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)

Xylanpoly-(hydrogen sulphate) disodium salt with a molecular weight of about 6000 daltons (HOE/BAY 946) completely inhibited syncytium formation induced by the infection of T lymphocytes with HIV as well as viral replication at concentrations above 25 micrograms/ml. This dose was found to be inhibitory for several strains of HIV-1 and HIV-2. Low molecular weight fractions of the compound were less active against HIV, and high molecular derivatives were as active as HOE/BAY 946. A direct influence of the drug on the infectivity of the virus could not be demonstrated. The drug inhibited the reverse transcriptase of HIV. Treatment of permanently HIV-infected U937 cells resulted in a drastic reduction of virus particles released into the supernatant and points to an additional mode of action. A therapeutic effect of HOE/BAY 946 against retroviruses in vivo could be demonstrated in Friend leukaemia virus-infected mice. A clinical pilot study with the compound was started recently in Germany with AIDS patients who did not tolerate or refused to take zidovudine and with asymptomatic virus carriers.
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PMID:Inhibition of HIV and virus replication by polysulphated polyxylan: HOE/BAY 946, a new antiviral compound. 246 49

Natural antiviral activity can be mediated by the interferon-induced synthesis of 2',5'-oligoadenylates (2-5As) and subsequent RNase L activation by these molecules. Analogues of 2-5A that are biologically active and metabolically stable were synthesized and analyzed for antiviral activity against the human immunodeficiency virus type 1 (HIV-1). Replacement of the 3' hydroxyl group of the adenosine moieties of 2-5A with hydrogen atoms (i.e., cordycepin analogues of 2-5A) converted authentic 2-5A trimer into anti-HIV-1 agents in vitro. These cordycepin analogues of 2-5A also inhibited partially purified HIV-1 reverse transcriptase. Introduction of chirality into the 2',5'-phosphodiester internucleotide linkages or 5'-phosphate moieties of the 2-5A molecule (i.e., phosphorothioate analogues of 2-5A) converted authentic 2-5A into more potent inhibitors of HIV-1 reverse transcriptase. However, these phosphorothioate 2-5As demonstrated little or no anti-HIV-1 activity in vitro. Thus, some analogues of 2-5A may form a class of anti-HIV-1 drugs with possible pleiotropic activities that include activation of latent RNase L and inhibition of reverse transcription.
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PMID:Phosphorothioate and cordycepin analogues of 2',5'-oligoadenylate: inhibition of human immunodeficiency virus type 1 reverse transcriptase and infection in vitro. 247 14

5-(p-Chlorobenzyl)-6-aminouracil (5-ClAU) inhibited RNA-dependent DNA polymerase (reverse transcriptase) from avian myeloblastosis virus. Inhibition was expressed only in the presence of a polyribonucleotide template such as mRNA or poly(rA), and kinetic analysis suggested that the action of 5-ClAU is competitive with template:primer. 5-ClAU did not inhibit HeLa DNA polymerase gamma, an enzyme that efficiently copies polyribonucleotide templates. A mechanism is proposed in which a 5-ClAU:template complex interferes with enzyme function, based partly on NMR studies indicating that 5-ClAU can form a hydrogen-bonded complex with deoxyadenosine in solution.
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PMID:Inhibition of RNA-directed DNA polymerase from avian myeloblastosis virus by a 5-benzyl-6-aminouracil. 257 88

We have investigated in detail the secondary and tertiary structures of the 16 S rRNA binding site of protein S8 using a variety of chemical and enzymatic probes. Bases were probed with dimethylsulfate (at A(N-1), C(N-3) and G(N-7)), with N-cyclohexyl-N'-(2-(N-methylmorpholino)-ethyl)-carbodiimide-p- toluenesulfonate (at G(N-1) and U(N-3)) and with diethylpyrocarbonate (at A(N-7)). The involvement of phosphates in hydrogen bonds or ion co-ordination was monitored with ethylnitrosourea. RNases T1, U2 and nuclease S1 were used to probe unpaired nucleotides and RNase V1 to monitor base-paired or stacked nucleotides. The RNA region, encompassing nucleotides 582 to 656 was probed within: (1) the complete 16 S rRNA molecule; (2) a 16 S rRNA fragment corresponding to nucleotides 578 to 756 obtained by transcription in vitro; (3) the S8-16 S rRNA complex; (4) the S8-RNA fragment complex; (5) the 30 S subunit. Cleavage or modification sites were detected by primer extension with reverse transcriptase. We present a three-dimensional model derived from mapping experiments and graphic modeling. Nucleotides in area 594-599/639-645 display unusual features: a non-canonical base-pair is formed between U598 and U641; and A595, A640 and A642 are bulging out of the major groove. The resulting helix is slightly unwound. Comparative analysis of probing experiments leads to several conclusions. (1) The synthesized fragment adopts the same conformation as the corresponding region in the complete RNA molecule, thus confirming the existence of independent folding domains in RNAs. (2) A long-range interaction involving cytosine 618 and its 5' phosphate occurs in 16 S rRNA but not in the fragment. (3) The fragment contains the complete information required for S8 binding. (4) The RNA binding site of S8 is centered in the major groove of the slightly unwound helix (594-599/639-645), with the three bulged adenines appearing as specific recognition sites. (5) This same region of the 16 S RNA is not exposed at the surface of the 30 S subunit.
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PMID:Binding of Escherichia coli ribosomal protein S8 to 16 S rRNA. A model for the interaction and the tertiary structure of the RNA binding site. 332 31

N2,3-Ethenoguanine (N2,3-epsilon G) was recently identified in the liver of vinyl chloride-exposed rats. We have now synthesized the nucleoside and the 5'-diphosphate which was copolymerized with CDP. The deoxypolynucleotide complement, synthesized by AMV reverse transcriptase contained, in addition to dG, dC and dT. The total pyrimidine content was approximately equivalent to the N2,3-epsilon G content of the template. Incorporation of dC is neither lethal nor mutagenic, while dT incorporation represents a mutagenic event, occurring with approximately 20% frequency. N2,3-epsilon G X dT base pairs can have two hydrogen bonds with minimal helical distortion, as is also the case for N2,3-epsilon G X C base pairs. N2,3-epsilon G is the only derivative formed in vivo by the human carcinogen, vinyl chloride, that can be shown to have a high probability of causing transitions which could initiate malignant transformation.
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PMID:The vinyl chloride-derived nucleoside, N2,3-ethenoguanosine, is a highly efficient mutagen in transcription. 358 34

Oligodeoxyribonucleoside methylphosphonates which are complementary to the 5' end, the initiation codon regions, or the coding regions of rabbit globin mRNA were synthesized. These oligomers were shown to interact with their complementary mRNA binding sites by their ability to serve as primers for reverse transcriptase. In several cases, the priming efficiency of the oligomers was enhanced when the oligomer was preannealed with the mRNA. This behavior correlates with the predicted secondary structure of the mRNA and suggests that some oligomer binding sites occur in hydrogen-bonded stem regions of the mRNA. Methylphosphonate oligomers inhibit translation of globin mRNA in reticulocyte lysates. Inhibition is due to the interaction of the oligomers with mRNA. The extent of inhibition is affected by the sequence and chain length of the oligomer, the location of the oligomer binding site on the mRNA, and the secondary structure of the binding site. Oligomers which bind to the 5' end and initiation codon regions of beta-globin mRNA inhibit both alpha- and beta-globin synthesis whereas oligomers which bind to the coding region of alpha-globin mRNA or the coding region of beta-globin mRNA inhibit translation of their target mRNA in a specific manner. Oligodeoxyribonucleoside methylphosphonates inhibit globin synthesis in rabbit reticulocytes. The effects of various oligomers on cellular globin synthesis are similar to those in the lysate system and suggest that the conformation of globin mRNA is the same in both systems during translation.
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PMID:Hybridization arrest of globin synthesis in rabbit reticulocyte lysates and cells by oligodeoxyribonucleoside methylphosphonates. 408 11

The enzymatic transcription of DNA from the 70S RNA of Rous sarcoma virus (RSV) is initiated on the 3' terminus of a molecule of 4S RNA which is hydrogen bonded to the viral genome. We labeled this primer with radioactive deoxynucleotides, and demonstrated that its release from 70S RNA by thermal denaturation was accompanied by a reduction in the template activity of the viral RNA. Two-dimensional electrophoresis in polyacrylamide gels separated the 4S RNAs associated with the 70S RNA of RSV into approximately eight fractions, each of which appeared to contain a discrete species of tRNA. The RNA in one of these fractions served as the principal primer for initiation of DNA synthesis by both detergent-disrupted virions of RSV and purified RNA-directed DNA polymerase with RSV 70S RNA as template.
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PMID:Transcription of DNA from the 70S RNA of Rous sarcoma virus. I. Identification of a specific 4S RNA which serves as primer. 413 19

In vitro DNA synthesis on single-stranded circular DNA can be initiated by RNA primers. RNA chains are covalently extended by DNA polymerase II from KB cells and DNA polymerase I from Micrococcus luteus, but not by an RNA-dependent DNA polymerase from avian myeloblastosis virus. The reaction product consists of DNA chains with a piece of RNA at their 5'-ends, hydrogen bonded to the template DNA. The primer RNA is linked to the product DNA via a 3':5'-phosphodiester bond, and can be specifically removed by ribonuclease H. The possible role of ribonuclease H in RNA-primed DNA synthesis in vivo is discussed.
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PMID:RNA-primed DNA synthesis in vitro. 433 98

We have studied the virus-like 30S (VL30) RNA sequences of mice. Previous work has shown that these sequences are coded in the mouse genome, expressed in some normal cells and released as pseudotypic particles from cells producing murine C-type retroviruses. VL30 sequences have some similarities to standard retrovirus RNA, but differences also exist. To further assess the similarities and differences, several aspects of VL30-specific metabolism were investigated. We studied the initiation of VL30-specific DNA synthesis during an endogenous reverse transcriptase reaction. Short initial VL30-specific cDNA transcripts were covalently attached to RNA as measured by equilibrium banding in caesium sulphate density gradients. Therefore, reverse transcription of VL30-specific cDNA is initiated by an RNA primer. The intracellular synthesis of VL30 RNA was investigated by pulse labelling uninfected JLS-V9 cells with 3H-uridine. Hybridization of the pulse-labelled nuclear RNA indicated that the major VL30-specific RNA evident after a 15 min label was the same size as the mature VL30 RNA. Thus, VL30 RNA is apparently not synthesized via a higher mol. wt. precursor. Both of these results demonstrate similarity of VL30 RNA sequences to standard retroviruses. One unique feature of VL30 RNA was detected. JLS-V9 cells contained both the monomeric VL30 RNA and a hydrogen-bonded 38S form which yielded the monomer when denatured. This contrasts with standard murine leukaemia virus which is only found as a monomer within cells.
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PMID:Further characterization of virus-like 30S (VL30) RNA of mice: initiation of reverse transcription and intracellular synthesis. 616 92

A series of substituted imidazo[1,5-b]pyridazines have been prepared and tested for inhibitory activity against the reverse transcriptase of HIV-1 (RT) and their ability to inhibit the growth of infected MT-4 cells. Crystal data are reported on two compounds, 15c and 33. From the structure-activity relationships developed within this and other series, it is proposed that key features of the interaction with RT include hydrogen-bond acceptor and aromatic pi-orbital bonding with the imidazopyridazine nucleus and a benzoyl function separated from the heterocycle by a suitable spacer group. Exceptional activity against the reverse transcriptase of HIV-1 (IC50 = 0.65 nM) was obtained with a 2-imidazolyl-substituted derivative, 7-[2-(1H-imidazol-1- yl)-5-methylimidazo-[1,5-b]pyridazin-7-yl]-1-phenyl-1-heptanone (33) which is attributed to additional binding of the imidazole sp2 nitrogen atom. A number of the compounds in this series also inhibit the replication of HIV-1 in vitro in MT-4 and C8166 cells at levels observed with the nucleoside AZT.
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PMID:Synthesis and anti-HIV-1 activity of a series of imidazo[1,5-b]pyridazines. 750 33


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