Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.7.7 (DNA polymerase)
 17,007 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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

Foscarnet is a pyrophosphate analogue with activity against herpesviruses, human immunodeficiency virus (HIV), and other RNA and DNA viruses. Foscarnet and its analogues achieve their antiviral effects via inhibition of viral polymerases, with such inhibition not being dependent on activation or phosphorylation of the compounds by viral or cellular proteins. Current evidence indicates that foscarnet interferes with exchange of pyrophosphate from deoxynucleoside triphosphate during viral replication by binding to a site on the herpesvirus DNA polymerase or HIV reverse transcriptase. Reviewed herein are basic findings regarding the mechanism of action and antiviral activity of foscarnet and the related compound phosphonoacetic acid (PAA), as well as findings regarding potential mechanisms of viral resistance and interactions with other antiviral agents.
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PMID:Mechanism of action of foscarnet against viral polymerases. 137 Oct 38

Herpes simplex virus (HSV) resistant to acyclovir can produce persistent mucocutaneous ulcerative disease in patients with the acquired immunodeficiency syndrome (AIDS). The incidence of clinically significant acyclovir-resistant HSV disease has dramatically increased since the advent of the AIDS epidemic. The primary mechanism of acyclovir resistance is induction of viral mutants defective or deficient in thymidine kinase, the viral-encoded enzyme, which catalyzes the rate-limiting step in the triphosphorylation of acyclovir to its active form (acyclovir triphosphate). Foscarnet, a potent inhibitor of HSV DNA polymerase, does not require phosphorylation for its antiviral activity. This compound has been found to be effective in the treatment of acyclovir-resistant HSV infection by several investigators. A recently completed dose-comparative trial of foscarnet in AIDS patients with acyclovir-resistant HSV has confirmed the safety and efficacy of two doses of foscarnet (40 mg/kg every 8 or 12 hours) in the treatment of this disease, as well as providing preliminary evidence supporting the utility of foscarnet maintenance therapy in delaying recurrence of HSV lesions. Analysis of data from this trial has been complicated by the tremendous variability in lesion size at initiation of therapy, making any statistically valid comparison of treatment regimens almost impossible. A further trial in AIDS patients with acyclovir-resistant HSV infection has been designed to define better the role of foscarnet maintenance and, in light of evidence that a significant proportion of initial recurrences are due to acyclovir-sensitive HSV, to examine the potential utility of acyclovir maintenance following foscarnet induction therapy.
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PMID:Foscarnet treatment of acyclovir-resistant herpes simplex virus infection in patients with acquired immunodeficiency syndrome: preliminary results of a controlled, randomized, regimen-comparative trial. 153 Dec 85

Both ganciclovir, a nucleoside analogue, and foscarnet, a pyrophosphate analogue, specifically bind cytomegalovirus (CMV) DNA polymerase and inhibit CMV replication at plasma concentrations achievable with intravenous administration. The agents have similar plasma half-lives, and both are cleared solely by the kidneys. Foscarnet has a low solubility and a high degree of ionization at physiologic pH, requiring it to be administered in higher doses and larger volumes. Both drugs are administered as an initial induction regimen followed by a long-term maintenance regimen. Among patients with the acquired immune deficiency syndrome (AIDS) who have CMV retinitis, the efficacy of long-term maintenance therapy, as measured by median time to retinitis progression, appears to be similar for the two drugs. The major toxicity of ganciclovir is myelosuppression, with dose-limiting neutropenia occurring in approximately 16% and thrombocytopenia in 5% of AIDS patients. The major toxicity of foscarnet is nephrotoxicity, with dose-limiting toxicity occurring in approximately 10-23% of patients; other effects of foscarnet include hypocalcemia, which may be associated with seizure and arrhythmia. Studies in vitro indicate an additive or synergistic inhibitory effect on CMV when these two drugs are combined, suggesting that lower-dose combination regimens or higher-dose alternating regimens may result in greater efficacy with less toxicity than with either drug alone.
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PMID:Approaches to the treatment of cytomegalovirus retinitis: ganciclovir and foscarnet. 184 16

Phosphonoformate (PFA) is a simple PPi analog which inhibits the activities of a variety of viral DNA polymerase, RNA polymerase, and reverse transcriptase enzymes. PFA is a topical and parenteral treatment for human herpesvirus infections and is currently in phase I trials for treatment of acquired immunodeficiency syndrome. Pharmacokinetic properties of PFA in young (growing) and adult specific-pathogen-free cats were compared. Mean PFA clearance from plasma was twofold higher in young cats (7.52 ml/min per kg of body weight) than in adult cats (3.70 ml/min per kg). Higher PFA clearance from plasma observed in young cats may result from higher renal clearance or enhanced accumulation of PFA in bone tissue of young versus adult cats. No plasma protein binding of PFA was observed. Mean oral bioavailability was 35% in young cats. These data indicate that age-related differences in PFA clearance from plasma occur in cats.
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PMID:Age-related differences in pharmacokinetics of phosphonoformate in cats. 214 79

Foscarnet (trisodium phosphonoformate) is a novel antiviral agent that inhibits viral-specific DNA polymerase. In the present study, eight males with chronic HBV carriage (HBeAg and HBV-DNA seropositivity greater than 12 months) showing chronic persistent hepatitis (CPH) or chronic active hepatitis (CAH) on liver biopsy received either a continuous infusion of foscarnet at 0.15 mg/kg/min for 7 days or 180 mg/kg/day divided into three daily boluses for 2 weeks. In all eight, HBV-DNA levels fell during therapy (median, 401 pg/40 microliters serum; range, 4-3, 100) vs. pretreatment levels (median, 533 pg/40 microliters; range, 30-4, 175), but in none was HBV-DNA undetectable at any stage. Within 1 month, the HBV-DNA had risen to pretreatment levels in all but one patient (with the lowest pretreatment level), who cleared HBeAg and developed anti-HBe within 3 months. Two further patients were anti-HBe positive at 6 months, but their pretreatment serum HBV-DNA levels were already low, suggesting a high probability of spontaneous seroconversion. Toxicity was not evident with the continuous infusion, but for those receiving IV bolus therapy, serum creatinine and phosphate levels rose in three of four patients, necessitating a 25% dose reduction. There was no difference in the effect on serum HBV-DNA between the two regimes. We conclude that foscarnet has only modest antiviral activity in chronic HBV carriers.
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PMID:Foscarnet therapy in chronic hepatitis B virus E antigen carriers. 253 40

Phosphonoformic acid (PFA) and its congener phosphonoacetic acid (PAA) are inhibitors of viral replication whose mechanism of action appears to be the inhibition of viral DNA polymerase. These drugs inhibit mammalian DNA polymerase to a lesser extent. We sought to characterize the effects of phonoformic acid on mammalian cells by examining mutants of S49 cells (a mouse T-lymphoma line), which were selected by virtue of their resistance to phosphonoformic acid. The 11 mutant lines that were resistant to growth inhibition by 3 mM PFA had a range of growth rates, cell cycle distribution abnormalities, and resistance to the inhibitory effects of thymidine, acycloguanosine (acyclovir), aphidicolin, deoxyadenosine, and novobiocin. Most mutant lines had pools of ribonucleoside triphosphates and deoxyribonucleoside triphosphates similar to those of wild-type S49 cells. However, one line (PFA 3-9) had a greatly elevated dCTP pool. When this mutant line was further characterized, no apparent defect in DNA polymerase alpha activity was seen, but an increased ribonucleotide reductase activity, as assayed by CDP reduction in permeabilized cells, was observed. The CDP reductase activity in the PFA 3-9 cells decreased to wild-type control levels, and the CDP reductase activity of wild-type cells was also greatly reduced when PFA (2-3 mM) was added to permeabilized cells during the enzyme assay. These results demonstrate that PFA can directly inhibit ribonucleotide reductase activity in permeabilized cells. In addition, when PFA was added to exponentially growing cultures of either wild-type or PFA 3-9 mutant cells, the drug caused an arrest in S phase of the cell cycle and a decrease in all four deoxyribonucleotide pools, with the most dramatic decrease in the dCTP pools. The reduction in the dCTP pool level could be reversed by addition of exogenous deoxycytidine, but this reversed PFA toxicity only marginally. These observations suggest that PFA is an inhibitor of mammalian ribonucleotide reductase and that partial resistance to PFA can be effected by mutation to increased CDP reductase activity resulting in a large dCTP pool. This mutation results in less than twofold resistance to PFA, suggesting that other sites of inhibition coexist.
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PMID:Selection and characterization of mutant S49 T-lymphoma cell lines resistant to phosphonoformic acid: evidence for inhibition of ribonucleotide reductase. 293 95

Foscarnet (trisodium phosphonoformate) is a new antiviral compound with in vitro inhibitory effects against the DNA polymerases of hepadna viruses. To study the effects of the drug in chronic hepadna virus infection, we treated ducks chronically infected with duck hepatitis B virus for 10 days with either low-dose foscarnet (50 mg/kg i.p. b.i.d.), high-dose foscarnet (250 mg/kg i.p. b.i.d.), or sterile water injections. Serum duck hepatitis B virus DNA and intrahepatic replicative forms of the virus were measured using molecular biological techniques with both a double-stranded radiolabeled DNA probe and a plus-strand (noncoding) specific RNA probe. We found a dose-related decrease in serum and intrahepatic duck hepatitis B virus DNA during treatment, with a rapid return toward baseline values after the cessation of treatment. There was a disproportionate decrease in the plus strand of viral DNA with treatment. We conclude that foscarnet exerts its effect in hepadna virus infection through inhibition of viral DNA polymerase. Further study is necessary to determine whether foscarnet, by itself or in combination with other treatment modalities, has a role to play in the treatment of chronic hepatitis B infections in humans.
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PMID:Foscarnet decreases serum and liver duck hepatitis B virus DNA in chronically infected ducks. 294 28

DNA polymerases induced by herpes simplex virus (HSV)-1 (KOS) and by three phosphonoformic acid-resistant strains were purified and the interaction of these enzymes with aphidicolin was examined. Incorporation of dATP, dCTP, and dTTP into activated DNA by parental enzyme was inhibited competitively by aphidicolin whereas dGTP incorporation was inhibited noncompetitively. Phosphonoformic acid-resistant enzymes were altered in KM and KI values for substrate and inhibitor, and two were inhibited by aphidicolin via the same modes as parental enzyme. However, aphidicolin competitively inhibited incorporation of dGTP by the third phosphonoformic acid-resistant enzyme under identical assay conditions. Two phosphonoformic acid-resistant enzymes were more sensitive than parental enzyme to inhibition by aphidicolin, indicating a close association between binding determinants for aphidicolin and for phosphonoformic acid on the virus DNA polymerase molecule. Aphidicolin inhibited hydrolysis of polynucleotide by HSV-1 DNA polymerase-associated nuclease. Inhibition was uncompetitive with DNA and the KI value (0.09 microM) was within the range of those calculated during nucleotide incorporation (0.071-0.74 microM). Therefore, aphidicolin may produce antiviral effects both by inhibition of deoxynucleotide incorporation and by deleterious effects resulting from inhibition of polymerase-associated nuclease.
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PMID:Novel interaction of aphidicolin with herpes simplex virus DNA polymerase and polymerase-associated exonuclease. 609 71

An exonuclease activity copurified with herpes simplex virus type I (HSV-1) DNA polymerase through DNA-cellulose column chromatography and comigrated with DNA polymerase activity on nondenaturing gel electrophoresis at varied polyacrylamide concentrations. A gapped duplex DNA was the preferred substrate for this exonuclease activity since the hydrolytic activity on this type of DNA was much greater than the hydrolysis of either native or heat-denatured DNA. Using 3'-terminally labeled activated calf thymus DNA as substrate, the exonuclease activity was found to be activated by salt and spermidine in a manner identical with HSV-1 DNA polymerase. This activation was accompanied by increases in apparent Km and Vmax values of the activated DNA substrate. Phosphonoformic acid inhibited both DNA polymerase and exonuclease activities uncompetitively with respect to activated DNA and had a Ki of 2.4 microM at an ionic strength of 0.25 mu. Of the nucleoside 5'-monophosphates tested only the purine ribonucleotides inhibited the exonuclease activity. The inhibition was noncompetitive with respect to DNA, and GMP was about twice as potent as AMP or IMP. 9-beta-D-arabinosyladenine 5'-monophosphate (araAMP) could be incorporated into DNA by HSV-1 DNA polymerase; however, 9-beta-D-arabinosyladenine 5'-triphosphate would not replace dATP in supporting in vitro HSV-1 DNA synthesis. AraAMP incorporated into primer termini caused a significant decrease in the rate of subsequent primer elongation. These 3'-terminal araAMP residues could be removed by the HSV-1 DNA polymerase-associated exonuclease activity in a manner dependent on GMP concentration.
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PMID:Herpes simplex virus type I DNA polymerase. Kinetic properties of the associated 3'-5' exonuclease activity and its role in araAMP incorporation. 616 79


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