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)

Since the discovery of human immunodeficiency virus (HIV) as the causative agent of acquired immune deficiency syndrome (AIDS), various attempts have been made to control this fatal disorder. In the replicative cycle of HIV, several steps have been identified as attractive targets for antiviral chemotherapy. Sulfated polysaccharides can block the virion binding to the CD4 receptor. 2',3'-Dideoxynucleosides including 3'-azido-3'-deoxythymidine (AZT) act as potent inhibitors of reverse transcriptase after intracellular phosphorylation. Only AZT and 2',3'-dideoxyinosine are available so far for the treatment of AIDS and AIDS-related complex. Non-nucleoside reverse transcriptase inhibitors of HIV-1 and viral protease inhibitors are the new classes of compounds that are now extensively studied. These compounds may add a new dimension to the prospects of anti-AIDS chemotherapy.
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PMID:Chemotherapeutic approaches to human immunodeficiency virus infections. 128 48

Didanosine is a dideoxynucleoside analogue which undergoes intracellular conversion to the putative active triphosphate metabolite. The active metabolite appears to inhibit viral reverse transcriptase and terminate the proviral DNA, and produces virustatic inhibition of actively replicating human immunodeficiency virus (HIV) at clinically relevant concentrations. In phase I studies didanosine had beneficial effects on various surrogate markers of clinical efficacy and also improved clinical manifestations of HIV infection, with a 21-month survival rate of 80% in patients with acquired immune deficiency syndrome (AIDS) and 93% in patients with AIDS-related complex (ARC) in 1 study. Didanosine also improved CD4+ cell counts in a phase II/III trial in patients previously treated with zidovudine, whereas cell counts declined in patients continuing zidovudine therapy. However, the effects of didanosine on clinical end-points (disease progression, survival, HIV encephalopathy) remain to be established. Peripheral neuropathy and pancreatitis are the predominant dose-limiting adverse events and didanosine therapy should be withdrawn in patients developing signs or symptoms of pancreatitis and during acute treatment of Pneumocystis carinii pneumonia. However, at currently recommended clinical dosages didanosine is generally well tolerated with minimal haematological toxicity. Thus, in a therapeutic area with few treatment options, didanosine offers a welcome alternative for patients intolerant of, or resistant to, zidovudine. There are a number of clinical trials in progress evaluating didanosine alone or in combination with other antiviral agents, and these results are awaited with considerable interest.
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PMID:Didanosine. A review of its antiviral activity, pharmacokinetic properties and therapeutic potential in human immunodeficiency virus infection. 137 14

The construction and preliminary biological characterization of three molecular clones of human immunodeficiency virus type 1 (HIV-1) are reported: HIV-1LAI from a French man with AIDS, HIV-1MAL from a Zairian boy with ARC, and HIV-1ELI from a Zairian woman with AIDS. All three sequences were found to code for infectious viruses. Both the host range and the kinetics of infection in CD4+ cells were different for the three viruses. Virus derived from each molecular clone was infectious on peripheral blood mononuclear cells (PBMC), although LAI and ELI displayed more rapid growth kinetics than MAL. The viruses had different tropisms and growth kinetics in six cell lines. LAI was infectious in all of the cell lines and produced high levels of reverse transcriptase activity. MAL and ELI had more restricted tropisms: MAL could only replicate on SupT1, whereas ELI grew on Jurkat and MT-4, was delayed on CEM and H9, and was unable to infect U937 cells. In addition, we observed that both the replicative capacity and the cell tropism of viruses could change after passage through some established cell lines. These results suggest that the genotypes of some viruses in vitro are not stable and that selection for growth can cause the fairly rapid appearance of variants with increased growth potential.
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PMID:Changes in growth properties on passage in tissue culture of viruses derived from infectious molecular clones of HIV-1LAI, HIV-1MAL, and HIV-1ELI. 168 26

An oriental remedy, Sho-saiko-to (SST) consisting of a mixture of aqueous extracts from seven different plants and whose most active component is the chemically defined compound baicalein was tested for its ability to inhibit the production of the human immunodeficiency virus (HIV). The testing was done with cultures of human lymphocytes obtained from HIV-positive asymptomatic subjects and patients with ARC or AIDS. The replication of the virus was monitored by quantitative assay of the reverse transcriptase (RT) activity and of the synthesis of antigen p24. The lymphocyte cultures (LC) were maintained in the absence and in the presence of 25, 50 or 100 micrograms/ml of SST, and monitored for up to 5 weeks. The results showed that in LC from asymptomatic subjects RT activity and synthesis of p24 was completely inhibited by low concentrations of SST. High concentrations of SST inhibited virus replication in 80% of LC from ARC patients, but were completely ineffective in LC from AIDS patients. It was observed that the RT activity was more sensitive to inhibition by SST than the synthesis of p24, and that the antiviral effect was dependent on the virus load of the LC.
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PMID:Inhibition of HIV replication in lymphocyte cultures of virus-positive subjects in the presence of sho-saiko-to, an oriental plant extract. 170 25

2',3'-dideoxyguanosine 5'-triphosphate (ddGTP) was found to be an efficient substrate for DNA polymerase beta when activated DNA was used as the template.primer. Under the optimized reaction conditions with activated DNA, the rate of the incorporation of ddGTP into DNA was almost equal to that of the corresponding normal substrate dGTP. The Km value for ddGTP (1.8 microM) was smaller than that for dGTP (7.8 microM). In contrast, ddGTP was not utilized as a substrate for DNA polymerase gamma with any of the activated DNA and (dC)n.(dG)12-18 as the template primer. Other DNA polymerases such as DNA polymerase alpha, E coli DNA polymerase I and retroviral reverse transcriptase could poorly utilize ddGTP as a substrate. Some of the kinetic properties of DNA polymerase beta revealed toward ddGTP are also described. Since DNA polymerase beta plays a role in DNA repair, the present results predict possible appearance of cytotoxicity or clinical side effect(s) of 2',3'-dideoxyguanosine (ddG), known as a potent inhibitor of human immunodeficiency virus, when ddG is administered to the patients with acquired immune deficiency syndrome (AIDS) or AIDS-related complex.
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PMID:Differential utilization of 2',3'-dideoxyguanosine 5'-triphosphate as a substrate for various DNA polymerases. 193 1

The polysulfated polyxylan HOE/BAY946, which has been tested in two pilot studies in ARC/AIDS patients and in asymptomatic HIV carries in Germany, was believed to act by inhibiting virus attachment to the cell. However, the drug was also found to reduce the amount of HIV particles released from infected peripheral blood mononuclear cells (PBMC) in vitro. Furthermore, preincubation of PBMC with the drug led to a partial inhibition of a following HIV infection, suggesting that the drug also affects virus entry. Electron Paramagnetic Resonance (EPR) measurements on uninfected human lymphocytes using 5-proxyl-nonane as spin label demonstrated smaller hyperfine coupling constant (aN) values in the presence of HOE/BAY946 or dextran sulfate 5000. Accordingly, h-1p/h-1H ratios were decreased, indicating increased plasma membrane hydrophobicity and a membrane-stabilizing effect of the drugs. Culture of the chronically HIV-infected monocytic cell line U937/HIV-2D194 in the presence of HOE/BAY946 specifically and drastically reduced the release of virions and the intracellular synthesis of viral proteins as determined by radioimmunoprecipitation and reverse transcriptase assays. In conclusion, although the EPR studies showed a physico-chemical effect on membrane polarity, HOE/BAY946 and dextran sulfate clearly affect processes beyond the cell membrane. Thus, in contrast to previous reports suggesting that polysulfated sugars affect HIV only by inhibiting virus binding to uninfected cells, they clearly inhibit HIV in infected cells as well and appear to have a pleiotropic mode of action. Such drugs may be less likely to result in viral resistance after prolonged application than substances acting only on one step in the life cycle of the virus.
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PMID:Anti-human immunodeficiency virus (HIV) drug HOE/BAY946 increases membrane hydrophobicity of human lymphocytes and specifically suppresses HIV-protein synthesis. 196 49

The reverse transcriptase inhibitor 2',3'-dideoxycytidine (ddC) is capable of mediating virologic and immunologic improvements in some patients with acquired immunodeficiency syndrome (AIDS) or AIDS-related complex. However, severe peripheral neuropathy often develops as a dose-limiting toxicity in ddC-treated patients. Lower doses of ddC may avoid this side effect, while retaining antiviral activity associated with this drug. A series of clinical trials is currently examining regimens employing simultaneous or alternating administration of ddC and 3'-azido-3'-deoxythymidine (zidovudine). Concurrent therapy with more than one drug may allow the use of decreased drug doses and thus reduce dose-dependent toxicities, whereas alternating schedules would provide rest periods from each drug without interrupting therapy. Since zidovudine and ddC possess different toxicity profiles and zidovudine-resistant strains remain susceptible to ddC in vitro, such regimens could theoretically provide additional benefits and reduced toxicity, compared with either agent administered alone. It is hoped that these ongoing and future studies will uncover new and better ways to exploit the therapeutic potential of ddC. However, at present, ddC is an experimental drug and should not be used outside the setting of an approved clinical protocol.
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PMID:Dideoxycytidine: current clinical experience and future prospects. A summary. 215 8

Recently, a newly discovered lentivirus--Feline Immunodeficiency Virus (FIV)--was identified as the cause of an AIDS-like syndrome in the cat. For the detection of FIV antigen in cell culture, an antigen capture ELISA was developed. In this assay FIV specific IgG was used as a capture antibody and the same preparation coupled to biotine as a conjugate. With this test viral antigen could be demonstrated in FIV infected cell cultures within four days after infection and the assay proved to be at least as sensitive as a reverse transcriptase test in demonstrating virus infected cultures. A modification of this assay in which a titrated amount of FIV antigen was incubated with dilutions of serum samples of naturally or experimentally infected cats, allowed the detection of FIV specific antibodies. In a serological survey, conducted among cats with different clinical histories in The Netherlands and The Federal Republic of Germany, the antibody inhibition ELISA was compared with a commercially (IDEXX) available indirect ELISA system. It was shown that both assays identified nine seropositive cats among 200 animals with a history of undefined chronic disease, whereas no positive reactions were obtained with 65 serum samples from apparently healthy animals. Both assays also gave positive results with serum samples from experimentally infected cats, within five weeks after infection. Of an additional panel of eight serum samples which had been found positive in the IDEXX indirect ELISA system, only five were found positive in the antibody inhibition ELISA and western blotting assay.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:An enzyme linked immunosorbent assay (ELISA) for the detection of feline immunodeficiency virus (FIV) antigen in cell culture and FIV specific antibodies in feline serum. 217 15

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

Zidovudine (ZDV) is the only approved antiviral for the treatment of human immunodeficiency virus infection (HIV) in the U.S. Although newer antivirals have reached Phase II testing, ZDV is now the accepted therapy against which all other agents will be compared. Zidovudine 1500 mg/d was previously prescribed only to adult HIV-infected patients who had developed AIDS or AIDS-related complex (ARC). However, results obtained from recently completed studies indicate that a lower daily dose (500 mg) appears to be equivalent. In addition, ZDV therapy appears to be beneficial to asymptomatic HIV-infected patients with CD4+ counts less than 500/mm3. The toxicity profile of ZDV, previously obtained from patients receiving 1500 mg/d, consisted of either acute (e.g., fever, rash, headache) or chronic (e.g., anemia, neutropenia, myopathy) adverse effects. ZDV pharmacokinetics are variable within and between the different subpopulations of HIV-infected patients who have been studied. Bioavailability ranges from 50 to 70 percent, and values for half-life, total body clearance, and volume of distribution are 1-2 h, 20-40 mL/min/kg, and 1-2 L/kg, respectively. Drug interactions occur primarily between ZDV and other agents that undergo hepatic glucuronidation (e.g., probenecid, sulfamethoxazole) resulting in decreased ZDV clearance. ZDV is currently measured by HPLC, radioimmunoassay and FPIA; however, the role of therapeutic monitoring is currently under investigation. Studies of ZDV therapy in neonates, pediatric patients, patients with resistant isolates of HIV, and HIV-infected patients receiving combined treatment with other reverse transcriptase inhibitors or immunomodulators are ongoing.
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PMID:Zidovudine update: 1990. 219 18


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