Comparison of the Antiviral Effects of 5-Methoxymethyl-deoxyuridine with 5-Iododeoxyuridine, Cytosine Arabinoside, and Adenine Arabinoside

La, Babiuk; Meldrum, Brian S.; Vs, Gupta; Bt, Rouse

doi:10.1128/aac.8.6.643

Cited by 49 publications

(27 citation statements)

References 19 publications

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“…HSV-I, KOS strain, was obtained from P. Schaeffer, Harvard University, Boston, MA. Stocks of HSV-I were prepared [ 131 and the titer of the virus was determined by a plaque assay [2]. The infectivity titer was calculated from the dilution of virus producing between I0 and 100 plaques per well and expressed in plaque forming units (PFU).…”

Section: Methodsmentioning

confidence: 99%

“…Half of the brain and a lobe of the liver, frozen at -70°C for virus isolation, were thawed quickly at 3 7 T , washed in minimal essential medium and homogenized by mortar and pestle in 2.0 and 5.0 ml of minimal essential medium, respectively. The virus titer of the tissue was determined by a modified plaque assay [2] and expressed as loglo of PFU/ml of tissue homogenate.…”

Section: Methodsmentioning

confidence: 99%

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The Effects of Dietary T-2 Toxin on Acute Herpes Simplex Virus Type 1 Infection in Mice

1983

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Abstract. Young male white Swiss mice were fed control diet or diet supplemented with 20 or 10 parts per million (ppm) of T-2 toxin for two or three weeks. These mice then were inoculated with herpes simplex virus type I (HSV-1) (9.6 X lo6 plaque forming units) intraperitoneally. To compare the effects of T-2 toxin against a known immunosuppressive drug, cyclophosphamide was injected intraperitoneally at I50 mg/kg, 24 hours after treatment with HSV-1. into mice fed the control diet. Mice were necropsied and tissues were collected for microscopic and virologic examination.White Swiss mice which consumed a daily diet containing 20 ppm of T-2 toxin for two or three weeks were highly susceptible to HSV-I infection and 27 of 36 (75%) died as a result of extensive hepatic and adrenal necrosis. Although HSV-1 was isolated from livers and brains of mice fed 20 ppm of T-2 toxin for two or three weeks, there was little or no inflammatory response found in the adrenals, livers, spinal cords, brains, or ganglia. The necrotizing encephalomyelitis observed in control mice was absent.High levels of dietary T-2 toxin appeared to be more immunosuppressive than cyclophosphamide because only one mouse died after treatment with HSV-1 and cyclophosphamide. Mice treated with cyclophosphamide had changes in brain, spinal cord, spleens, thymus, and bone marrow which were similar to those fed 20 ppm of T-2 toxin and infected with HSV-I, however, liver lesions were much less severe.HSV-I-infected mice on a diet with 10 ppm T-2 toxin had lesions of intermediate severity when compared with HSV-I-infected mice fed a diet with 20 ppm T-2 toxin and HSV-Iinfected mice on control diets. Necrosis was less extensive in the livers and adrenals. The infrequent isolation of virus from liver and brain was consistent with the lack of intranuclear inclusion bodies and a more marked inflammatory response. Ten ppm of dietary T-2 toxin only depressed bone marrow and splenic red pulp to a mild or moderate degree. This may have enhanced the necrotizing encephalomyelitis observed in mice killed on days 6 and 8 after HSV-1 infection.Liver lesions were mild and those of the adrenals were moderate in mice fed control diet. The rare isolation of HSV-I from the liver and brain and the finding of a moderate to severe necrotizing encephalomyelitis in these mice was consistent with an essentially functional immune system. T-2 toxin, a trichothecene mycotoxin produced by Fzisurizim spp fungi [5 1, 737

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

The Effects of Dietary T-2 Toxin on Acute Herpes Simplex Virus Type 1 Infection in Mice

1983

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“…Our laboratory has been interested in viral chemotherapy, and, more specifically, the effect of nucleoside analogs on herpes simplex virus infections (1)(2)(3)(4)(5)(6)(7)(8). The nucleoside, 5-methoxymethyl-2'-deoxyuridine (MMdUrd), was synthesized (9) and its selective activity against herpes simplex virus was discovered in the early seventies (2).…”

Section: Introductionmentioning

confidence: 99%

Structure and conformation of 5-methoxymethyl-1-(2′-deoxy-β-D-lyxofuranosyl)uracil

Quail¹,

Ekiel²,

El‐Kabbani³

et al. 1986

Can. J. Chem.

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). The structure of the nucleoside 5-methoxymethyl-l-(2'-deoxy-~-~-lyxofuranosyl)uracil (MMdLU) was deduced by X-ray crystallographic analysis. MMdLU crystallized in space group P2' with a = 8.719(4), b = 13.188(3), c = 5.701(3) A, P = 109.56(2)" and Z = 2; R = 0.040 for 1208 unique reflections with net I > 2u(I). The furanose ring adopts the rare C(4'fiexo envelope conformation (4E). The glycosyl linkage is anti (X = 243.5") and the C(5') side chain has the t conformation. The conformation was also determined in solution by nmr analysis. The sugar ring exists in the N-conformation (97 f 5%), the populations of the three rotamers about the exocyclic C(4')-C(5') bond were estimated to be g+: t:g-= 23%:59%:18% and the glycosidic conformation is predominantly anti. Faisant appel B la diffraction des rayons X, on a dCterminC la structure du nuclkoside mCthoxymCthyl-5 (dCoxy-2' P-D-lyxofurannosy1)-1 uracil (MMdLU). Le MMdLU cristallise dans le groupe d'espace P2, avec a = 8,719(4), b = 13,188(3) et c = 5,701(3) A. P = 109,56(2)" et Z = 2; R = 0,040 pour 1208 rkflexions uniques avec I > 2u(1). Le cycle furannose adopte la configuration enveloppe C(4')-exo (4E) qui est rare. La liaison glycosidique est anti (X = 243,5") alors que la chaine latkrale C(5 ') adopte une conformation t. On a aussi dCterminC la conformation en solution en se basant sur une analyse par rmn. Le cycle du sucre existe dans la conformation-N (97 f 5%) et on a kvaluk que les populations des trois rotamtres autour de la liaison exocyclique C(4')-C(5') sont g+: t:g-= 23%:59%:18% et la conformation glycosidique est principalement anti.[Traduit par la revue]

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“…In contrast, more recently discovered 5-substituted deoxyuridine analogues, such as MMdUrd (Babiuk et et., 1975;Gupta, 1981), EtdUrd (Swierkowski and Shugar, 1969)and BrVdUrd (DeClercq et al, 1979)have a selective inhibitory effect on HSV replication. These compounds appear to owe their selectivity to preferential phosphorylation initially by viral-induced thymidine kinase (TK)* to the monophosphate, (Cheng et sl., 1981a(Cheng et sl., , 1981bLarder et al, 1983;Gupta et aI., 1987) followed by subsequent phosphorylation by cellular kinases to the triphosphate which is the active drug (Allaudeenet al, 1981(Allaudeenet al, ,1982Ruth and Cheng, 1981;Mancini et al, 1983;Otto and Prusoff, 1984;Reid et al, 1987).…”

mentioning

confidence: 99%

Interaction of 5-Methoxymethyl-2′-Deoxyuridine Triphosphate with DNA Polymerases: Effects of the 5-Substituent and Comparison with the Deoxycytidine Derivative

Aduma

Gupta

1992

Antivir Chem Chemother

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Summary 5-Methoxymethyl-2'-deoxyuridine (MMdUrd) is a selective anti-herpes agent that is dependent upon initial phosphorylation by Herpes simplex virus-' induced deoxythymidine kinase. In order to determine its mechanism of action, MMdUrd was converted to the 5' -triphosphate (MMdUTP) and the nature of interaction of MMdUTP and dTTP with DNA polymerase of E. coli, HSV-1, and human a was investigated. The order of utilization of deoxyuridine analogues by bacterial and HSV-1 DNA polymerases for DNA synthesis was: dTTP > MMdUTP. In contrast, 5-methoxymethyl-2'-deoxycytidine-5'·triphosphate (MMdCTP) was a better substrate for HSV DNA polymerase compared to dCTP. MMdUTP is a competitive inhibitor of HSV-1 DNA polymerase with respect to dTTP incorporation (Kj = 2.9 x 10-6 M). The IC so values of MMdUTP for both HSV and human aDNA polymerases were 4.5 x 10-6 M . These data suggest that the selective activity of MMdUrd is due to its preferential phosphorylation by viral thymidine kinase and not at the DNA polymerase level. These results may also account for the difference in anti-HSV activity between MMdUrd and its deoxycytidine analogue.The first generation antivirals, such as iododeoxyuridine and triflurothymidine (Prusoff, 1979;King and Heidelberger, 1979), are useful drugs for treatment of herpes Received 2 December, 1991; revised 15 February, 1992 simplex virus (HSV) infections but lack selectivity. In contrast, more recently discovered 5-substituted deoxyuridine analogues, such as MMdUrd (Babiuk et et., 1975;Gupta, 1981), EtdUrd (Swierkowski and Shugar, 1969)and BrVdUrd (DeClercq et al., 1979)have a selective inhibitory effect on HSV replication. These compounds appear to owe their selectivity to preferential phosphorylation initially by viral-induced thymidine kinase (TK)* to the monophosphate, (Cheng et sl., 1981a(Cheng et sl., , 1981bLarder et al., 1983; Gupta et aI., 1987) followed by subsequent phosphorylation by cellular kinases to the triphosphate which is the active drug (Allaudeenet al., 1981(Allaudeenet al., ,1982Ruth and Cheng, 1981;Mancini et al., 1983;Otto and Prusoff, 1984;Reid et al., 1987). The lack of activity against HSV mutants (with a mutation in the TK gene) further lends credibility to the suggestion that viral TK is required for their activation.Deoxycytidine analogues are more selective inhibitors of HSV than their corresponding deoxyuridine derivatives (Doberson and Greer, 1978; De Clercq et aI., 1982). Our studies with BrVdCyd and MMdCyd (5-methoxymethyl-2'-deoxycytidine) in combination with deaminase inhibitors have shown that the selectivity of these compounds is most likely due to specific interaction with HSV TK and viral DNA polymerase (Aduma et al., 1990a(Aduma et al., , 1990b(Aduma et al., , 1991 Gupta et el., 1991).The substrate specificity towards viral-TK appears to be related to the chain length of the substituent at the C(5) position of the pyrimidine ring. This in turn seems to determine specificity and cytotoxicity of nucleoside analogues. For example, EtdUrd inhibits r...

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Comparison of the Antiviral Effects of 5-Methoxymethyl-deoxyuridine with 5-Iododeoxyuridine, Cytosine Arabinoside, and Adenine Arabinoside

Cited by 49 publications

References 19 publications

The Effects of Dietary T-2 Toxin on Acute Herpes Simplex Virus Type 1 Infection in Mice

The Effects of Dietary T-2 Toxin on Acute Herpes Simplex Virus Type 1 Infection in Mice

Structure and conformation of 5-methoxymethyl-1-(2′-deoxy-β-D-lyxofuranosyl)uracil

Interaction of 5-Methoxymethyl-2′-Deoxyuridine Triphosphate with DNA Polymerases: Effects of the 5-Substituent and Comparison with the Deoxycytidine Derivative

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