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)

Infection of HSB-2 cells with human herpesvirus 6 (HHV6) results in an approximately 51-fold increase in the level of DNA polymerase activity and a 4.44-fold increase in the level of DNase activity when compared to mock-infected cells. There was no increase in thymidine kinase, uracil-DNA glycosylase, or deoxyuridine triphosphate nucleotidohydrolase activities in the infected cells. The HHV6-induced DNase and DNA polymerase activities could be distinguished from their normal cellular counterparts on the basis of immunological specificities and in the case of DNA polymerase based upon differences in electrophoretic migration. Serological studies also demonstrated reactivity of the antisera not only for HHV6 but also for Epstein-Barr virus.
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PMID:Demonstration of the human herpesvirus 6-induced DNA polymerase and DNase. 255 71

Clinically acquired acyclovir resistance in herpes simplex has usually been associated with a deficiency in viral thymidine kinase, which, in turn, has been linked with attenuated virulence in animal models. Diminished pathogenicity in thymidine kinase-deficient isolates has been partly responsible for controversies about the clinical significance of antiviral resistance. We report on a series of resistant virus isolates from a patient who had severe, progressive esophagitis. These isolates had various thymidine kinase activities, ranging from 2.8% to 130% when compared with the activity of the isolate obtained before treatment; the resistant isolate 615 retained enzyme activity as well as neurovirulence in an encephalitis model. Plaque purification showed a heterogeneous mixture containing at least one acyclovir-resistant, foscarnet-resistant plaque isolate (615.8) fully able to phosphorylate acyclovir. The 3.3-kbp BamHI fragment containing most of the DNA polymerase gene from isolate 615.8 was purified and used to successfully transfer both acyclovir and foscarnet resistance. Acquisition of in-vitro acyclovir resistance was associated with progression of clinical disease, as well as with maintenance of pathogenicity in an animal model and at least one mutation in viral DNA polymerase. Patients with herpes simplex infections that progress during acyclovir therapy should be observed for acquisition of resistance in the setting of antiviral chemotherapy; future studies should also consider the presence of heterogeneous virus populations in such patients.
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PMID:Progressive esophagitis from acyclovir-resistant herpes simplex. Clinical roles for DNA polymerase mutants and viral heterogeneity? 255 68

We report a case of orofacial herpes simplex virus (HSV) infection that was progressive despite multiple courses of acyclovir sodium in a patient with the acquired immunodeficiency syndrome. The viral isolate was shown to be resistant to acyclovir in vitro, but proved susceptible to vidarabine and foscarnet sodium (trisodium phosphonoformate). The patient failed to respond to a 2-week course of intravenous vidarabine. However, rapid improvement in the orofacial lesion occurred with intravenous foscarnet. Most HSV isolates that are resistant to acyclovir are spontaneous mutants partially or completely lacking in thymidine kinase. Because foscarnet is a direct inhibitor of HSV DNA polymerase, this compound is expected to have efficacy against acyclovir-resistant strains. This report documents successful treatment of clinically significant HSV with intravenous administration of foscarnet, suggesting that further study is indicated.
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PMID:Successful treatment of progressive acyclovir-resistant herpes simplex virus using intravenous foscarnet in a patient with the acquired immunodeficiency syndrome. 255 19

Citrusinine-I, a new acridone alkaloid isolated from the root bark of the citrus plant (Rutaceae), exhibited potent activity against herpes simplex virus (HSV) type 1 and type 2 at low concentrations relative to their cytotoxicity; 50% effective concentrations (ED50) of citrusinine-I were 0.56 micrograms/ml and 0.74 micrograms/ml against HSV-1 and HSV-2, respectively. Inhibitory action was also demonstrated against cytomegalovirus (CMV) and thymidine kinase-deficient or DNA polymerase mutants of HSV-2. The compound markedly suppressed HSV-2 and CMV DNA synthesis at concentrations which did not inhibit the synthesis of virus-induced early polypeptides. However, citrusinine-I had no inhibitory activity against HSV and CMV DNA polymerases in cell-free extracts. Although the target of this inhibitor remains to be elucidated, the most plausible candidate is a virus-coded ribonucleotide reductase. Citrusinine-1, when combined with acyclovir or ganciclovir, synergistically potentiated the antiherpetic activity of these agents. Based on a comparative study of the antiherpetic activity of citrusinine-1 and 28 related compounds, a structure-activity relationship could be established.
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PMID:Anti-herpesvirus activity of citrusinine-I, a new acridone alkaloid, and related compounds. 255 60

In chick embryo retina during development, DNA synthesis and the activities of DNA polymerase, thymidine kinase, thymidylate synthetase, and ornithine decarboxylase (ODC) declined in parallel from day 7 to 12. The administration in ovo of hydrocortisone reduced significantly, particularly at 8-10 days of incubation, both DNA synthesis and the four enzyme activities tested. The effect was dose dependent, reaching the maximum with 50-100 nmol of hydrocortisone, 8-16 h after treatment. The highest inhibition was found for ODC activity (70%), followed by thymidine kinase activity (62%) and DNA synthesis (45%), whereas activities of DNA polymerase and thymidylate synthetase were reduced only by 30%. The inhibitory effect was exerted by all the glucocorticoids tested, with dexamethasone and hydrocortisone being the most efficacious. The results support the view that glucocorticoids reduce the proliferative events in chick embryo retina, particularly at 8-10 days of embryonic life.
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PMID:Biochemical aspects of chick embryo retina development: the effects of glucocorticoids. 270 12

Exponentially growing human lymphoblasts (culture LS-2) were separated by cell sorting (FACS II, Becton Dickinson) according to their deoxyribonucleic acid (DNA) content, designating them at particular phases of the cell cycle. Prior to cell sorting the DNA has been fluorochrome-labeled with the Hoechst stain H 33342. Maximum cell enrichments of 94% for G0 + G1 cells, 96% for S cells and 74% for G2 + M cells could be achieved. The enzyme activities of thymidine kinase (TK), thymidylate synthase (TS), DNA polymerase (DNA-P), dihydrofolate reductase (FH2-R), methionine synthase (MS), and hexokinase (HK) were determined in the obtained cell fractions. Although incorporation of 3H-thymidine (3H-dTR) and the 3H-dTR labeling index were significantly inhibited by the dye, no evidence of cell staining's having a significant effect on the enzyme activities was found. The enzyme activities for approximately 100% pure G0 + G1, S, and G2 + M cells were computed. With exception of TK, all the enzymes under study were shown to exhibit activities--although of differing degree--in the G0 + G1, S, and G2 + M cells. No TK activity was shown in G0 and G1 cells; its activity, however, was approximately the same in S and G2 + M cells. This applies likewise for TS which, in contrast to TK, exhibits minor activity in G0 + G1 cells. DNA-P was highly active in G0 + G1 cells, but maximum activity was in S cells. FH2-R exhibited maximum activity in S cells, although the difference in activity between S and G2 + M cells was not significant. None of the observed differences in MS activity was significant, indicating equally high activity in cells of all cell cycle phases. HK activity is approximately twice as high in G2 + M cells as in G0 + G1 cells.
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PMID:Relation between cell cycle stage and the activity of DNA-synthesizing enzymes in cultured human lymphoblasts: investigations on cells separated according to DNA content by way of a cell sorter. 271 50

Treatment of HSV-infected cells with 5-10 mM beta-hydroxynorvaline (Hnv), a threonine analog, specifically affects herpesvirus DNA replication: both the rate of and total DNA synthesis are reduced, the former approximately 15-fold by Hnv (6 h post-infection) and the latter by 12-fold (between 3 and 12 h post-infection). The effect on DNA replication was due to inhibition of HSV-1 thymidine kinase (TK) and DNA polymerase (DP) activities; the former is reduced by 75% and whereas DP returns to baseline levels (when compared to untreated and/or uninfected cells). Host cell TK and DP activities are unaffected. It is suggested that beta-hydroxynorvaline is incorporated into these enzyme(s), either close to or at the active site thus perturbing viral DNA synthesis. beta-Hydroxynorvaline should have unique utility as a targeted antiviral compound, acting on both membrane-mediated phenomena (fusion, penetration and attachment) and DNA replication.
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PMID:Inhibition of herpesvirus-induced thymidine kinase and DNA polymerase by beta-hydroxynorvaline. 282 76

Buciclovir is an example of an antiherpes, acyclic guanosine analog activated by the viral thymidine kinase and inhibiting viral DNA synthesis in infected cells. An investigation of closely related buciclovir-analogs with similar antiherpes activities in cell cultures and similar, or identical, modes of action but with disparate effects in vivo, revealed the following critical determinants of antiherpes efficacy. (1) The accumulation of guanosine analog-triphosphates in infected cells, which is cell-type-specific and analog-dependent. (2) The potencies of the triphosphates as inhibitors of the viral DNA polymerase. (3) The plasma kinetics of the analogs, which are widely different despite the similar structures. (4) The penetration into nervous tissue relative to penetration into non-nervous tissues, of importance in connection with the neurotropic behavior of the virus. (5) The concentration of the antagonist thymidine in certain tissues. (6) The difference in pathogenesis between primary infections and recurrent infections, exemplified in the different efficacies of topically applied drugs in cutaneous and genital HSV-2 infections in guinea pigs.
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PMID:Critical determinants of antiherpes efficacy of buciclovir and related acyclic guanosine analogs. 282 2

First generation progeny herpes simplex type 1 (HSV-1) virions grown in the presence of 5-iodo-2'-deoxyuridine (IdUrd) were irradiated with either 254 or 302 nm ultraviolet (u.v.) light. The kinetics of virus inactivation revealed decreased sensitivity of IdUrd-substituted virions to irradiation with 302 nm light under all conditions examined, and with 254 nm u.v. light when substituted and control virions were irradiated at equal particle concentrations. Comparison of virus survival after irradiation measured in Vero or Xeroderma Pigmentosum (complementation group A) cells indicated that cellular repair of ultraviolet-induced lesions was not a significant factor in the observed decrease in u.v. sensitivity. IdUrd substitution altered neither the formation of ultraviolet-induced thymidine photoproducts nor the ability of irradiated virions to express delayed early viral enzymes (thymidine kinase, DNA polymerase). It is suggested that nucleocapsid proteins or the highly ordered structure of IdUrd-substituted virions play a key role in u.v. desensitization, either by the formation of non-lethal photoproducts or by the prevention of the formation of DNA-uracilyl free radicals.
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PMID:Effect of incorporation of 5-iodo-2'-deoxyuridine into HSV-1 DNA on virion sensitivity to ultraviolet light. 282 22

The acyclovir-induced herpes simplex virus Type 1 (HSV-1) strain, R9C2, a double mutant in thymidine kinase (TK) and DNA polymerase (DNA pol), and its parental strain SC16 were compared for their effects on ocular pathology and systemic immunity after unilateral inoculation into the anterior chamber (AC) of BALB/c mouse eyes. Although AC-injected R9C2 produced no retinal necrosis (0/18 eyes), this mutant induced active suppression (33-87%) of anti-HSV delayed type hypersensitivity similar to that induced by another HSV strain, KOS. AC-injected parental strain, SC16, caused fatal disease within 7-10 days, and induced bilateral retinal necrosis and suppression of DTH in 100% of the mice. Preimmunization with R9C2 protected mice in a dose-dependent fashion from the pathologic and lethal effects of AC-injected parental virus. These data suggest that the immunogenicity of the TK and DNA pol double mutant remains intact despite the decreased ocular and systemic pathogenicity observed after intracameral inoculation.
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PMID:Immunogenicity versus pathogenicity after anterior chamber inoculation of an acyclovir-induced double mutant of HSV-1. 282 59


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