Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.7.7.7 (DNA polymerase)
17,007 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Phosphonoacetic acid (PAA) inhibits the replication of herpes simplex virus in BSC-1 cells and the in vitro synthesis of deoxyribonucleic acid (DNA) in isolated nuclei. Phosphonopropionic acid at a concentration of 100 mug/ml had no effect on herpes simplex virus replication. PAA-resistant mutants were obtained at a rate of 1 in 10(4) plaque-forming units after 5-bromodeoxyuridine mutagenization of the virus. These mutants replicate in BSC-1 cells in the presence of 100 mug of PAA per ml and induce a PAA-resistant DNA polymerase that synthesizes DNA in vitro in the presence of PAA.
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PMID:Phosphonoacetic acid-resistant mutants of herpes simplex virus: effect of phosphonoacetic acid on virus replication and in vitro deoxyribonucleic acid synthesis in isolated nuclei. 19 14

A DNA- temperature-sensitive mutant of herpes simplex virus type 1 exhibiting thermolabile DNA polymerase activity, tsD9, was shown to be resistant to phosphonoacetic acid (PAA) when plated at the permissive temperature. ts+ revertants of tsD9 were PAA sensitive and exhibited DNA polymerase activity intermediate between that of the wild-type virus and tsD9, indicating that both temperature sensitivity and sensitivity to PAA are controlled by the same gene. Since the position of tsD9 on the existing herpes simplex virus type 1 linkage map is known, the locus for PAA resistance--and therefore for the structural gene for viral DNA polymerase--has been identified.
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PMID:Genetics of resistance to phosphonoacetic acid in strain KOS of herpes simplex virus type 1. 19 75

Temperature-sensitive (ts) mutants in a number of complementation groups of herpes simplex virus type 1 (HSV-1) are deficient in DNA polymerase induction at the restrictive temperature. Twenty-two mutants in 15 complementation groups were tested for sensitivity to phosphonoacetate (PAA), a compound that inhibits HSV replication in vivo and the DNA polymerase in vitro. One mutant, tsD9, was resistant to PAA (Pr), whereas all others were sensitive. Revertants of tsD9 to the ts+ phenotype simultaneously lost PAA resistance. Additional Pr mutants were isolated from ts mutants belonging to several complementation groups of HSV-1. Double mutants (ts Pr phenotype) were used in three-factor recombination analyses to locate the PAA locus on the genetic map at a position indistinguishable from the ts lesion in tsD9. In all cases, resistance or sensitivity to PAA in vivo was correlated with resistance or sensitivity of DNA polymerase in vitro. These data are compatible with the temperature-sensitive lesion of tsD9 and the determinant of PAA sensitivity both residing in the structural gene for DNA polymerase.
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PMID:Herpes simplex virus DNA polymerase as the site of phosphonoacetate sensitivity: temperature-sensitive mutants. 19 34

Herpes simplex virus (HSV), which was partially resistant to the inhibitory effect of disodium phosphonoacetate (PAA), could be recovered following four virus passages in the presence of 100 microgram/ml PAA. Resistant strains were isolated from both HSV type 1 and HSV type 2. Virus resistance to PAA was not complete, and in most isolations a significant proportion of the virus stock remained susceptible to the drug. Resistance was shown to be heritable and persisted through virus passage and cloning experiments. PAA inhibited the replication of virus-specific DNA in sensitive strains of HSV but not in resistant strains of HSV. In vitro experiments directly demonstrated that PAA inhibited the activity of the virus-specific DNA polymerase 10 times more effectively in PAA-susceptible HSV than in PAA-resistant HSV. The treatment of HSV-infected mice with high levels of PAA did not induce the formation of resistant virus strains.
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PMID:Characteristics of herpes simplex virus resistance to disodium phosphonoacetate. 20 88

A guanine derivative with an acyclic side chain, 2-hydroxyethoxymethyl, at position 9 has potent antiviral activity [dose for 50% inhibition (ED(50)) = 0.1 muM] against herpes simplex virus type 1. This acyclic nucleoside analog, termed acycloguanosine, is converted to a monophosphate by a virus-specified pyrimidine deoxynucleoside (thymidine) kinase and is subsequently converted to acycloguanosine di- and triphosphates. In the uninfected host cell (Vero) these phosphorylations of acycloguanosine occur to a very limited extent. Acycloguanosine triphosphate inhibits herpes simplex virus DNA polymerase (DNA nucleotidyltransferase) 10-30 times more effectively than cellular (HeLa S3) DNA polymerase. These factors contribute to the drug's selectivity; inhibition of growth of the host cell requires a 3000-fold greater concentration of drug than does the inhibition of viral multiplication. There is, moreover, the strong possibility of chain termination of the viral DNA by incorporation of acycloguanosine. The identity of the kinase that phosphorylates acycloguanosine was determined after separation of the cellular and virus-specified thymidine kinase activities by affinity chromatography, by reversal studies with thymidine, and by the lack of monophosphate formation in a temperature-sensitive, thymidine kinase-deficient mutant of the KOS strain of herpes simplex virus type 1 (tsA1).
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PMID:Selectivity of action of an antiherpetic agent, 9-(2-hydroxyethoxymethyl) guanine. 20 61

The phosphonacetic acid (PAA)-susceptible deoxyribonucleic acid (DNA) polymerase of herpes simplex virus type 1 was partially purified and isolated in sucrose gradients and on double-strand DNA cellulose columns. The DNA polymerase isolated from cells infected with the PAA-resistant mutant had the same molecular weight as the wild-type enzyme (140,000 to 149,000) but was consistently more resistant to PAA.
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PMID:Deoxyribonucleic acid polymerase of wild-type and phosphonoacetic acid-resistant mutant of herpes simplex virus. 20 49

Replication of herpes simplex virus type I (HSV-I) was studied in various cell lines of rat nervous system origin. Infection of neonatal rat glial primary cells with HSV-I, strain KOS, produced normal yields of progeny virus. Glioma lines B9 and B15 were permissive, the neuronal line B50 was partially restricted (10 to 100-fold reduction) and the neuronal line B103 was non-permissive (greater than 1000-fold reduction) for HSV-I (KOS) replication. Synthesis of virus DNA in infected B103 cells was not detected. However, at least some virus macromolecular synthesis was induced, including production of thymidine kinase, DNA polymerase and virus structural proteins.
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PMID:Infection by herpes simplex virus and cells of nervous system origin: characterization of a non-permissive interaction. 20 30

Phosphonoformate was found to be an inhibitor of the deoxyribonucleic acid polymerase induced by the herpesvirus of turkeys. The apparent inhibition constants were 1 to 3 muM. Phosphonoformate was also able to block the replication in cell culture of Marek's disease herpesvirus, the herpesvirus of turkeys, and herpes simplex virus. It was as effective as phosphonoacetate. Phosphonoformate was not an effective inhibitor of a phosphonoacetate-resistant mutant of the herpesvirus of turkeys nor of its induced deoxyribonucleic acid polymerase.
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PMID:Inhibition of herpesvirus replication and herpesvirus-induced deoxyribonucleic acid polymerase by phosphonoformate. 20

Ultraviolet irradiation of herpes simplex virus (HSV) did not affect the transfer of uncoated virus DNA to the nuclei of infected cells but the synthesis of virus DNA was suppressed. The virus-specific DNA polymerase was synthesized in cells infected with the u.v.-irradiated HF strain of HSV. In cells infected with the u.v.-irradiated KOS strain, the virus DNA polymerase activity was hardly detectable. The two strains of HSV differ in the sensitivity of the virus DNA polymerase gene to u.v.-irradiation.
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PMID:Interaction of ultraviolet-irradiated herpes simplex virus type 1 with BSC-1 cells. 20 61

DNA synthesis in chromatin isolated from herpes simplex virus type 1-infected HeLa cells (HSV chromatin) was examined in vitro. The HSV chromatin was found to carry out an initial limited synthesis of DNA in vitro, 50 to 64 pmol of dTMP incorporated in 10(6) nuclei per 10 min, which is comparable to that found in nuclei isolated from HSV-infected cells. DNA synthesis in vitro proceeded for only 30 min, and both HSV DNA and host DNA were synthesized in significant amounts. The HSV and host DNA synthesis in isolated chromatin were inhibited to the same extent by anti-HSV antiserum or by phosphonoacetic acid. The results indicate that the HSV-induced DNA polymerase is most likely involved in the synthesis of host and HSV DNA in isolated chromatin, even though this chromatin contains small amounts of the host gamma-polymerase in addition to the HSV-induced DNA polymerase. The HSV chromatin contains no detectable levels of DNA polymerases alpha and beta, even though infected cells have normal, or increased, levels of these enzymes.
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PMID:Synthesis of viral and host DNA in isolated chromatin from herpes simplex virus-infected HeLa cells. 20 89


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