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:3.1.26.4 (RNase H)
2,751 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In an effort to develop new drugs preventing the growth of human immunodeficiency virus (HIV), we developed an in vitro assay method of ribonuclease H (RNase H) activity associated with reverse transcriptase (RT) from HIV-1. Some naphthoquinones, such as 1,4-naphthoquinone (1), vitamin K(3) (2), juglone (3) and plumbagin (6), moderately inhibited RNase H activity, and others, including naphthazarin (5) and shikonins (8-9, 18-23), showed weak inhibition. Diterpenoid quinones, tanshinones (24-28), had also moderate inhibition against RNase H activity. Of these quinones, compound 1 showed the most potent inhibition on RNase H activity with a 50% inhibitory concentration (IC(50)) of 9.5 microM, together with moderate inhibition against RNA-dependent and DNA-dependent DNA polymerase (RDDP and DDDP) activities with IC(50) values of 69 and 36 microM, respectively. Compounds 3 and 5 showed significant inhibition against RDDP (IC(50) = 8 and 10 microM, respectively) and DDDP (IC(50) = 5 and 7 microM, respectively) activities. The structure-activity relationship of the naphthoquinones suggested that non-hydroxylated naphthoquinones (1 and 2) showed significant inhibition of RNase H activity, whereas 5-hydroxylated naphthoquinones (3 and 5) showed potent inhibition against RDDP and DDDP activities.
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PMID:Inhibitory effects of quinones on RNase H activity associated with HIV-1 reverse transcriptase. 1193 41

Inhibitory antibodies to the reverse transcriptase (RT) of human immunodeficiency virus type-1 (HIV-1) can be used to block the life cycle of the virus. We have isolated five different human single chain Fv (ScFv) antibodies specific for HIV-1 RT from an antibody phage display library. Three of these antibodies inhibited the RNA-dependent DNA polymerase (RDDP) activity of RT and one of the three (F-6) inhibited also its DNA-dependent DNA polymerase (DDDP) activity. Unexpectedly, F-6 binds to the carboxyl terminus of the large subunit of RT, which contains the ribonuclease H (RNase H) domain, and not the polymerase domain of the protein. Moreover, this binding did not inhibit the RNase H enzymatic activity. To further characterize F-6 antibody, two cyclic synthetic peptides based on the amino acids sequences of the CDR3 of F-6 were synthesized. Peptide F-6CDRH3, with the sequence of CDR3 of the heavy chain, inhibited the RDDP activity of RT while peptide F-6CDRL3, with the sequence of CDR3 of the light chain, had no effect on this activity of RT. These results indicate that some of the effects of F-6 are mediated by the CDR3 of the heavy chain. The antibodies identified here will be further tested as intrabodies for their capacity to protect human cells from HIV-1 infection.
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PMID:Recombinant human antibodies against the reverse transcriptase of human immunodeficiency virus type-1. 1275 58

High-throughput screening of a National Cancer Institute library of pure natural products identified the hydroxylated tropolone derivatives beta-thujaplicinol (2,7-dihydroxy-4-1(methylethyl)-2,4,6-cycloheptatrien-1-one) and manicol (1,2,3,4-tetrahydro-5-7-dihydroxy-9-methyl-2-(1-methylethenyl)-6H-benzocyclohepten-6-one) as potent and selective inhibitors of the ribonuclease H (RNase H) activity of human immunodeficiency virus-type 1 reverse transcriptase (HIV-1 RT). beta-Thujaplicinol inhibited HIV-1 RNase H in vitro with an IC50 of 0.2 microM, while the IC50 for Escherichia coli and human RNases H was 50 microM and 5.7 microM, respectively. In contrast, the related tropolone analog beta-thujaplicin (2-hydroxy-4-(methylethyl)-2,4,6-cycloheptatrien-1-one), which lacks the 7-OH group of the heptatriene ring, was inactive, while manicol, which possesses a 7-OH group, inhibited HIV-1 and E.coli RNases H with IC50 = 1.5 microM and 40 microM, respectively. Such a result highlights the importance of the 2,7-dihydroxy function of these tropolone analogs, possibly through a role in metal chelation at the RNase H active site. Inhibition of HIV-2 RT-associated RNase H indirectly indicates that these compounds do not occupy the nonnucleoside inhibitor-binding pocket in the vicinity of the DNA polymerase domain. Both beta-thujaplicinol and manicol failed to inhibit DNA-dependent DNA polymerase activity of HIV-1 RT at a concentration of 50 microM, suggesting that they are specific for the C-terminal RNase H domain, while surface plasmon resonance studies indicated that the inhibition was not due to intercalation of the analog into the nucleic acid substrate. Finally, we have demonstrated synergy between beta-thujaplicinol and calanolide A, a nonnucleoside inhibitor of HIV-1 RT, raising the possibility that both enzymatic activities of HIV-1 RT can be simultaneously targeted.
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PMID:Selective inhibition of HIV-1 reverse transcriptase-associated ribonuclease H activity by hydroxylated tropolones. 1574 Nov 78

Employing a novel strategy, we have virtually screened a large library of compounds to identify novel inhibitors of the reverse transcriptase (RT) of HIV-1. Fifty-six top scored compounds were tested in vitro, and two of them inhibited efficiently the DNA polymerase activity of RT. The most effective compound, N-{2-[4-(aminosulfonyl)phenyl]ethyl}-2-(2-thienyl)acetamide (NAPETA), inhibited both RNA-dependent and DNA-dependent DNA polymerase activities, with apparent IC50 values of 1.2 and 2.1 microM, respectively. This inhibition was specific to the RT-associated polymerase activity and did not affect the RNase H activity. NAPETA also inhibited two drug-resistant HIV-1 RT mutants as well as HIV-2 RT and other DNA polymerases. Kinetic analysis of RT inhibition indicated that the DNA polymerase activity of HIV-1 RT was inhibited in a classic noncompetitive manner with respect to dTTP, demonstrating a Ki value of 1.2 microM. In contrast, the inhibition with respect to the RNA.DNA template was a mixed linear type with a Ki value of 0.12 microM and was not affected by the order in which the template.primer and inhibitor were added to the reaction mixture. Gel shift and surface plasmon resonance analyses confirmed that NAPETA interfered with the formation of the RT.DNA complex (that is crucial for the polymerization activity) by reducing the affinity of RT for DNA, accounting at least partially for the inhibition. It is likely that NAPETA inhibited RT via a mechanism that is different from that of the classic non-nucleoside RT inhibitors used for treating AIDS/HIV patients and, thus, may serve as a lead compound for the development of novel anti-HIV drugs.
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PMID:Mechanism of inhibition of HIV-1 reverse transcriptase by the novel broad-range DNA polymerase inhibitor N-{2-[4-(aminosulfonyl)phenyl]ethyl}-2-(2-thienyl)acetamide. 1805 56

Reverse transcription is a crucial step in the life cycle of human immunodeficiency virus type 1 (HIV-1). In this process, multiple functional enzymes including RNA-dependent DNA polymerase, DNA-dependent DNA polymerase and RNase H are indispensable. The RNase H functions to degrade RNA of the RNA-DNA heteroduplex into small fragment. These properties of HIV-1 RNase H make it an attractive target for rational anti-HIV-1 drug design and development. In this review, we summarized the HIV-1 RNase H inhibitors that were recently reported in the literature, including their chemical structure, mechanism and structure-activity relationship. It seems likely that HIV-1 RNase H as a prominent non-traditional target may lead to the development of anti-HIV agents which could be used alone or in the combination with other HIV inhibitors in AIDS chemotherapy.
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PMID:Recent advances in the research of HIV-1 RNase H inhibitors. 1885 38

The HIV-1 genomic RNA reverse transcription is an essential step in the virus cycle carried out by the viral-coded reverse transcriptase (RT), which has two associated functions: the RNA- and DNA-dependent DNA polymerase (RDDP and DDDP) function and the ribonuclease H (RNase H) function. The RNase H function catalyzes the selective hydrolysis of the RNA strand of the RNA:DNA heteroduplex replication intermediate. The RT associated activities are both essential for HIV-1 replication and validated targets for drug development, but only the polymerase function has been widely investigated as drug target. In fact, either nucleoside or non-nucleoside RT inhibitors currently used in therapy act on the polymerase associated activity. In this review, we describe the compounds, reported up to today, which inhibit the HIV-1 RNase H function, their chemical structures, the structure-activity relationships and the mechanism of action.
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PMID:HIV-1 RT-associated RNase H function inhibitors: Recent advances in drug development. 2085 67

All replication-competent retroviruses possess a characteristic enzyme, reverse transcriptase (RT), which is present at 20-70 mol/virus particle (1-3). The enzyme is cleaved, and thereby activated, from an inactive precursor by the action of another retroviral enzyme, the viral protease. All RTs possess three distinct enzymatic activities: (1) an RNA-dependent DNA polymerase, which is the RT in the strict sense of the word, (2) an RNase H, and (3) a DNA-dependent DNA polymerase. After infection of a new host cell, these different activities serve in turn to synthesize a cDNA of the viral RNA, to degrade RNA from the cDNA-RNA heteroduplex, and to duplicate the cDNA strand (reviewed in ref. 4).
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PMID:Reverse transcriptase assay based on product enhancement for assessing the drug susceptibility of retroviruses. 2133 18

The HIV-1 integrase (IN) and reverse transcriptase (RT) are essential enzymes in the virus cycle. RT is crucial for the retrotranscription of the RNA viral genome, while IN is involved in the insertion in host chromosome of the proviral double strand DNA produced by RT. This enzyme has two associated functions: the RNA- and DNA-dependent DNA polymerase (RDDP and DDDP) and the ribonuclease H (RNase H). The RNase H function catalyzes the selective hydrolysis of the RNA strand of the RNA:DNA heteroduplex replication intermediate. Since the discovery that catalytic cores of both HIV-1 RNase H and IN are folded in a very similar way, have very similar active site geometries, and show the same DDE triad absolutely required for catalytic activity, some researches were devoted to study IN and RNase H dual inhibitor. Our decennial interest in design and synthesis of IN inhibitors led us to study the activity of our compounds also on RNase H activity. The results of the activities showed by pyrrolyl and quinolonyl diketo acids are reported and discussed.
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PMID:Diketo acids derivatives as dual inhibitors of human immunodeficiency virus type 1 integrase and the reverse transcriptase RNase H domain. 2172 68

This mini-review summarizes the process of reverse-transcription, an obligatory step in retrovirus replication during which the retroviral RNA/DNA-dependent DNA polymerase (RT) copies the single-stranded genomic RNA to generate the double-stranded viral DNA while degrading the genomic RNA via its associated RNase H activity. The hybridization of complementary viral sequences by the nucleocapsid protein (NC) receives a special focus, since it acts to chaperone the strand transfers obligatory for synthesis of the complete viral DNA and flanking long terminal repeats (LTR). Since the physiological microenvironment can impact on reverse-transcription, this mini-review also focuses on factors present in the intra-cellular or extra-cellular milieu that can drastically influence both the timing and the activity of reverse-transcription and hence virus infectivity.
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PMID:Implications of the nucleocapsid and the microenvironment in retroviral reverse transcription. 2199 62

Reverse transcription of human immunodeficiency virus type 1 (HIV-1) is a crucial step in the life cycle initiated by the viral-coded reverse transcriptase (RT), functioning as RNA- and DNA-dependent DNA polymerase (RDDP and DDDP) and the ribonuclease H (RNase H). The RNase H functions to degrade the RNA strand of the RNA:DNA heteroduplex, which makes it an attractive target for rational anti-HIV-1 drug design and development. Although development of drugs targeting the DNA polymerase have been highly successful, the discovery of drugable inhibitors of HIV RNase H is still in its infancy and none of RNase H inhibitors has reached the clinical development stage currently. This review describes the recent progress in the HIV-1 RNase H inhibitors, focusing on their chemical feature, mechanism and the structure-activity relationship (SAR).
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PMID:Recent progress in the research of small molecule HIV-1 RNase H inhibitors. 2443 23


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