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

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

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

The emergence of human immunodeficiency virus resistant to 3'-azido-3'-deoxythymidine (zidovudine, AZT) in patients with acquired immunodeficiency syndrome (AIDS) or AIDS-related complex has been documented. Isolates from non-AZT-treated persons or those who had received AZT for less than six months showed a narrow range of susceptibility to the drug; on the other hand, isolates from those who had received AZT for six months or more consistently showed reduced susceptibility. Five highly AZT-resistant isolates were also insensitive to other compounds containing a 3'-azido group. No cross-resistance was found to other nucleoside analogues, including 2',3'-dideoxycytidine and 2',3'-dideoxyinosine. That cross-resistance occurred only in compounds containing a 3'-azido group suggests that mutations in the reverse transcriptase gene prohibit the enzyme from using nucleoside triphosphate containing a 3'-azido group. Progressive, stepwise increases in resistance have been associated with the sequential accumulation of specific amino acid changes in the reverse transcriptase gene. It is not yet known whether the resistant phenotype as determined in vitro results in clinical resistance to AZT. The gradual appearance of resistant isolates, the variable course of human immunodeficiency virus infections, and the absence of a consistent pattern of resurgent p24 antigen will make the emergence of AZT resistance difficult to correlate with clinical status or other markers. The combination of AZT with other drugs that do not share cross-resistance is a promising area for investigation to identify regimens that are more active and less likely to induce resistance.
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PMID:Susceptibility to nucleoside analogues of zidovudine-resistant isolates of human immunodeficiency virus. 218 29

We studied the effect of AZT on the replication of HIV-1 in freshly and chronically infected U-937 monocytoid cells over a period of 2 months. Expression of viral antigens was monitored by indirect immunofluorescence, and viral replication was assessed by reverse transcriptase assay on virus pelleted from culture fluids. In U-937 cells not treated by AZT, viral antigens were expressed by 7 days after infection. The inclusion of a variety of concentrations of AZT in the culture medium was shown to retard virus replication in a dose-dependent fashion, although a complete inhibitory effect was not seen with any clinically attainable concentration of drug. Exposure of HIV-1-inoculated cells to AZT did not give rise to progeny virus possessing a drug-resistant phenotype. However, the study of clonal derivatives of U-937 cells revealed cellular variants with increased susceptibility to HIV-1, and against which AZT had reduced effectiveness in comparison with the parental line. No effect of AZT was seen on cells already infected by HIV-1, suggesting that this drug had no influence on viral replication in U-937 cells into which viral DNA had previously integrated.
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PMID:Inhibition by AZT of HIV-1 replication in acutely infected U-937 cells. 219 Oct 63

Therapy of AIDS comprises two aspects: (1) causative therapy, directed against HIV, and (2) symptomatic therapy of opportunistic infections and malignancies. The best results regarding antiretroviral therapy - both in vitro and in vivo - have been obtained, so far, with inhibitors of reverse transcriptase. We discuss the mechanism of action, the efficacy, and the side effects of AZT, a nucleoside analogue, and comment on combined therapies with acyclovir and immunomodulators. We report on the therapy of the most frequent opportunistic infection - i.e. Pneumocystis carinii pneumonia - with sulfamethoxazole/trimethoprim and pentamidine as well as the chemoprophylaxis of this disease. During the last few years, important progress has been made in the field of antiviral chemotherapy (HSV, CMV, VZV) and the therapy of gastrointestinal infections. Moreover, the therapy of Kaposi's sarcoma associated with AIDS and that of non-Hodgkin's lymphoma has been established by now.
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PMID:[AIDS therapy]. 220 64


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