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Results for “Phosphonoacetic Acid”

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At least 19 recordsLinked to original sources
PubMed1978

Inhibition of activities of DNA polymerase alpha, beta, gamma, and reverse transcriptase of L1210 cells by phosphonoacetic acid.

Phosphonoacetic acid has been shown to suppress replication of DNA tumor viruses by inhibiting the activity of virus-induced DNA polymerase and consequently viral DNA synthesis. We now have evidence to show that phosphonoacetic acid inhibits also the cellular DNA polymerases alpha, beta, and gamma of L1210 cells as well as reverse transcriptases of two type C viruses. Particularly, the DNA polymerase alpha is just as sensitive as the herpes virus induced DNA polymerase. The DNA polymerases beta and gamma required seven times more phosphonoacetic acid for a 50% inhibition of their activities. Phosphonoacetic acid inhibited the activities of the reverse transcriptase and terminal deoxyribonucleotidyltransferase only at higher concentrations. Kinetic analysis with the DNA polymerase alpha showed that the compound is a non-competitive inhibitor with respect to the substrates and uncompetitive inhibitor with the activated DNA template. Studies on time course of phosphonoacetic acid inhibition revealed that the compound is inhibitory even after the initiation of DNA synthesis. Phosphonoacetic acid also inhibited cell growth as well as the type C virus production; at concentrations above 50 microgram/ml, the inhibitory effect was more profound on the type C virus production than on cell growth.

Animals↗
PubMed1975

Human cytomegalovirus. IV. Specific inhibition of virus-induced DNA polymerase activity and viral DNA replication by phosphonoacetic acid.

Phosphonoacetic acid specifically inhibited human cytomegalovirus DNA synthesis in virus-infected human fibroblasts as detected by virus-specific nucleic acid hybridization. Inhibition was reversible; viral DNA synthesis resumed upon the removal of the drug. The compound partially inhibited DNA synthesis of host cells in the log phase of growth but had little effect on confluent cells. Studies of partially purified enzymes indicated that phosphonoacetic acid specifically inhibited virus-induced DNA polymerase and had only a slight effect on normal host cell enzymes. The drug was shown to interact directly with virus-induced enzyme but not with the template-primers.

Acetates↗
PubMed1978

Inhibition of African swine fever (ASF virus replication by phosphonoacetic acid.

Phosphonoacetic acid (PAA) inhibits the multiplication of African swine fever (ASF) virus in VERO cells. The observed inhibition of the in vivo DNA synthesis could be related to the in vitro inhibition of a virus-induced DNA polymerase activity present in cytoplasmic extracts from infected VERO cells.

African Swine Fever Virus↗
PubMed1977

Herpes simplex virus resistance and sensitivity to phosphonoacetic acid.

Phosphonoacetic acid (PAA) inhibited the synthesis of herpes simplex virus DNA in infected cells and the activity of the virus-specific DNA polymerase in vitro. In the presence of concentrations of PAA sufficient to prevent virus growth and virus DNA synthesis, normal amounts of early virus proteins (alpha- and beta-groups) were made, but late virus proteins (gamma-group) were reduced to less than 15% of amounts made in untreated infected cells. This residual PAA-insensitive synthesis of gamma-polypeptides occurred early in the virus growth cycle when rates were identical in PAA-treated and untreated infected cells. Passage of virus in the presence of PAA resulted in selection of mutants resistant to the drug. Stable clones of mutant viruses with a range of drug sensitivities were isolated and the emergence of variants resistant to high concentrations of PAA involved the sequential selection of mutants progressively better adapted to growth in the presence of the drug. Increased drug resistance of virus yield or plaque formation was correlated with increased resistance of virus DNA synthesis, gamma-protein synthesis, and resistance of the virus DNA polymerase reaction in vitro to the inhibitory effects of the drug. PAA-resistant strains of herpes simplex virus type 1 (HSV-1) complemented the growth of sensitive strains of homologous and heterologous types in mixed infections in the presence of the drug. Complementation was markedly dependent upon the proportions of the resistant and sensitive partners participating in the mixed infection. Intratypic (HSV-1A X HSV-1B) recombination of the PAA resistance marker(s), Pr, occurred at high frequency relative to plaque morphology (syn) and bromodeoxyuridine resistance (Br, thymidine kinase-negative phenotype) markers, with the most likely order being syn-Br-Pr. Recombinant viruses were as resistant or sensitive to PAA as the parental viruses, and viruses recombinant for their PAA resistance phenotype were also recombinant for the PAA resistance character of the virus DNA polymerase. The results provide additional evidence that the herpesvirus DNA polymerase is the site of action of PAA and illustrate the potential usefulness of PAA-resistant mutants in genetic studies of herpesviruses.

Acetates↗
PubMed1977

Antiviral potential of phosphonoacetic acid.

Phosphonoacetate has been found to inhibit specifically the replication of herpes-viruses. A partial inhibition of vaccinia virus represents the only activity outside the herpesvirus class. The drug was found to be a specific inhibitor of the virus-induced DNA polymerases. Normal cellular polymerases were relatively insensitive to phosphonoacetate, resulting in low cellular toxicity. Our working hypothesis is that the drug binds to the enzyme and that initiation of polynucleotide synthesis occurs in the presence of the drug and the required template, substrates, and cations. However, addition of deoxynucleosides to the elongating nascent chain is prevented by the enzyme-bound drug. Kinetic analyses indicated that phosphonoacetate did not interfere with the binding of DNA template to polymerase; and it did not compete with nucleotide substrate binding. The highly specific inhibitory effects of phosphonoacetate allowed for the selection of partially resistant strains of HSV. Resistance of virus to the drug in cell culture was directly correlated with the same relative resistance of the corresponding cell-free DNA polymerases. Phosphonoacetate was also effective therapeutically in herpesvirus skin and ocular infections in animals. Intraperitoneal administration of the drug reduced death and severity of disease in experimental encephalitis in hamsters. High specificity, low toxicity, and reproducible efficacy in lower animals suggested that phosphonoacetate could be a useful new antiviral drug. Sensitivity to phosphonoacetate also is a useful research tool as a genetic marker for herpesviruses.

Animals↗
PubMed1981

Characterization of purified Epstein--Barr virus induced deoxyribonucleic acid polymerase: nucleotide turnover, processiveness, and phosphonoacetic acid sensitivity.

The Epstein--Barr (EB) virus induced DNA polymerase has been further purified and characterized with respect to nucleotide turnover activity, processiveness of synthesis, and interaction with phosphonoacetic acid (PAA). The polymerase as purified through denatured DNA--cellulose chromatography was inseparable from a labile nuclease activity associated with an equally labile DNA-dependent nucleotide turnover function. The EB virus induced DNA polymerase even in the absence of detectable nuclease or nucleotide turnover activity was less processive in its synthesis than were lymphocyte alpha polymerase or procaryotic polymerases, and this processiveness decreased with increasing purity of the enzyme. PAA was shown to inhibit nucleotide incorporation by the EB virus induced DNA polymerase in the presence of nuclease-activated native DNA template in the manner of a pyrophosphate analogue. Under conditions in which the concentration of 3'-hydroxyl termini in the template was more limited, PAA was not inhibitory. PAA likewise failed to significantly decrease the processiveness and the nucleotide turnover function of the polymerase.

Animals↗
PubMed1973

Suppression of herpes simplex virus infection by phosphonoacetic acid.

Disodium phosphonoacetate when administered orally or topically to mice experimentally infected with herpes simplex virus was able to significantly reduce the mortality associated with the agent. In addition, this compound was able to reduce herpesvirus lesions on the corneas of infected rabbits.

Acetates↗
PubMed2006

Phosphonoacetic acid utilization by fungal isolates: occurrence and properties of a phosphonoacetate hydrolase in some penicillia.

Among a collection of 18 fungal strains representing eight genera, only two strains (Penicillium oxalicum and P. minioluteum) were capable of growth on phosphonoacetic acid as sole phosphorous source. Enrichment liquid cultures in minimal medium with the compound as the only P-source selected four isolates, that were also identified as Penicillium spp. Phosphonoacetate metabolism did not lead to extracellular release of inorganic phosphate. In all cases phosphonoacetate hydrolase activity was detected in partially purified extracts, and a protein of the expected molecular mass reacted with polyclonal antibodies raised against the enzyme from P. oxalicum. There was no relation between phosphonoacetate hydrolase specific activity and growth rate or yield. Phosphonoacetic acid was the inducer of the hydrolase, independently of the concurrent availability of inorganic phosphate. Notwithstanding this, the utilization of the phosphonate was significantly inhibited in the presence of phosphate, suggesting an interference of the latter with phosphonoacetic acid uptake.

Alkaline Phosphatase↗
PubMed1993

Bacteriophage T4 DNA polymerase mutations that confer sensitivity to the PPi analog phosphonoacetic acid.

Mutations that conferred sensitivity to the pyrophosphate analog phosphonoacetic acid in bacteriophage T4 DNA polymerase were identified. The mutations were loosely clustered in four regions of the gene. As found for herpes simplex virus DNA polymerase, T4 mutations that altered sensitivity to phosphonoacetic acid also altered sensitivity to nucleotide analogs. Some of the T4 DNA polymerase mutations also altered the ability of the enzyme to translocate from one template position to the next and affected DNA replication fidelity. Kornberg (A. Kornberg, Science 163:1410-1418, 1969) envisioned a DNA polymerase active center which accommodates primer terminus and template DNAs and the incoming nucleotide. Some mutations identified on the basis of sensitivity to phosphonoacetic acid may be part of such an active center because single amino acid substitutions simultaneously alter several DNA polymerase functions.

Bacteriophage T4↗
PubMed1977

Effect of phosphonoacetic acid in the treatment of experimental herpes simplex keratitis.

In the rabbit 5% phosphonoacetic acid ointment suppressed herpetic keratitis as well as 0-5% idoxuridine ointment. After 5 days of treatment quantitative virus titres showed that phosphonoacetic acid was superior to idoxuridine in the inhibition of herpes virus replication. Phosphonoacetic acid was found to be nontoxic to the eye in both clinical and histopathological studies. Recent reports suggest that the mechanism of action of phosphonoacetic acid appears to be the blocking of the virus DNA polymerase, which is essential for the synthesis of herpes virus DNA.

Animals↗
PubMed1977

Preclinical toxicological study of phosphonoacetic acid: determination in blood by selected ion monitoring.

Confirmed observations of the inhibition of oncogenic viruses by phosphonoacetic acid led to preclinical trials in animal model systems. Circulating phosphonoacetic acid was detected in the blood of mouse, rabbit and monkey after oral or subcutaneous administration of the drug. Phosphonoacetic acid is quantified in blood, after removing proteins and lipids, as the trimethylsilylated derivative, by monitoring the intensity of the protonated molecular ion and also that of phosphonopropionic acid (internal standard) using chemical ionization mass spectrometry combined with gas chromatography. The detection limit is 20 ng ml-1 when 0.2 ml serum is analyzed. A dosage of 230 mg kg-1 day-1 by continuous infusion is proposed for therapeutic trials in monkeys. This dose is well tolerated and results in slowly increasing blood levels of phosphonoacetic acid which reach a maximum of approximately 50 microgram ml-1 in a four day infusion, and decrease to 2 microgram ml-1 24 h after termination.

Animals↗
PubMed1980

Phosphonoacetic Acid inhibition of frog virus 3 replication.

Phosphonoacetic acid at concentrations above 200 mug/ml inhibited the replication of frog virus 3 in BHK cells. The inhibition of viral DNA replication observed in these cells was reversible and correlated with the inhibition of the virus-induced DNA polymerase activity in an in vitro assay. The synthesis of frog virus 3-induced late or gamma polypeptides was also inhibited by phosphonoacetic acid, although the early (alpha and beta) polypeptides were unaffected.

Journal Article↗
PubMed1981

In vitro and in vivo inhibition of myxoma virus by treatment with phosphonoacetic acid.

Both myxoma and fibroma viruses were found to be sensitive in vitro to the effects of phosphonoacetic acid. Detectable myxoma virus replication was inhibited at a drug concentration of 100 micrograms/ml. Fibroma virus replication was inhibited at a concentration of 500 micrograms/ml. Because of this difference in sensitivity, myxoma virus was used to infect rabbits to test that efficacy of phosphonoacetic acid in the treatment of a systemic viral disease. Rabbits were given 400 mg kg-1 day-1 of phosphonoacetic acid subcutaneously in two injections. Phosphonoacetic acid-treated animals showed a reduction in the severity of disease. Neither serum viral antigen nor infectious virus could be detected. In phosphate buffered saline-treated animals both serum viral antigen and infectious virus were found. All animals treated with phosphate buffered saline died of myxomatosis.

Animals↗
PubMed1989

Phosphonoacetic acid inhibits replication of human herpesvirus-6.

Phosphonoacetic acid (PAA) inhibits the replication of human herpesvirus-6 (HHV-6) in mononuclear cells from cord bloods which are susceptible for natural HHV-6 infection in humans. Nuclear extracts of uninfected or HHV-6-infected mononuclear cells were applied to phosphocellulose column chromatography, and DNA polymerase activity was measured with or without the addition of 100 mM ammonium sulfate. The major DNA polymerase activities eluted at 0.47 M KCl were suppressed in both uninfected and HHV-6 infected cells by the addition of 100 mM ammonium sulfate. DNA polymerase activity eluted at 0.47 M KCl was observed only from HHV-6-infected cells; it was enhanced by 100 mM ammonium sulfate and neutralized with immune serum. DNA polymerase activity eluted at 0.73 M KCl was determined to be HHV-6 specific and had the properties of a typical herpesvirus-induced DNA polymerase. PAA inhibited HHV-6-specific DNA polymerase activity.

Cells, Cultured↗
PubMed1978

Phosphonoacetic acid in the treatment of simian varicella.

Phosphonoacetic acid inhibited replication of simian varicella virus (Delta herpesvirus) in tissue culture. The drug was tested in patas monkeys 40 h after infection with Delta herpesvirus. A total of 200 mg/kg per day was given intramuscularly, divided into two doses every day for a total of 10 days. The treated monkeys were protected from clinical illness, and Delta herpesvirus was not recovered from their lymphocytes. Complement-fixing and neutralizing antibody titers were significantly lower in phosphonoacetic acid-treated monkeys than in the untreated controls. In animals given the drug alone, there was dermatitis and blackening of the skin and hair, serum glutamic oxalacetic transaminase and serum glutamic pyruvic transaminase enzymes were significantly increased, and liver biopsy revealed diffuse cytoplasmic swelling and granulation of the hepatocytes. The therapeutic range of this drug should be studied carefully before considering its use in severe varicella-zoster infection in humans.

Animals↗
PubMed1976

Experimental encephalitis caused by herpes simplex virus: comparison of treatment with tilorone hydrochloride and phosphonoacetic acid.

A mouse model of encephalitis caused by herpes simplex virus was used to compare the antiviral activity of tilorone hydrochloride with that of phosphonoacetic acid. These compounds were also administered simultaneously to determine whether the combination had a synergistic effect. Rates of survival and concentrations of virus in brain were used as criteria for judging the effectiveness of treatment. The fatal course of encephalitis was not altered by any treatment protocols in which tilorone hydrochloride was used alone. Four days of treatment with phosphonoacetic acid resulted in a long-term survival rate of about 15% of the infected, treated animals, and extension of this therapy for an additional three days resulted in an overall survival rate of about 35%. No increase in survival rate was obtained by use of phosphonoacetic acid and tilorone hydrochloride in combination. The concentration of virus in the brains of tilorone hydrochloride treated animals did not differ significantly from that in the untreated, infected control animals. Treatment with phosphonoacetic acid resulted in a reduction in titer of virus in brain and in an increased rate of survival.

Acetates↗
PubMed1989

Effects of phosphonoformic and phosphonoacetic acids on developing enamel of rat molars.

The effect of a single subcutaneous injection of different dosages of phosphonoformic or phosphonoacetic acid on the developing dental tissues of the rat molar was studied. The substances were injected at different rat ages and effects on the developing teeth were analyzed by means of histochemistry of frozen sections and scanning electron microscopy. Molars of rats injected at the age of 10 or 15 days showed no pathologic changes. Administration of phosphonoacetic acid in a dosage of 10 or 20 mg P/kg b.w. had no demonstrable effect on the dental tissues in any of the animals. Phosphonoformic or phosphonoacetic acid in a dosage of 10 or 30 mg P/kg b.w. respectively induced subameloblastic cysts 24 h after injection to 4-7-day-old rats. The cysts were mainly localized on the mesial sides of the cusps under ameloblasts in the late secretory stage. Calcified depositions were seen in the ameloblastic layer lining the cystic cavities. A thin zone, the staining of which indicated a high mineral content, was seen in the outermost enamel layer under the cysts. A few days later, enamel hypoplasias were seen in areas previously occupied by cysts. A lightly stained line was observed in the enamel matrix demarcating the amount of enamel matrix formed before and after the injection. Hypoplastic lesions were also noted in the enamel surface of newly erupted molars. These findings suggest that the two injected monophosphonates can induce pathologic changes in the developing enamel organ and hypoplasias in the enamel.

Ameloblasts↗