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)

Peripheral blood mononuclear cells from seronegative donors were stimulated with phytohemagglutinin and then infected with human immunodeficiency virus (HIV-1). Using this experimental system, the antiviral activity of two translation inhibitory proteins (pokeweed antiviral protein, PAP-S, and Luffa ribosomal inhibitory protein, LRIP-I) isolated from plants and a recombinant form of ricin A chain were studied. Previously, it had been shown that toxin polypeptides linked to monoclonal antibodies could inhibit HIV-infected cells. In the present study, the free, unconjugated, proteins were found to inhibit HIV replication at doses in which they were nontoxic to uninfected peripheral blood mononuclear cells. Among the inhibitory proteins, PAP-S and recombinant ricin A chain markedly reduced the reverse transcriptase activity and the expression of p24 core protein in infected cultures. Dose response studies indicate that the anti-HIV activity of PAP-S was comparable to AZT. The other ribosome inhibitory proteins (RIPs) showed moderate but significant antiviral activity.
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PMID:Ribosomal inhibitory proteins from plants inhibit HIV-1 replication in acutely infected peripheral blood mononuclear cells. 172 58

To investigate a possible potentiation of Azidothymidine activity by immunomodulators, two in vitro models of HIV infection were analyzed. Peripheral blood lymphocytes on one hand, and cells from the CEM line on the other hand, were infected in vitro with HIV1 and reverse transcriptase activity was monitored daily in the cultures. When Azidothymidine was added, reverse transcriptase activity was significantly reduced. When Isoprinosine or Diethyldithiocarbamate was added in vitro, the reverse transcriptase was only slightly decreased (to a much less significant degree). When Azidothymidine was added together with either Isoprinosine or Diethyldithiocarbamate, a synergistic effect was observed with a very potent inhibition of reverse transcriptase activity. Before a possible application of such a combined therapy to patients, the pharmacokinetics of Azidothymidine was analyzed after the compound had been given alone or in combination with Isoprinosine. No alteration of pharmacokinetics was observed, suggesting that the immunomodulator will not alter the metabolism of the antiretroviral therapy in vivo, and may even enhance its biological activity, as it does in vitro.
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PMID:Rationale for a combined use of antiretroviral and immunomodulatory therapies in HIV infection. 172 84

The combination of S-dC28 (a phosphorothioate oligodeoxcytidine 28 mer) with AZT, recombinant interferon alpha-A (IFN-alpha A) or dextran sulfate (DS) against replication of human immunodeficiency virus type 1 (HIV-1) were studied in MT4 cells, using both p24 core antigen and reverse transcriptase (RT) assays. Under the standardized conditions, the anti-HIV-1 dose-effect relationships of all test drugs showed sigmoidal curves with the following EC50 values: for the p24 core antigen assay, S-dC28, 0.03 microM; AZT, 0.004 microM; IFN-alpha A, 9.2 U/ml; DS, 0.26 micrograms/ml; for the RT assay, S-dC28, 0.04 microM; AZT, 0.01 microM; IFN-alpha A, 11.6 U/ml; and DS, 0.31 micrograms/ml. A computer software based on the median-effect principle and isobologram techniques were used to quantitatively analyze drug interactions by calculating the combination index (CI) where CI less than 1, = 1, and greater than 1 indicates synergism, additive effect and antagonism, respectively. For p24-ELISA, the interaction of S-dC28 and AZT in combination produced a slight antagonism on HIV-1 replicative inhibition with CI values of 1.29-1.10; for RT assays, at EC50-EC95 levels, the CI values are 1.96-1.11. For p24 core antigen assay, the combination of S-dC28 with IFN-alpha A exhibited a dose-dependent anti-HIV synergism with CI values of 1.15-0.87 at EC75-EC95 levels. The RT assays for the same combination showed a broad synergistic effect with CI values of 0.62-0.60, at EC50-EC95 levels. S-dC28 plus DS showed a nearly additive effect based on both assay methods.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Differential alteration of the anti-HIV-1 effect of phosphorothioate oligonucleotide S-dC28 by AZT, interferon-alpha, and dextran sulfate. 176 Feb 31

Inhibition mechanisms of 5'-triphosphates of 3'-azido-3'-deoxythymidine (AZT-TP) and 3'-deoxythymidine (ddTTP) on extensively purified DNA polymerase gamma from bovine testes were examined by analysis of the products synthesized on singly primed M13 single-stranded DNA or synthetic oligonucleotide template-primer in the presence of analogues. The results indicate that AZT-TP inhibits DNA polymerase gamma in competition with dTTP but is not incorporated into DNA, whereas ddTTP is incorporated into DNA and causes chain termination. In contrast, both analogues were used by reverse transcriptase and caused chain termination.
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PMID:The 5'-triphosphates of 3'-azido-3'-deoxythymidine and 2', 3'-dideoxynucleosides inhibit DNA polymerase gamma by different mechanisms. 189 99

Interferon alpha was one of the first drugs tested for the treatment of patients with AIDS-related Kaposi's sarcoma based on its known antiviral properties and its abilities to modulate immune function and inhibit neoplastic cell proliferation. In vitro studies demonstrated defective production of interferon by blood cells of HIV-infected individuals and suppression of HIV replication by interferons alpha and beta. Interferons have also been shown to inhibit angiogenesis induced by tumour cells or by allogeneic lymphocytes in mice. The efficacy of recombinant interferon alpha for the treatment of AIDS-related Kaposi's sarcoma has been well documented with antitumour responses seen in approximately 30% of all patients treated in single agent efficacy trials with doses of at least 20 MU/m2. In several uncontrolled studies, response of Kaposi's sarcoma to treatment with interferon alpha was associated with longer survival and few opportunistic infections. Tumour response appears to be correlated with an absence of opportunistic infection and with CD4 cell numbers. Several studies using high interferon alpha doses have demonstrated decreases in serum HIV P24 core antigens which appear to be confined to patients whose tumours also regressed. The use of interferon alpha in HIV-infected patients with or without Kaposi's sarcoma have demonstrated in vivo anti-HIV activity. Studies have recently evaluated the tolerance and therapeutic potential of interferon alpha in combination with the reverse transcriptase inhibitor, zidovudine (azidothymidine AZT). Synergistic suppression of HIV replication in vitro has been demonstrated with the combination of interferon alpha and zidovudine. The description of HIV isolates with reduced sensitivity to zidovudine following prolonged treatment, and the finding that interferon alpha, but not zidovudine, prevents HIV expression in chronically infected cell lines, suggests that this combination might be useful in long-term treatment of patients with HIV infection.
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PMID:Interferon alpha in the treatment of AIDS-related Kaposi's sarcoma. 193 14

Antiretroviral therapy for children is still at an early stage, although progress is being made slowly. Zidovudine administered at 180 mg/m2/dose every 6 hours is the current standard therapy for symptomatic children and those with low CD4 counts. This standard is likely to evolve as further testing clarifies the optimal dosage for ZDV in different populations. Children on ZDV need to be monitored very closely (at least monthly) for hematologic side effects, which are most common in the more seriously ill children. The role of some of the newer antiretrovirals, like ddI and ddC, which are likely to be licensed, has yet to be established. They have a different toxicity profile than ZDV and thus may work well in combination with it. The issue of peripheral neuropathy and the lack of an easy test to measure it makes using ddC or ddI in young, preverbal children a daunting proposition. As with ZDV, the optimum dosage and timing have yet to be fixed for ddC or ddI alone, and even less available are regimens for combination therapy. Antiretroviral drugs other than the dideoxynucleosides are less well developed. Some, like high-titer antiviral immunoglobulin, involve technology that is already available and thus will be relatively easy to study. Others, like the antisense oligomers, are such a new technology that there are many hurdles to be overcome as the agents move from the laboratory to the clinic. The goal of agents that work on sites other than reverse transcriptase is a reasonable one, but the work in perfecting such new categories of drug is difficult and slow. In the meantime, children with HIV should be symptomatically supported and offered the most effective antiretroviral regimens available.
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PMID:Antiviral therapy for human immunodeficiency virus infection in children. 198 14

A series of synthetic lipids containing a two- or three-carbon backbone substituted with a thio, oxy, or amidoalkyl functionality and either a phosphocholine or quaternary ammonium moiety was evaluated as potential anti-HIV-1 agents. Several analogues were identified as possessing activity with the most promising compound being rac-3-octadecanamido-2-ethoxypropylphosphocholine (8). Compound 8 exhibited an IC50 for the inhibition of plaque formation of 0.16 microM which was 84-fold lower than the IC50 value determined for CEM-SS cell growth inhibition. Initial mechanistic studies have indicated that these compounds, unlike AZT, are not reverse transcriptase (RT) inhibitors, but instead appear to inhibit a late step in HIV replication involving virus assembly and infectious virus production. Since these lipids are acting via a different mechanism, they represent an alternative approach to the chemotherapeutic treatment of AIDS as well as candidates for combination therapy with AZT.
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PMID:In vitro evaluation of phosphocholine and quaternary ammonium containing lipids as novel anti-HIV agents. 201 13

The development of reduced susceptibility to zidovudine (AZT) has been documented in isolates of human immunodeficiency virus (HIV) from patients receiving prolonged therapy with the drug. Resistance emerges more quickly and to a higher degree in patients in later stages of disease. Progressive stepwise reductions in susceptibility occur with sequential isolates in conjunction with the cumulative acquisition of mutations in the gene for reverse transcriptase. Cross resistance to other compounds has been observed to date only with nucleosides possessing a 3'-azido moiety. The clinical significance of reduced drug susceptibility and strategies to deal with this issue are under investigation.
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PMID:AZT resistance in isolates of HIV. 205 36

Several dideoxynucleosides, including 3'-azido-2',3'-dideoxythymidine (zidovudine, azidothymidine, AZT), 2',3'-dideoxycytidine (ddC), and 2',3'-dideoxyinosine (ddI), have been shown to be potent inhibitors of human immunodeficiency virus (HIV) replication in human T cells and macrophages. These compounds undergo anabolic phosphorylation within target cells to a 3'-triphosphate moiety; as triphosphates, they act at the level of HIV DNA polymerase (reverse transcriptase). AZT has been shown to reduce the morbidity and mortality of patients with severe HIV infection and to at least temporarily ameliorate certain cases of HIV-induced dementia. In phase 1 studies, ddC and ddI have been shown to induce immunologic and virologic improvements in patients with AIDS or related disorders; phase 2 studies of ddC and ddI are underway. The use of these drugs can be associated with toxicity. AZT can cause bone marrow toxicity or myositis with prolonged use, ddC can cause peripheral neuropathy at high doses, and ddI can cause sporadic pancreatitis and peripheral neuropathy at high doses. For each compound, however, a therapeutic window exists in which an anti-HIV effect can be attained without short-term toxicity in most patients. Dose-intensity appears to be an important determinant of the toxicity of dideoxynucleosides. Studies are underway to explore how the therapeutic profiles of these compounds may be enhanced by attention to scheduling or through the use of combination therapy.
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PMID:Initial clinical experience with dideoxynucleosides as single agents and in combination therapy. 207 27

Human immunodeficiency virus (HIV), the cause of AIDS, was the second retrovirus to be associated with human diseases. The unique life cycle of retroviruses involves reverse transcription of their RNA to DNA, which is incorporated into their host's genes. HIV, despite its small genome, contains multiple structural and regulatory genes, the latter controlling the rate of viral replication. Experimental vaccines are aimed at inhibiting binding of HIV to host cells. Azidothymidine (AZT) and other nucleoside analogues inhibit the reverse transcriptase enzyme. HIV induces profound and specific immunosuppression by depleting helper lymphocytes that bear the cluster determinant 4 (CD4, formerly T4). The clinical course of HIV infection is mainly determined by the number of CD4 lymphocytes in the blood. A comprehensive, multidisciplinary approach to patient management can reduce the adverse medical, psychosocial, and economic impact of AIDS.
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PMID:Virology, immunology, and clinical course of HIV infection. 218 Oct 4


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