Mode of inhibition of Herpes simplex virus DNA polymerase by phosphonoacetate

Mao, James C.-H.; Robishaw, Ellen E.

doi:10.1021/bi00696a015

Cited by 141 publications

(59 citation statements)

References 20 publications

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“…We first examined the transcription of viral genes as a function of viral DNA replication. Cells were infected with the wild-type strain HSV-1 KOS1.1 in the presence or absence of phosphonoacetic acid, a specific inhibitor of the viral DNA polymerase (37). Transcription was assayed in nuclei pre- The film was preflashed and exposed at -70°C for 24 hr with an intensifying screen.…”

Section: Resultsmentioning

confidence: 99%

Transcriptional control of herpesvirus gene expression: gene functions required for positive and negative regulation.

Godowski¹,

Knipe²

1986

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

157

160

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We have used an in vitro nuclear run-off assay to measure the levels of transcription of specific herpes simplex virus genes at different times during a lytic infection. We analyzed the effects of inhibition of DNA replication and of defects in two herpes simplex virus regulatory proteins on the transcription of these genes. We present evidence that the transcription of the aJCP4 gene is negatively regulated during a lytic infection. The regulation of ICP4 gene transcription requires the fi protein ICP8 (where ICP = infected cell polypeptide). Transcription of the PICP8, yICP5, and y2 glycoprotein C (gC) genes was dependent on ICP4, and transcription of the y2gC gene was strongly inhibited when DNA replication was blocked. Defects in ICP8 also resulted in increased levels of transcription of the ICP4, ICP8, ICP5, and gC genes from parental viral genomes. Our results suggest that ICP8 may be important in maintaining the highly ordered cascade of viral gene expression. 256The publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact.

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Section: Resultsmentioning

confidence: 99%

Transcriptional control of herpesvirus gene expression: gene functions required for positive and negative regulation.

Godowski¹,

Knipe²

1986

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

157

160

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“…In recent years several compounds have been described which are all endowed with selective anti-herpes properties. These compounds include phosphonoacetic acid (3,4), phosphonoformic acid (5, 6), 9-f3-D-arabinofuranosyladenine (araA) (7,8), 5-iodo-5'-amino-2',5'-dideoxyuridine (AIDDU) (9, 10), 9-(2-hydroxyethoxymethyl)guanine (acycloguanosine) (11,12), 1-f3-D-arabinofuranosylthymine (araT) (13,14), 5-iodo-and 5-bromo-2'-deoxycytidine (15, 16), 5,6-dihydro-5-azathymidine (17,18), and erythro-9-[3-(2-hydroxynonyl)]adenine (EHNA) (19). Among the 5-substituted 2'-deoxyuridines, various compounds-namely, 5-methylamino-dUrd (20), 5-methoxymethyl-dUrd (21), 5-propyl-dUrd (22), and 5-propynyloxy-dUrd (23)-proved more inhibitory to herpes than to any other DNA (or RNA) virus.…”

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confidence: 99%

(E)-5-(2-Bromovinyl)-2'-deoxyuridine: a potent and selective anti-herpes agent.

Clercq¹,

Descamps²,

Somer³

et al. 1979

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

437

198

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Of a series of five newly synthesized 2'-deoxyuridine derivatives, including 5(1-chlorovinyl)-dUrd, (E--(2-bromovinyl)-dUrd, and (E)5-(2-iodovinyl).dUrd, the last two compounds were found to exert a marked inhibitory effect on the replication of herpes simplex virus type 1 [ID50 (mean inhibitory dose), 0.004-0.02 ;tg/mll.Both (E)5(2-bromovinyl).dUrd and (E>5S(2-iodovinyl).dUrd were highly selective in their anti-herpes activity in that they did not affect the growth or metabolism of the host (primary rabbit kidney) cells unless drug concentrations were used that were 5,000-to 10,000-fold greater than those required to inhibit virus multiplication. In this sense (E-5-2-bromovinyl Idoxuridine (5-iodo-2'-deoxyuridine) and trifluorothymidine (5-trifluoromethyl-2'-deoxyuridine) are among the best known antiviral agents currently used in the chemotherapy of-herpesvirus infections (1). Their clinical usefulness is restricted to the topical treatment of local herpes simplex virus (HSV) infections such as herpetic keratitis and "cold sores" (herpes labialis). The unfavorable therapeutic index of Idoxuridine when administered parenterally-as most dramatically exemplified by its inefficacy in patients with herpes simplex encephalitis (2)-has prompted the search for more effective and less toxic anti-herpes agents. In recent years several compounds have been described which are all endowed with selective anti-herpes properties. These compounds include phosphonoacetic acid (3, 4), phosphonoformic acid (5, 6), 9-f3-D-arabinofuranosyladenine (araA) (7, 8), 5-iodo-5'-amino-2',5'-dideoxyuridine (AIDDU) (9, 10), 9-(2-hydroxyethoxymethyl)guanine (acycloguanosine) (11, 12), 1-f3-D-arabinofuranosylthymine (araT) (13, 14), 5-iodo-and 5-bromo-2'-deoxycytidine (15, 16), 5,6-dihydro-5-azathymidine (17, 18), and erythro-9-[3-(2-hydroxy- vinyl)-dUrd. These compounds surpassed all previously described anti-herpes agents, including acycloguanosine, in both potency and selectivity, at least in primary rabbit kidney (PRK) cells infected with herpes simplex virus type 1 (HSV-1). Compounds 5-Vinyl-dUrd, 5-ethynyl-dUrd, (E)-5-(2-bromovinyl)-dUrd, and (E)-5-(2-iodovinyl)-dUrd were obtained by condensing the trimethylsilyl derivatives of the appropriate 5-substituted uracils with 2'-deoxy-3,5-di-0-p-toluoyl-a-D-erythropentofuranosyl chloride to give a mixture of the a-and f3-anomers of the protected nucleosides. T anomers were separated by chromatography on silica gel and the p-toluoyl protecting groups were removed by treatment with sodium methoxide in methanol. The results indicated for the biological experiments were all obtained by using the f3-anomers (Fig. 1). The a-anomers were also tested for biological activity, but they were inactive. The synthesis of 25). The synthesis of (E)-5-(2-bromovinyl)-dUrd, (E)-5-(2-iodovinyl)-dUrd, and 5-(1-chlorovinyl)-dUrd has been published elsewhere (ref. 26 and unpublished data). The structures assigned to these compounds were established by elemental analysis and UV and NMR spectroscopy.The sour...

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“…The major DBP is encoded as an E gene product (Quinlan et al, 1984), that is transcription and translation occur before virus DNA synthesis. To study the kinetics of network formation, cells were infected with HSV-2 in the presence of AraA or PAA, conditions known to inhibit virus DN A synthesis (Mao & Robishaw, 1975), after which the distribution of the major DBP was studied. Immunofluorescence studies showed that in the absence of virus DNA synthesis the formation of the network was inhibited.…”

Section: Network Formation Requires Dna Synthesismentioning

confidence: 99%

A Filamentous Distribution for the Herpes Simplex Virus Type 2-encoded Major DNA-binding Protein

Rose¹,

Shriver

Latchman

et al. 1986

Journal of General Virology

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SUMMARYMonoclonal antibodies reacting with the herpes simplex virus (HSV)-encoded major DNA-binding protein defined an intracellular filamentous network. This network was associated predominantly with the infected cell nucleus and occurred in cells infected with HSV type 2. It did not co-distribute with microfilaments, microtubules or intermediate filaments, and DNA synthesis was required for its formation. We suggest explanations for the occurrence and function of this novel filamentous network structure.

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Mode of inhibition of Herpes simplex virus DNA polymerase by phosphonoacetate

Cited by 141 publications

References 20 publications

Transcriptional control of herpesvirus gene expression: gene functions required for positive and negative regulation.

Transcriptional control of herpesvirus gene expression: gene functions required for positive and negative regulation.

(E)-5-(2-Bromovinyl)-2'-deoxyuridine: a potent and selective anti-herpes agent.

A Filamentous Distribution for the Herpes Simplex Virus Type 2-encoded Major DNA-binding Protein

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