalovirus requires cellular deoxycytidylate deaminase for replication in quiescent cells

Human cytomegalovirus requires cellular deoxycytidylate deaminase for replication in quiescent cells

Synthesis of Deoxytetrahydrouridine

Relationship Between Conformation and Antiviral Activity -IV. 5-Ethyl-2′-Deoxyurldine and 5-Ethyl-2′-Deoxycytidine⁺

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Regulatory effects of deoxyribonucleosides on the activity of 5-methoxymethyl-2′-deoxycytidine: Modulation of antiherpes activity by deoxyguanosine and tetrahydrodeoxyuridine

Cited by 7 publications

References 15 publications

Human cytomegalovirus requires cellular deoxycytidylate deaminase for replication in quiescent cells

Human cytomegalovirus requires cellular deoxycytidylate deaminase for replication in quiescent cells

Synthesis of Deoxytetrahydrouridine

Relationship Between Conformation and Antiviral Activity -IV. 5-Ethyl-2′-Deoxyurldine and 5-Ethyl-2′-Deoxycytidine+

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Product

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Relationship Between Conformation and Antiviral Activity -IV. 5-Ethyl-2′-Deoxyurldine and 5-Ethyl-2′-Deoxycytidine⁺