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:2.7.7.49 (reverse transcriptase)
31,746 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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

Potential specific inhibitors of HIV RNA-dependent DNA polymerase (RDDP) were examined in an in-vitro test system containing purified HIV-1 RDDP, or functionally purified cellular DNA-dependent DNA polymerases alpha, beta and gamma. A wide variety of drugs were tested for their specific inhibitory activity against the viral enzyme to identify substances which, at the same concentration, did not inhibit the cellular DNA polymerases. Phosphonoformic acid and derivatives were found to be the most specific inhibitors, followed by chlortetracycline.
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PMID:Inhibition of HIV-1 RNA-dependent DNA polymerase and cellular DNA polymerases alpha, beta and gamma by phosphonoformic acid and other drugs. 245 49

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

Antiviral agents under investigation for the treatment of patients infected with the human immunodeficiency virus (HIV) are reviewed. Multiple mechanisms exist by which antiviral agents might inhibit the replication of HIV or eradicate its latent form in affected cells, or both. These mechanisms include (1) interference with the cell surface receptor for HIV, (2) prevention of uncoating of viral particles, (3) inhibition of reverse transcriptase, (4) prevention of integration and posttranscription processing, (5) interference with viral assembly, and (6) interference with virus release. Most agents developed thus far work by inhibiting HIV reverse transcriptase. Suramin, ribavirin, ammonium 21-tungsten-9-antimoniate (HPA-23), foscarnet (phosphonoformate, PFA), inosine pranobex (isoprinosine), peptide T, ampligen, AL 721, dideoxycytidine, and zidovudine (formerly azidothymidine) have antiretroviral activity in vitro. To date zidovudine is the only antiretroviral agent approved by the FDA as clinically effective. However, zidovudine has serious toxicities, including neutropenia and anemia; in some patients dosage reduction or cessation of therapy may be necessary. Because treatment with zidovudine does not cure HIV infection, numerous studies are under way with other anti-HIV agents. Ultimately, combinations of agents probably will be used to suppress or eradicate HIV. While the search for more efficacious and less toxic treatments continues, the development of zidovudine in such a short time provides hope that progress toward a cure will be made rapidly.
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PMID:Development of antiviral agents for the treatment of human immunodeficiency virus infection. 332 38

The inhibitory activities of human immunodeficiency virus reverse transcriptase (HIV-RT) inhibitors PFA and Suramin against HIV-RT and equine infectious anemic virus reverse transcriptase (EIAV-RT) were studied in this paper. The 50% inhibitory concentration (IC50) of HIV-RT and EIAV-RT treated by PFA and Suramin were 0.2 mumol, 9.8 mumol and 17 mumol, 19.9 mumol, respectively. More than thirty Chinese medicines, including recipes, herbs, extracts of traditional materia medica and isolated compounds were tested using HIV-RT and EIAV-RT as target enzymes. It was found that 5 crude extracts such as Rhizoma Polygoni Cuspidati, and Radix Notoginseng, 7 isolated compounds like Flavone of Ramulus Visci, Flavone of Ajuga Decumbens Thumb, and Aristolochic acid, as well as the extract of the complex prescription Xiao Chai Hu Tang have shown various inhibitory actions on these two enzymes. The activities of the two enzymes were comparable, but HIV-RT was more sensitive, suggesting that HIV-RT can be used as index for the screening of anti-aids drugs.
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PMID:Screening anti-HIV Chinese materia medica with HIV and equine infectious anemic virus reverse transcriptase. 751 33

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

The DNA polymerase of human herpes viruses, including cytomegalovirus (CMV), and the reverse transcriptase of human immunodeficiency virus (HIV) are selectively inhibited in vitro by the pyrophosphate analogue foscarnet. Inhibition is reversible on withdrawal of foscarnet and additive or synergistic effects have been demonstrated in vitro with other antiviral drugs, including ganciclovir and zidovudine. Foscarnet appears to have negligible effects on host enzymes and cells. Complete or partial clinical resolution of ocular symptoms is obtained in more than 89% of patients with acquired immunodeficiency syndrome (AIDS) and CMV retinitis during foscarnet induction therapy, but relapse occurs soon after ceasing treatment. Maintenance treatment given daily can extend the period of remission considerably. Foscarnet and ganciclovir monotherapy had similar efficacy in the treatment of CMV retinitis in patients with AIDS in several studies, and have been used concomitantly in immunocompromised patients with recalcitrant CMV infections. In 1 trial, patients receiving foscarnet survived for significantly longer than those receiving ganciclovir. Foscarnet has been used successfully in the treatment of limited numbers of immunocompromised patients with CMV-associated gastrointestinal (improvement in over 67% of patients) and other infections. Aciclovir-resistant herpes simplex infections in immunocompromised patients have also been treated successfully with foscarnet. Almost 90% of a foscarnet dose is excreted in the urine. Reversible nephrotoxicity is common during foscarnet therapy, but may be reduced by dosage adjustment and adequate hydration. Anaemia, nausea and vomiting, disturbances in electrolyte levels and genital ulceration have also been associated with administration of the drug. The different tolerability profiles of foscarnet and zidovudine facilitate the use of these agents in combination in patients with AIDS and CMV infection; whereas ganciclovir, like zidovudine, is associated with dose-limiting haematological toxicity. The apparent survival benefits seen in these patients when receiving foscarnet and zidovudine (possibly linked to synergy between zidovudine and foscarnet and/or the inherent anti-HIV activity of foscarnet), appear to offer potentially important advantages for foscarnet over ganciclovir in the treatment of selected patients with AIDS and CMV infections.
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PMID:Foscarnet. A reappraisal of its antiviral activity, pharmacokinetic properties and therapeutic use in immunocompromised patients with viral infections. 752 25

Foscarnet (phosphonoformic acid) is a pyrophosphate analog that inhibits the replication of human immunodeficiency virus type 1 (HIV-1) in vitro and in patients with AIDS. HIV-1 resistance to foscarnet has not been reported despite long-term foscarnet therapy of AIDS patients with cytomegalovirus disease. We therefore attempted to select foscarnet-resistant HIV-1 in vitro by serial endpoint passage of virus in 400 microM foscarnet. After 13 cycles of passage in MT-2 cells, virus exhibiting > or = 8.5-fold foscarnet resistance was isolated. The reverse transcriptase (RT) from resistant virions exhibited a similar level of foscarnet resistance in enzyme inhibition assays (approximately 10-fold resistance). Foscarnet-resistant virus showed increased susceptibility to 3'-azido-3'-deoxythymidine (90-fold) and to the HIV-1-specific RT inhibitors TIBO R82150 (30-fold) and nevirapine (20-fold). DNA sequence analysis of RT clones from resistant virus revealed the coexistence of two mutations in all clones: Gln-161 to Leu (CAA to CTA) and His-208 to Tyr (CAT to TAT). Sequence analysis of six clinical HIV-1 isolates showing reduced susceptibility to foscarnet revealed the Tyr-208 mutation in two, the Leu-161 mutation in one, and a Trp-88-to-Ser or -Gly mutation in four isolates. Site-specific mutagenesis and production of mutant recombinant viruses demonstrated that the Leu-161, Ser-88, and Tyr-208 mutations reduced HIV-1 susceptibility to foscarnet 10.5-, 4.3-, and 2.4-fold, respectively, in MT-2 cells. In the crystal structure of HIV-1 RT, the Gln-161 residue lies in the alpha E helix beneath the putative deoxynucleoside triphosphate (dNTP) binding site. The Gln-161-to-Leu mutation may affect the structure of the dNTP binding site and its affinity for foscarnet. The location of the Trp-88 residue in the Beta5a strand of HIV-1 RT suggest that the Ser-88 mutation affects template-primer binding, as do several mutations that affect RT susceptibility to nucleoside analogs.
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PMID:Novel mutations in reverse transcriptase of human immunodeficiency virus type 1 reduce susceptibility to foscarnet in laboratory and clinical isolates. 754 60

Foscarnet is a broad-spectrum viral DNA polymerase inhibitor active in vitro and in vivo against human immunodeficiency virus type 1 (HIV-1). Strains of HIV-1 resistant to foscarnet were selected by in vitro passage in increasing concentrations of drug. Reduced susceptibility to foscarnet was evident at the levels of both HIV-1 replication and reverse transcriptase. Biologically cloned, foscarnet-resistant strains with distinct genotypes were hypersensitive to zidovudine, azidodeoxyuridine, nevirapine, and R82913 but had unchanged susceptibility to zalcitibine and didanosine. The reverse transcriptase of foscarnet-resistant strains had unique substitutions Glu89-Lys, Leu92-Ile, or Ser156-Ala, the third being associated with six polymorphic changes. Introduction of these mutations into wild-type HIV-1 by site-directed mutagenesis confirmed their role in foscarnet resistance. In the three-dimensional structure of the reverse transcriptase enzyme these amino acids are located close to the template strand of the template primer and far away from the putative pyrophosphate binding site, suggesting that the mechanism by which HIV-1 becomes resistant to foscarnet is indirect. Foscarnet resistance is thus likely to be mediated through an altered interaction of the mutant enzyme with the template strand of the template primer which distorts the geometry of the polymerase active site and thereby decreases foscarnet binding.
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PMID:Characterisation of foscarnet-resistant strains of human immunodeficiency virus type 1. 754 54


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