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)

Four flavonoids (i.e., baicalein, quercetin, quercetagetin, and myricetin), known to be inhibitors of HIV-reverse transcriptase, have been shown to be more or less inhibitory to the activities of various cellular DNA and RNA polymerases. The degree of the inhibition varied depending on the combination of the flavonoid and the enzyme species: baicalein was moderately inhibitory to DNA polymerase gamma and E. coli DNA polymerase I; quercetin was strongly inhibitory to DNA polymerase beta and E. coli RNA polymerase and moderately inhibitory to DNA polymerase I; quercetagetin was a potent inhibitor for all of DNA polymerases alpha, beta, gamma, and I and RNA polymerase; myricetin was a strong inhibitor of DNA polymerases alpha and I and RNA polymerase. However, terminal deoxynucleotidyltransferase was virtually insensitive to inhibition by these flavonoids. The inhibition by the flavonoids was due to competition with the template.primer in the case of the DNA polymerases, whereas the inhibition was due to competition with the triphosphate substrate (GTP) in the case of RNA polymerase. The Ki values of these flavonoid inhibitors for DNA and RNA polymerases was determined.
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PMID:Mechanisms of inhibition of various cellular DNA and RNA polymerases by several flavonoids. 229 90

The effect of human interferons (IFNs) (alpha, beta, and gamma) on the in vitro replication of AIDS viruses (LAV, HTLV-III, and ARV-2) in human peripheral blood lymphocytes was investigated. At the time of peak virus production, IFN-alpha preparations (leukocyte, Namalwa, alpha 1, and alpha 2) at 100 U/ml, suppressed LAV, HTLV-III, and ARV-2 replication as measured by reverse transcriptase (RT) activity by greater than 50%. This suppression was dose dependent and high dosages (500 U/ml) of IFN-alpha resulted in almost complete suppression of RT activities (77-99%). A low dose (100 U/ml) of IFN-beta suppressed all three AIDS viruses by 75%. In contrast, human IFN-gamma at a dose range from 100 U/ml to 500 U/ml had no significant effect on the production of infectious viruses. These results indicate that only IFN-alpha and -beta are effective against LAV, HTLV-III, and ARV-2 replication. A continuous supply of IFN appeared to be essential for the constant suppression of RT activity. In fact, upon termination of single IFN treatment, enhanced virus production resulted.
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PMID:Human alpha- and beta-interferon but not gamma- suppress the in vitro replication of LAV, HTLV-III, and ARV-2. 242 14

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

A series of 5'-phosphorylated derivatives of 3'-azido-2',3'-dideoxythymidine (AzddThd), including AzddThd 5'-mono- and 5'-triphosphate, alpha, beta-methylene AzddThd-5'-diphosphate, alpha,beta-methylene AzddThd-5'-triphosphate, and beta,gamma-methylene AzddThd-5'-triphosphate, were evaluated for their cytostatic and anti-retrovirus properties, and their inhibitory effects on the reverse transcriptases of Moloney murine leukemia virus and human immunodeficiency virus. In contrast with the 5'-mono- and 5'-triphosphates of AzddThd, which showed cytostatic and anti-retrovirus activities comparable to those of AzddThd, the alpha,beta-methylene 5'-phosphonates of AzddThd were considerably less cytostatic and also much less inhibitory to cell transformation by Moloney murine sarcoma virus and cytopathogenicity of human immunodeficiency virus. The decreased biological activity of the phosphonate derivatives of AzddThd is most likely due to the resistance of these compounds to phosphorolytic attack by phosphodiesterases and phosphatases, and the reduced affinity for the retrovirus-associated reverse transcriptase.
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PMID:Alpha, beta- and beta, gamma-methylene 5'-phosphonate derivatives of 3'-azido-2',3'-dideoxythymidine-5'-triphosphate. Correlation between affinity for reverse transcriptase, susceptibility to hydrolysis by phosphodiesterases and anti-retrovirus activity. 245 21

The chemically modified DNA, apurinic acid (APA), is cytotoxic for human lymphocytes at concentrations above 100 micrograms/ml. At low concentrations (0.05-1 micrograms/ml) APA acts as an inducer interferon gamma (IFN-gamma) in lymphocytes in vitro; the maximum interferon titer of 50 units/ml was reached at 0.4 micrograms/ml. When added to the cells in combination with phytohemagglutinin A (PHA), APA displays a significant synergistic interferon-inducing ability; the maximum titer of 940 units/ml was obtained with 10 micrograms/ml of APA and 6.25 micrograms/ml of PHA. APA also proved to be an effective inhibitor of human immunodeficiency virus (HIV-1) replication in H9 cells. At a concentration of 10 micrograms/ml, APA causes a 49% inhibition of virus growth, while 20 micrograms/ml of APA are required to inhibit expression of HIV-1 p17 and p24 gag proteins by 60%. The mechanism of anti HIV-1 activity of APA likely occurs at the level of viral reverse transcriptase. This enzyme is inhibited by APA in a noncompetitive way with a Ki of 0.39 microM, while the cellular DNA polymerases alpha, beta and gamma are 140- to 300-fold less sensitive to APA.
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PMID:Dual biological activity of apurinic acid on human lymphocytes: induction of interferon-gamma and protection from human immunodeficiency virus infection in vitro. 245 40

Avarol is a sesquiterpenoid hydroquinone, which displays no inhibitory potencies on mammalian DNA polymerases alpha, beta, and gamma, on mammalian RNA polymerases I, II, and III, or on reverse transcriptases from Moloney murine leukemia virus (Mo-MuLV) and from HIV. For a further elucidation of the antiviral effect of Avarol, we used NIH-3T3 cells infected with Mo-MuLV as a model system. The results show that in uninfected NIH-3T3 cells Avarol (i) causes a 50% reduction of the growth rate only at the high concentration of 29.6 microM and (ii) is accumulated in the cytoplasm close to the nucleus. At the much lower concentrations of 1-3 microM, Avarol causes an almost complete inhibition of viral progeny release. Moreover, it is shown that at 3 microM Avarol, the increase of the Mo-MuLV-induced UAG suppressor glutamine tRNA (tRNA(UmUGGln) was reduced to the normal level. Dot blot hybridization studies revealed that Avarol displays no inhibitory activity on cellular and viral mRNA synthesis. Taking the processing pathway of viral polyprotein Pr180gag,pol to p80 (reverse transcriptase) as an example, our Western blotting experiments showed that the final maturation process, conversion of p110 to p80, is inhibited in Avarol-treated cells. From these data we conclude that Avarol prevents the suppression of the UAG termination codon at the gag-pol junction of the retroviral genome. The functional consequence of this event is very likely an inhibition of the readthrough of the retroviral protease gene which overlaps the pol and gag genes, resulting in the reduction of the protease synthesis which is necessary for the viral proliferation.
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PMID:Selective inhibition of formation of suppressor glutamine tRNA in Moloney murine leukemia virus-infected NIH-3T3 cells by Avarol. 245 80

The inhibitory effects of two anionic compounds, Evans blue and aurintricarboxylic acid (ATA), on various kinds of polynucleotide-synthesizing enzymes were examined. Under the assay conditions, optimized for each enzyme species, both these compounds strongly inhibited the activities of the purified human DNA polymerases alpha, beta, gamma, and DNA primase as well as those of DNA polymerase I and RNA polymerase from Escherichia coli and Rauscher leukemia virus reverse transcriptase. ATA was particularly effective in inhibiting retroviral reverse transcriptase and cellular DNA polymerase alpha. Evans blue, which is a structural analogue of suramin, exerted its inhibitory action largely by competing with the template.primer for the same binding site of the enzyme. On the other hand, ATA inhibited most, if not all, of these enzyme activities noncompetitively with respect to either the template.primers or nucleoside 5'-triphosphate substrates. The inhibition constants for ATA were, in general, smaller than those for Evans blue.
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PMID:Differential inhibition of various deoxyribonucleic acid polymerases by Evans blue and aurintricarboxylic acid. 246 Mar 49

Several analogues of 2',3'-dideoxythymidine 5'-triphosphate [i.e., 3'-azido-2', 3'-dideoxythymidine 5'-triphosphate(Azdd TTP), 2',3'-didehydro-2',3'-dideoxythymidine 5'-triphosphate (ddeTTP), alpha, beta-methylene 3'-azido-2',3'-dideoxythymidine 5'-diphosphate, alpha, beta-methylene 3'-azido-2',3'-dideoxythymidine 5'-triphosphate, and beta, gamma-methylene 3'-azido-2',3'-dideoxythymidine 5'-triphosphate] and 2',3'-didehydro-2',3'-dideoxycytidine 5'-triphosphate (ddeCTP) have been evaluated for their inhibitory effects on murine retroviral reverse transcriptase and various other DNA polymerases, including DNA polymerases alpha, beta, and gamma, terminal deoxynucleotidyl transferase, and DNA polymerase I. None of the compounds inhibited the activity of DNA polymerase alpha under the reaction conditions employed. When Mg2+ was replaced by Mn2+, however, DNA polymerase alpha was strongly inhibited only by ddeTTP. DNA polymerase beta activity was inhibited only by ddeTTP and ddeCTP. All the compounds, except for ddeCTP, inhibited DNA polymerase gamma activity, ddeTTP being a particularly strong inhibitor of gamma-polymerase (Ki = 3.5 nM). Terminal deoxynucleotidyl transferase was only slightly inhibited by any of the compounds. AzddTTP was a potent inhibitor of reverse transcriptase (Ki = 42 nM), but it also inhibited the activities of DNA polymerase gamma and DNA polymerase I.
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PMID:Differential inhibitory effects of several pyrimidine 2',3'-dideoxynucleoside 5'-triphosphates on the activities of reverse transcriptase and various cellular DNA polymerases. 247 Oct 54

Carbocylic 2',3'-didehydro-2',3'-dideoxyguanosine (Carbovir; NSC 614846) is an antiretroviral agent which may be useful in the treatment of AIDS. We have synthesized the 5'-triphosphate of Carbovir and examined its ability to inhibit human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (EC 2.7.7.49) and other retroviral reverse transcriptases, as well as human DNA polymerases alpha, beta, gamma (EC 2.7.7.7) and DNA primase (EC 2.7.7.6). Carbovir triphosphate emerges as a highly selective inhibitor of reverse transcriptases with little, if any, effect on the cellular enzymes. 3'-Azido-2',3'-dideoxythymidine (AZT) triphosphate and the two dideoxynucleoside triphosphates, ddTTP and ddGTP, inhibited HIV-1 reverse transcriptase to the same degree as Carbovir triphosphate, but were less selective in that they also inhibited DNA polymerases beta and gamma. We conclude that Carbovir is a highly selective antiretroviral agent.
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PMID:Comparison of the effect of Carbovir, AZT, and dideoxynucleoside triphosphates on the activity of human immunodeficiency virus reverse transcriptase and selected human polymerases. 247 36

During senescence in the filamentous fungus Podospora anserina, specific regions of the mitochondrial genome, termed senDNA are excised, ligated and amplified. We have cloned in their entirety three such autonomously replicating plasmids, alpha, beta and epsilon senDNA. None of these plasmids displayed cross-hybridization nor did we detect any significant DNA homology by computer analysis. The complete DNA sequence of the 2.5 kb alpha, the 5.5 kb epsilon and about 3.4 kb of the 9.8 kb beta senDNA is presented (kb = 10(3) base-pairs). These sequences were analyzed for the presence of consensus sequences common to introns, and it was found that alpha senDNA has the characteristics of a group II intron, epsilon senDNA contains three group I introns, and beta senDNA did not show relevant sequences in the 3.4 kb examined. Comparison of the 5' and 3'-flanking sequences of alpha senDNA with oxi 3 (Co I) amino acid sequences from Neurospora crassa and Saccharomyces cerevisiae revealed significant homology and provided strong support that the excised alpha senDNA itself consists entirely of an intron. Upstream from the oxi 3 gene a transfer RNA cysteine sequence was detected. beta senDNA contained four tRNA sequences, aspartic acid, serine, valine and tryptophan, and sequences homologous to URFC (untranslated reading frame C) as well as two new URFs. epsilon senDNA contained sequences homologous to ATPase 8 and URFl; URFl was interrupted by three group I introns. The excision site sequences, as located by S1 nuclease mapping were unique for each senDNA. Analysis for repeated units showed that each plasmid contained elements which could be involved in secondary structure required for the alignment of distal ends preparatory to excision. These results are interpreted in terms of the structural requirements of mobile elements including the possible involvement of reverse transcriptase in the excision-ligation-amplification process.
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PMID:Excision-amplification of mitochondrial DNA during senescence in Podospora anserina. DNA sequence analysis of three unique "plasmids". 299 55


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