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Journal of Enzyme Inhibition and... Dec 2018Small molecule inhibitors have a powerful blocking action on viral polymerases. The bioavailability of the inhibitor, nevertheless, often raise a significant selectivity...
Small molecule inhibitors have a powerful blocking action on viral polymerases. The bioavailability of the inhibitor, nevertheless, often raise a significant selectivity constraint and may substantially limit the efficacy of therapy. Phosphonoacetic acid has long been known to possess a restricted potential to block DNA biosynthesis. In order to achieve a better affinity, this compound has been linked with natural nucleotide at different positions. The structural context of the resulted conjugates has been found to be crucial for the acquisition by DNA polymerases. We show that nucleobase-conjugated phosphonoacetic acid is being accepted, but this alters the processivity of DNA polymerases. The data presented here not only provide a mechanistic rationale for a switch in the mode of DNA synthesis, but also highlight the nucleobase-targeted nucleotide functionalization as a route for enhancing the specificity of small molecule inhibitors.
Topics: DNA-Directed DNA Polymerase; Enzyme Inhibitors; HIV-1; Molecular Structure; Moloney murine leukemia virus; Nucleotides; Phosphonoacetic Acid
PubMed: 29372656
DOI: 10.1080/14756366.2017.1417275 -
Antimicrobial Agents and Chemotherapy Sep 1978Phosphonoacetic acid inhibited replication of simian varicella virus (Delta herpesvirus) in tissue culture. The drug was tested in patas monkeys 40 h after infection...
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.
Topics: Animals; Erythrocebus patas; Haplorhini; Herpesviridae Infections; Herpesvirus 3, Human; Organophosphorus Compounds; Phosphonoacetic Acid
PubMed: 213014
DOI: 10.1128/AAC.14.3.331 -
Lancet (London, England) Sep 1985
Topics: Animals; Antiviral Agents; Deltaretrovirus; Foscarnet; Humans; Organophosphorus Compounds; Phosphonoacetic Acid; Virus Diseases
PubMed: 2863637
DOI: No ID Found -
Annals of the New York Academy of... Mar 1977Phosphonoacetate has been found to inhibit specifically the replication of herpes-viruses. A partial inhibition of vaccinia virus represents the only activity outside...
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.
Topics: Animals; Antiviral Agents; Cell-Free System; Cells, Cultured; Cricetinae; DNA-Directed DNA Polymerase; Drug Resistance, Microbial; Herpesviridae; Herpesviridae Infections; Macromolecular Substances; Mesocricetus; Microbial Sensitivity Tests; Organophosphorus Compounds; Phosphonoacetic Acid; Simplexvirus; Species Specificity
PubMed: 212978
DOI: 10.1111/j.1749-6632.1977.tb21966.x -
Journal of Biotechnology Apr 1993In this paper, the synthesis of new phosphonoacetic acid derivatives and their applications in fields of biotechnological interest are discussed. Phosphonoacetic acids...
In this paper, the synthesis of new phosphonoacetic acid derivatives and their applications in fields of biotechnological interest are discussed. Phosphonoacetic acids are competitive inhibitors of alkaline phosphatase, an enzyme widely used in diagnostics, as colorimetric detection tool. The phosphonoacetic acid's inhibition activity has been exploited by us for the obtainment of an innovative technique for non-radioactive DNA probes detection, the last being based on DNA labeling with the enzyme inhibitor, followed by detection by means of the chromogenic enzyme and substrate. Moreover, we have found a further application of phosphonoacetic acids, by the preparation of an affinity chromatography support that has been revealed to be very effective in the purification of alkaline phosphatase. Finally, phosphonoacetic acid derivatives have been tested also for their antiviral activity. Some of them, examined in preliminary in vitro experiments, have been found very active against Herpes simplex virus.
Topics: Antiviral Agents; Chromatography, Affinity; DNA; DNA Probes; Kinetics; Molecular Structure; Phosphonoacetic Acid; Simplexvirus
PubMed: 7764051
DOI: 10.1016/0168-1656(93)90180-u -
Medicinal Chemistry (Shariqah (United... Nov 2005NDP kinase catalyzes the last step in the phosphorylation of nucleotides. It is also involved in the activation by cellular kinases of nucleoside analogs used in... (Comparative Study)
Comparative Study
NDP kinase catalyzes the last step in the phosphorylation of nucleotides. It is also involved in the activation by cellular kinases of nucleoside analogs used in antiviral therapies. Adenosine phosphonoacetic acid, a close analog of ADP already proposed as an inhibitor of ribonucleotide reductase, was found to be a poor substrate for human NDP kinase, as well as a weak inhibitor with an equilibrium dissociation constant of 0.6 mM to be compared to 0.025 mM for ADP. The X-ray structure of a complex of adenosine phosphonoacetic acid and the NDP kinase from Dictyostelium was determined to 2.0 A resolution showing that the analog adopts a binding mode similar to ADP, but that no magnesium ion is present at the active site. As ACP may also interfere with other cellular kinases, its potential as a drug targeting NDP kinase or ribonucleotide reductase is likely to be limited due to strong side effects. The design of new molecules with a narrower specificity and a stronger affinity will benefit from the detailed knowledge of the complex ACP-NDP kinase.
Topics: Adenosine; Adenosine Diphosphate; Animals; Binding Sites; Catalysis; Crystallization; Dictyostelium; Enzyme Inhibitors; Humans; Kinetics; Models, Molecular; Molecular Structure; Nucleoside-Diphosphate Kinase; Phosphonoacetic Acid; Structure-Activity Relationship; X-Ray Diffraction
PubMed: 16787337
DOI: 10.2174/157340605774598162 -
Antimicrobial Agents and Chemotherapy Sep 1974Replication of herpes simplex virus in WI-38 cells was inhibited by phosphonoacetic acid, as measured by decreased virus cytopathogenic effect and incorporation of...
Replication of herpes simplex virus in WI-38 cells was inhibited by phosphonoacetic acid, as measured by decreased virus cytopathogenic effect and incorporation of radiolabeled thymidine in virus-infected cells. The drug appeared to have no effect on adsorption, penetration, or release of the virus nor on the synthesis of ribonucleic acid or protein. It appeared to inhibit virus deoxyribonucleic acid synthesis.
Topics: Antiviral Agents; Fibroblasts; Humans; Phosphonoacetic Acid; Simplexvirus; Virus Replication
PubMed: 15830487
DOI: 10.1128/AAC.6.3.360 -
Antiviral Research Nov 1981The activity of phosphonoacetic acid (PAA) and phosphonoformic acid (PFA) against four strains of herpes simplex virus type 1 (HSV-1) and four strains of HSV-2 were... (Comparative Study)
Comparative Study
The activity of phosphonoacetic acid (PAA) and phosphonoformic acid (PFA) against four strains of herpes simplex virus type 1 (HSV-1) and four strains of HSV-2 were compared in tissue culture and in a murine model of genital herpes. In mouse embryo fibroblast cells, both drugs were three-fold more active against the HSV-1 strains than against the HSV-2 strains. In contrast, in the animal model infections, PAA appeared to be more active against the HSV-2 strains, while PFA was equally effective against both HSV types. In mice infected intravaginally with HSV-2 and treated with intravaginal 5% PAA, none of the treated mice became infected, replication of virus in the genital tract was completely inhibited, none of the infected mice died from encephalitis, and latent infection in lumbosacral ganglia of surviving animals was completely prevented. In HSV-1 genital infection treated with PAA, 20-60% of mice became infected, replication of virus in the genital tract was strikingly reduced, none of the infected mice died, and latent infection was completely prevented. In both HSV-2 and HSV-1 genital infections, 20-70% of animals treated with 8% PFA became infected, growth of virus in the genital tract was reduced significantly but not completely suppressed, mortality was variably altered, and there was a trend towards reduction in the frequently of latent infection. These results indicate that HSV-1 strains are more sensitive to PAA and PFA in tissue culture, but the HSV-2 strains are generally more amenable to therapy in the murine model of genital herpes. Although PAA appeared to be more active that PFA in the genital infection, both drugs significantly altered the course of the infection. Since dermal toxicity associated with PAA precludes its use in humans and since PFA is already undergoing trials in patients with recurrent herpes labialis, the current results suggest that topical PFA deserved further evaluation in the treatment of mucocutaneous HSV infections, including genital herpes.
Topics: Animals; Antiviral Agents; Drug Evaluation, Preclinical; Female; Foscarnet; Ganglia, Spinal; Herpes Genitalis; Male; Mice; Organophosphorus Compounds; Phosphonoacetic Acid; Simplexvirus; Virus Replication
PubMed: 6280607
DOI: 10.1016/0166-3542(81)90013-9 -
DICP : the Annals of Pharmacotherapy Jan 1991Cytomegalovirus (CMV), a major opportunistic viral pathogen frequently causing disease in immunocompromised patients such as organ transplant recipients and people with... (Review)
Review
Cytomegalovirus (CMV), a major opportunistic viral pathogen frequently causing disease in immunocompromised patients such as organ transplant recipients and people with AIDS, may present as pneumonitis, gastrointestinal disease, or encephalitis. Its most common manifestation in patients with AIDS is retinitis which, if left untreated, invariably progresses to extensive retinal necrosis and ultimately to blindness. Ganciclovir sodium, currently the only licensed antiviral agent for the treatment of CMV retinitis, effectively controls this infection in a majority of AIDS patients, but significant granulocytopenia or thrombocytopenia related to ganciclovir therapy often limit its clinical application. Myelosuppression may be further exacerbated in AIDS patients by such other agents as zidovudine or trimethoprim/sulfamethoxazole, often necessitating dosage reductions or discontinuation of these agents in patients receiving ganciclovir. Foscarnet sodium, a pyrophosphate analog active against both cytomegalovirus and the human immunodeficiency virus type 1 (HIV), may be an effective alternative to ganciclovir in the management of CMV retinitis. Trials with intravenous foscarnet in CMV retinitis have reported favorable results using initial daily doses of 180-230 mg/kg/d given as intermittent infusions every eight hours, followed by maintenance regimens of 60-90 mg/kg/d given as single daily one- or two-hour infusions. Foscarnet therapy may result in renal impairment, and indefinite intravenous maintenance therapy may be required to prevent recurrence of CMV infection. Despite these drawbacks, foscarnet's lack of major myelosuppressive toxicity, and its activity in suppressing HIV replication, make this a potentially safe and effective alternative agent for the management of CMV infection, especially in AIDS patients.
Topics: Acquired Immunodeficiency Syndrome; Antiviral Agents; Cytomegalovirus Infections; Eye Infections, Viral; Foscarnet; Herpes Simplex; Humans; Phosphonoacetic Acid; Retinitis
PubMed: 1848959
DOI: 10.1177/106002809102500109 -
Virologie 1982
Topics: Animals; Herpesviridae Infections; Keratitis, Dendritic; Organophosphorus Compounds; Phosphonoacetic Acid; Rabbits
PubMed: 6280376
DOI: No ID Found