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:3.1.30.2 (endonuclease)
18,621 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A novel anti-influenza virus compound, flutimide, was identified in extracts of a recently identified fungal species, Delitschia confertaspora (F. Pelaez, J.D. Polishook, M. Valldosera, and J.Guarro, Mycotaxon 50:115-122, 1994). The compound, a substituted 2,6-diketopiperazine, selectively inhibited the cap-dependent transcriptase of influenza A and B viruses and had no effect on the activities of other polymerases. Similar to the 4-substituted 2,4-dioxobutanoic acids, a series of transcriptase inhibitors which we described previously (J. Tomassini, H. Selnick, M.E. Davies, M.E. Armstrong, J. Baldwin, M. Bourgeois, J.Hastings, D. Hazuda, J. Lewis, W. McClements, G. Ponticello, E. Radzilowski, G. Smith, A. Tebben, and A. Wolfe, Antimicrob. Agents Chemother. 38:2827-2837, 1994), this inhibitor, which is a natural product, affected neither the initiation nor the elongation of influenza virus mRNA synthesis, but it specifically targeted the cap-dependent endonuclease of the transcriptase. Additionally, the compound was inhibitory to the replication of influenza A and B viruses in cell culture. The selective antiviral properties of this compound further demonstrate the utility of influenza virus endonuclease as a target of antiviral agents.
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PMID:A novel antiviral agent which inhibits the endonuclease of influenza viruses. 872 64

We previously identified a series of compounds which specifically inhibited the transcription of influenza A and B viruses (J. Tomassini, H. Selnick, M.E. Davies, M.E. Armstrong, J. Baldwin, M. Bourgeois, J. Hastings, D. Hazuda, J. Lewis, W. McClements, G. Ponticello, E. Radzilowski, G. Smith, A. Tebben, and A. Wolfe, Antimicrob. Agents Chemother. 38:2827-2837, 1994). The compounds, 4-substituted 2,4-dioxobutanoic acids, selectively targeted the cap-dependent endonuclease activity of the transcriptase complex. Additionally, several of these compounds effectively inhibited the replication of influenza virus but not other viruses in cell culture assays. Here, we report on the anti-influenza virus activities of other potent derivatives of the series evaluated in both in vitro and in vivo infectivity assays. These compounds inhibited the replication of influenza virus in yield reduction assays, with 50% inhibitory concentrations ranging from 0.18 to 0.71 microM. These 50% inhibitory concentrations were similar to those observed for inhibition of in vitro transcription (0.32 to 0.54 microM). One selected compound also elicited a dose-dependent inhibition of influenza virus replication in mice following an upper respiratory tract challenge. These studies demonstrate the antiviral efficacy of this inhibitor class and thereby establish the utility of influenza virus endonuclease as a chemotherapeutic target.
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PMID:Anti-influenza virus activities of 4-substituted 2,4-dioxobutanoic acid inhibitors. 872 91

We have investigated the endonuclease activity of the influenza A virus RNA polymerase in an in vitro assay with an artificial influenza-like mRNA containing a cap structure at its 5' terminus, followed by a 10 nt beta-globin mRNA sequence, and the 5' and 3' conserved termini of a truncated nucleoprotein (NP) cRNA influenza sequence. Results showed that partially purified virion ribonucleoprotein complexes (RNPs) and micrococcal nuclease treated RNPs cleaved the artificial influenza-like mRNA substrate specifically at positions near the 5' terminus to generate capped 14 and 15 nucleotide long RNA fragments which subsequently served as primers to initiate transcription. The endonuclease activity was completely blocked by addition of cap analog and competitively inhibited by added globin mRNA. Furthermore, an in vitro reconstituted influenza RNA transcription reaction containing a truncated NP vRNA as template, micrococcal nuclease treated RNPs and globin mRNA as primer, synthesized capped and uncapped full length (+) sense products. Enzyme kinetics showed that capped RNA was made earlier in the reaction; it reached a peak at 120 min and then declined. However, uncapped cRNA synthesis appeared later and remained as the dominant product later in the reaction. The nature of these products was confirmed by ribonuclease protection assays and by primer extension.
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PMID:Influenza A virus RNA-dependent RNA polymerase cleaves influenza mRNA in vitro. 880 82

Influenza virus, a negative strand RNA virus, cannibalizes host cell, capped RNA polymerase II transcripts in the nucleus via a process termed "cap-snatching". The viral transcriptase enzyme; which is composed of a complex of the three viral polymerase (P) proteins, contains a cap-dependent endonuclease that cleaves capped cellular RNAs in the nucleus 10-13 nucleotides from their 5' ends. The resulting capped RNA fragments are required as primers for the initiation of viral mRNA synthesis. In the 18 year since the discovery of "cap-snatching" it has not been determined how the viral transcriptase exhibits selectivity and "snatches" caps from cellular, but not viral, mRNAs. Here we elucidate the surprising mechanism of this selectivity: the complex of the same three viral P proteins that catalyzes "cap-snatching" is also responsible for selectivity protecting the 5' ends of viral, but not cellular, mRNAs from "cap-snatching". The viral P protein complex is able to acquire these two very different functions because this complex lacks any detectable activity unless it binds to one or more specific RNA sequences. Here we demonstrate that the viral P protein complex binds to the common sequence in all the viral mRNAs that is immediately 3' to the 5' sequence that is "snatched" from host cell RNAs. This binding activates the cap-binding activity of the P protein complex, thereby enhancing its binding to the capped viral mRNA. We show that these P protein complexes protect the 5' ends of viral mRNAs from endonucleolytic cleavage by the viral transcriptase, whereas the 5' ends of nonviral mRNAs are not protected.
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PMID:Surprising function of the three influenza viral polymerase proteins: selective protection of viral mRNAs against the cap-snatching reaction catalyzed by the same polymerase proteins. 895 65

A polymerase chain reaction-restriction (PCR-restriction) endonuclease assay was developed to allow rapid analysis of influenza A H3N2 viruses circulating in England during 1995-1996. Restriction endonuclease digestion with two enzymes of amplicons derived from PCR of the HA1 portion of the influenza haemagglutinin (HA) gene was able to differentiate antigenically similar influenza strains into two groups. Group I variants were similar genetically to the 1995/96 vaccine strain, A/Johannesburg/33/94, whereas the HA sequences of Group II variants were similar genetically to the reference virus A/Thessaloniki/1/95. Of the 700 England A H3N2 strains isolated between February 1995 and the end of April 1996, 384 were analysed by this method. PCR-restriction analysis of sequential influenza isolates revealed a temporal alteration in prevalence of two variants. Groups I and II variants cocirculated with equal frequency during a period of sporadic influenza activity, but following the onset of epidemic influenza activity in 1995, only Group II variants were detected. PCR- restriction analysis was found to be a rapid method for studying genetic variation which could be applied to a large number of samples and provide information about the direction of genetic drift in the HA gene of influenza virus.
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PMID:Analysis of influenza A H3N2 strains isolated in England during 1995-1996 using polymerase chain reaction restriction. 913 90

Influenza virus-associated RNA polymerase is composed of one molecule each of three viral P proteins and carries the complete activity of capped RNA-primed vRNA-directed transcription. The RNA polymerase holoenzyme also carries capped RNA endonuclease to generate capped oligonucleotide primers for transcription and 3'-to-5' exonuclease to remove erroneously polymerized nucleotides at nascent RNA 3' termini prior to the addition of correct substrates. PB1 is the core subunit for not only RNA synthesis but also the assembly of PB2 and PA into the holoenzyme complex, while PB2 plays a key role in capped RNA cleavage. The transcriptase is converted into the RNA replicase with the full activity of replication, ie vRNA-directed cRNA synthesis and cRNA-directed vRNA synthesis, after interaction with an as yet unidentified host factor(s).
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PMID:A multi-functional enzyme with RNA polymerase and RNase activities: molecular anatomy of influenza virus RNA polymerase. 915 Aug 90

The RNA-dependent RNA polymerase of influenza virus transcribes messenger RNA through a unique cap scavenging mechanism. Viral enzyme binds to the cap structure of host mRNA, cleaves the molecule 9-15 bases downstream of the cap, and uses the short capped oligonucleotide as a primer for mRNA synthesis. Previously, we have shown that the viral polymerase can efficiently bind capped RNAs shorter than 9 nucleotides in length, but the viral enzyme can not utilize these RNAs as primers. For this reason, these short capped oligonucleotides are potent inhibitors of influenza virus transcription. In these studies, it is now shown that short capped oligomers inhibit capped-RNA dependent transcription at the initial step of cap binding. In contrast, low concentrations of these short capped RNAs can actually stimulate viral transcription primed with high concentrations of the dinucleotide ApG. Another capped RNA derivative containing phosphorothioate oligonucleotides was also investigated as a potential polymerase inhibitor. This longer capped RNA was able to bind to the polymerase, but could not be cleaved to primer length by the enzyme associated endonuclease. Thus, the capped phosphorothioate RNA inhibited cap-primed transcription at the step of cap binding. However, in contrast to the short capped oligonucleotide, it also inhibited ApG primed viral transcription.
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PMID:Differential effect of modified capped RNA substrates on influenza virus transcription. 925 36

The tick-borne Thogoto virus (THOV) is the type species of a new genus in the family Orthomyxoviridae. Its genome comprises six segments of single-stranded, negative-sense RNA. Each segment possesses conserved regions of semicomplementary nucleotides at the 3' and 5' termini which strongly resemble those of influenza virus. An in vitro polymerase assay based on reconstituted THOV viral cores was developed, and activity was shown to rely on an interaction between the conserved 3'- and 5'-terminal sequences and to be primer dependent. Addition of globin mRNA primed transcription, catalyzing the addition of an extra nucleotide to the transcripts, corresponding to the 5'-terminal m7G cap residue. Priming with various cap analogs suggested that THOV transcription is initiated preferentially with m7GpppAm and involves base pairing. This is the first experimental evidence of endonuclease activity in THOV as part of a unique cap-snatching mechanism.
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PMID:In vitro polymerase activity of Thogoto virus: evidence for a unique cap-snatching mechanism in a tick-borne orthomyxovirus. 934 88

The genome of influenza virus is composed of eight RNA segments of negative polarity. The RNA-dependent RNA polymerase is associated with each viral RNA (vRNA) segment and after infection, involved in both transcription (vRNA-directed synthesis of viral mRNA) and vRNA replication (vRNA-dependent synthesis of complementary RNA(cRNA) and cRNA-dependent synthesis of vRNA). The RNA polymerase is composed of three viral proteins, PB1, PB2 and PA. PB1 is the core subunit for not only the RNA synthesis but also the assembly of PB2 and PA into this multifunctional enzyme complex. PB1 alone is able to catalyze vRNA-dependent RNA synthesis, but PB2 is required for capped RNA-dependent transcription, both together forming the transcriptase. The third P protein, PA, and an as yet unidentified host factor(s) are involved for the conversion of RNA polymerase from transcriptase to replicase. The functional map including both subunit-subunit contact sites and catalytic sites for capped RNA endonuclease and RNA polymerization is being made for both PB1 and PB2 proteins.
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PMID:[Transcription and replication of influenza virus genome]. 936 Mar 71

Antiviral research for influenza viruses (FluV) is proceeding actively whereas few compounds are available for clinical use. Amantadine, an inhibitor of M2 ion-channel of FluV-A has been a key compound which disclosed important function of M2 protein, however, its clinical efficacy is restricted only in chemoprophylaxis of infection. Recently several compounds which showed novel antiviral mechanism for FluV replication emerged. They are inhibitors of conformation change of HA, of fusion of envelope and cellular membrane, of endonuclease on mRNA, of viral RNA replication, and of NA activity. Although most of these inhibitors are under investigations some of them are in clinical trial of phase II or phase III. It is obvious that most important problem in clinical use of anti-FluV drugs should be its side effects, bioavailability and stability in human bodies.
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PMID:[Current status of research and development for anti-influenza virus drugs--chemotherapy for influenza]. 936 Apr 3


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