Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:2.7.7.49 (reverse transcriptase)
 31,746 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Phosphonoformate (PFA) inhibits multiplication of visna virus in sheep choroid plexus cells; a 50% reduction of virus yield was obtained by 20 to 80 microM PFA. Morphological changes, such as syncytial formation and cell degeneration, could be reversibly prevented by PFA. Cell growth was not significantly affected at 500 microM PFA, although prolonged treatment with 2 mM PFA did arrest cell growth. Cell-free reverse transcriptase activity primed with various synthetic template-primers was inhibited about 90% in the presence of 100 microM PFA. The results from kinetic experiments suggested that reverse transcriptase was utilized early but not late in the infection cycle. A structurally related substance, phosphonoacetate, did not inhibit visna virus multiplication and had no inhibitory effect on reverse transcriptase activity at a concentration of 500 microM.
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PMID:Phosphonoformate inhibition of visna virus replication. 9 Jan 68

The new antiviral substance phosphonoformate (PFA) has been tested in a cell-free system for its effect on reverse transcriptases from an avian retrovirus (avian myeloblastosis virus, AMV) and from mammalian retroviruses (Rauscher leukaemia virus, RMuLV; bovine leukaemia virus; baboon endogenous virus; simian sarcoma virus; visna virus). The observed inhibitory effect of PFA has been compared with that of a structurally related substance, phosphonoacetate (PAA). Phosphonoformate, at a concentration of 100 microM, reduced the activities of all the above mentioned polymerases by 90% when (rA)n.(dT)10 was used as a template/primer. The dose-response curves for AMV and RMuLV polymerases primed with (rA)n.(dT)10 showed PFA to be a 1000-fold more active than PAA; the RMuLV polymerase activity was reduced to 50% after incubation with 0.7 microM-PFA and 0.7 mM-PAA, respectively. There was no difference in PFA inhibition of virus-associated and purified reverse transcriptase activity. Results with various synthetic templates showed that both the RNA- and the DNA-dependent polymerase activities of reverse transcriptase were inhibited by PFA. The endogenous polymerase activity of AMV was inhibited to 50% at 100 microM-PFA, while PAA had no effect. The PFA inhibition was dependent on whether Mg2+ or Mn2+ was used as divalent cation in the assay. Phosphonoformate arrested DNA synthesis immediately after being added to the assay system. The mechanism of inhibition of the AMV polymerase was non-competitive with respect to substrate and template and the apparent inhibition constants were 16 microM and 9 microM, respectively.
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PMID:Phosphonoformate inhibits reverse transcriptase. 9 44

The bisheteroarylpiperazines (BHAPs) are potent inhibitors of human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT) and specifically block HIV-1 replication (Romero, D. L., Busso, M., Tan, C.-K., Reusser, F., Palmer, J. R., Poppe, S. M., Aristoff, P. A., Downey, K. M., So, A. G., Resnick, L., and Tarpley, W. G. (1991) Proc. Natl. Acad. Sci. U.S.A. 88, 8806-8810). Here we show that the radiolabeled BHAP [3H]U-88204 binds specifically to HIV-1 RT with high affinity (KD of 50 nM) and a stoichiometry of 1 mol of U-88204 per 1 mol of p66/p51 RT heterodimer. Binding of [3H]U-88204 to RT is unaffected by the presence of saturating poly(rC).oligo (dG)12-18 template-primer. Direct measurement of competition between [3H]U-88204 and other RT inhibitors for binding to RT reveals mutually exclusive competition between [3H]U-88204 and the non-nucleoside RT inhibitor BI-RG-587 (Kopp, E. B., Miglietta, J. J., Shrutkowski, A. G., Shih, C.-K., Grob, P. M. and Skoog, M.T. (1991) Nucleic Acids Res. 19, 3035-3039), indicating that both share the same binding site. Phosphonoformate in concentrations up to 50 microM shows no competition with [3H]U-88204 for binding to RT either alone or in the presence of template-primer. Dideoxynucleotide RT inhibitors affect the binding of [3H]U-88204 to RT when complementary template-primer is present. [3H]U-88204 and the dideoxynucleotide ddGTP can bind RT simultaneously, but the presence of one ligand decreases the affinity of RT for the second. Inasmuch as ddGTP approximates the nucleotide substrate of RT, the direct demonstration of an RT-dideoxynucleotide-[3H]U-88204 complex validates the use of indirect kinetic methods to assess the strength of BHAP interaction with RT and suggests that RT inhibition by U-88204 is achieved via effects on nucleotide substrate binding.
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PMID:The binding of a novel bisheteroarylpiperazine mediates inhibition of human immunodeficiency virus type 1 reverse transcriptase. 137 Apr 45

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

Phosphonoformate (PFA), a noncompetitive inhibitor of reverse transcriptase (RT), inhibited feline leukemia virus (FeLV) infection of 2 feline cell lines and inhibited progeny virus RT activity in a chronically FeLV-infected cell line. Feline leukemia virus infection of 3201 cells, an FeLV-negative lymphoma cell line, was inhibited by greater than 70% at a concentration of only 1 microM PFA and by greater than 90% at concentrations of 64 to 256 microM PFA, as evidenced by RT activity. However, FeLV antigen expression by 3201 cells remained relatively constant over noncytotoxic concentrations of PFA. Because the persistence of viral antigen expression with concomitant suppression of RT activity appears to be unique and because 3201 cells express small amounts of an endogenous retrovirus (RD-114) and contain endogenous FeLV proviral sequences, a possible role of endogenous retroviruses acting as helper viruses was suggested. Feline leukemia virus infection of 81C cells, a sarcoma-positive, leukemia-negative fibroblast cell line, was inhibited by greater than 50% at a concentration of 64 microM PFA and by greater than 98% at concentrations of 256 to 512 microM PFA, as indicated by suppression of focus formation. The feline lymphoid cell line FL-74 is a large producer of FeLV. When FL-74 cells were cultured in the presence of 256 microM PFA, virus production (virus budding and viral antigen) was not affected, but progeny virus lost RT activity and infectivity. Direct addition of PFA (256 microM) to FeLV also reduced RT activity and infectivity. These data indicate that PFA can directly and rapidly inactivate retrovirus independent of cellular processing, presumably by inhibiting RT.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Prophylactic and therapeutic effects of phosphonoformate against feline leukemia virus in vitro. 172 22

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

Phosphonoformate, an inhibitor of reverse transcriptase in a number of retroviruses, was shown to have a dose-related inhibitory effect on human T-cell lymphotropic virus type III (HTLV-III) replication in the H9 cell line in vitro. HTLV-III replication was eliminated at a concentration of 680 mcgmol, a noncytotoxic dose. A lower dose of 132 mcgmol inhibited HTLV-III replication by more than 98%, as measured by reverse transcriptase activity, compared with untreated infected cultures. Reverse transcriptase activity in HTLV-III particles was completely inhibited by 5 mcgmol of phosphonoformate. Growth of uninfected H9 cells was not affected by the concentration of the drug. In clinical trials to treat cytomegalovirus infection in immunocompromised patients, constant serum levels of between 100-450 mcgmol of phosphonoformate have been achieved in 140 subjects. Further studies are recommended to evaluate the potential of phosphonoformate in patients infected with HTLV-III. It may be the least toxic of the antiviral agents that have been shown to have anti-HTLV-III activity.
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PMID:Inhibition of human T-cell lymphotropic virus type III in vitro by phosphonoformate. 240 14

Twenty-six PPi analogs were tested for inhibitory effects on human T-lymphotropic virus type III reverse transcriptase. The structural requirements for inhibition and mechanism of action of the most active inhibitors have been investigated. Foscarnet (phosphonoformic acid) was the most potent inhibitor of human T-lymphotropic virus type III reverse transcriptase with 50% inhibition at 0.5 microM. The mechanism was a noncompetitive type of inhibition of a (riboadenylic acid)n . (deoxythymidylic acid)12-18 [(rA)n(dT)12-18]-directed transcription at varied dTTP concentration. At constant substrate (dTTP) concentration and varied amounts of template, (rA)n(dT)12-18, the inhibitory action of foscarnet was of an uncompetitive type. The same pattern of inhibition was seen when the less active inhibitor carbonyldiphosphonate was studied under identical conditions. The structural requirements for inhibition of human T-lymphotropic virus type III reverse transcriptase by PPi analogs were similar to those shown by other reverse transcriptases.
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PMID:PPi analogs as inhibitors of human T-lymphotropic virus type III reverse transcriptase. 242 31

Phosphonoformate (PFA; a pyrophosphate analogue) is an effective inhibitor of the reverse transcriptase enzyme in many animal retroviruses. In vitro studies have shown that PFA is also an effective inhibitor of HIV (HTLV III/LAV) at doses readily attainable in vitro. A pilot study was therefore performed with a 3-week intravenous infusion of PFA in 11 patients with AIDS and AIDS-related complex (ARC). Viral isolations were performed before and at regular intervals up to 3 months post-infusion on treated patients, as well as on four untreated control patients. Virus isolation was negative after therapy in eight patients, six of whom were negative throughout the follow-up period. Virus was isolated on 70% of attempts from the four control subjects and on 20% of attempts from treated subjects. Three patients showed an improvement in delayed hypersensitivity responses. No obvious improvement was seen in patients' OKT4 positive lymphocyte counts. Treatment was not limited by side-effects with the exception of one patient who developed an axillary vein thrombosis within 4 days of treatment via a subclavian line. Treatment was therefore discontinued following administration of only one dose and the patient was excluded from further study. A further patient had reversible renal dysfunction. Other side-effects were minor, consisting of headache or thrombophlebitis at the site of infusion. These results suggest that a further trial with PFA administered over a longer period and with a longer follow-up period in AIDS and ARC patients may be warranted, particularly if an oral preparation becomes available.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Phosphonoformate (foscarnet): a pilot study in AIDS and AIDS related complex. 296 89

Two mutants of HIV-1 reverse transcriptase (RT), Tyr-188-->His and Glu-138-->Arg have been prepared and their catalytic properties and sensitivities to inhibitors studied. As compared to wild type RT, a reduction in catalytic efficiency and turn over number was observed, especially for the Tyr-188-->His mutant. The non-nucleoside inhibitors nevirapine, L-697,661 and 9-Cl-TIBO caused a mixed type of inhibition of RT (Arg-138) with respect to substrate, and with the exception of a non-competitive inhibition by nevirapine, also a mixed type of inhibition of RT (His-188). Foscarnet (PFA) caused a non-competitive type of inhibition of RT (Arg-138) and a mixed inhibition of RT (His-188). The inhibition by ddG-TP was competitive with both mutant RTs. Inhibition by nevirapine gave IC50 values of 0.15, 0.23 and 0.72 microM; by 9-Cl-TIBO of 0.20, 2.50 and 10.3 microM; by L-697,661 of 0.064, 0.28 and 0.60 microM; by ddGTP of 0.13, 0.14 and 0.02 microM; by PFA of 17.0, 48.0 and 15.0 microM for RT wt, RT (Arg-138) and RT (His-188), respectively.
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PMID:Enzymatic properties and sensitivity to inhibitors of human immunodeficiency virus type 1 (HIV-1) reverse transcriptase with Glu-138-->Arg and Tyr-188-->His mutations. 752 39


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