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:2.7.7.6 (RNA polymerase)
34,946 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The currently circulating H3N2 and H1N1 subtypes of influenza A virus cause a transient, febrile upper respiratory illness in most adults and children ("seasonal influenza"), but infants, the elderly, immunodeficient and chronically ill persons may develop life-threatening primary viral pneumonia or complications such as bacterial pneumonia. By contrast, avian influenza viruses such as the H5N1 virus that recently emerged in Southeast Asia can cause severe disease when transferred from domestic poultry to previously healthy people ("avian influenza"). Most H5N1 patients present with fever, cough and shortness of breath that progress rapidly to adult respiratory distress syndrome. In seasonal influenza, viral replication remains confined to the respiratory tract, but limited studies indicate that H5N1 infections are characterized by systemic viral dissemination, high cytokine levels and multiorgan failure. Gastrointestinal infection and encephalitis also occur. The licensed anti-influenza drugs (the M2 ion channel blockers, amantadine and rimantadine, and the neuraminidase inhibitors, oseltamivir and zanamivir) are beneficial for uncomplicated seasonal influenza, but appropriate dosing regimens for severe seasonal or H5N1 viral infections have not been defined. Treatment options may be limited by the rapid emergence of drug-resistant viruses. Ribavirin has also been used to a limited extent to treat influenza. This article reviews licensed drugs and treatments under development, including high-dose oseltamivir; parenterally administered neuraminidase inhibitors, peramivir and zanamivir; dimeric forms of zanamivir; the RNA polymerase inhibitor T-705; a ribavirin prodrug, viramidine; polyvalent and monoclonal antibodies; and combination therapies.
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PMID:Current and future antiviral therapy of severe seasonal and avian influenza. 1832 78

Current anti-influenza drugs target the viral neuraminidase or inhibit the function of the ion channel M2 protein. Not only is the supply of these drugs unlikely to meet the demand during a large influenza epidemic/ pandemic, but also has an emergence of drug resistant influenza virus variants been documented. Thus a new effective drug or antiviral alternative is required. The influenza virus RNA polymerase complex consists of nucleoproteins (NP) that bind to three polymerase subunits: two basic polymerases, PB1 and PB2, and an acidic polymerase (PA). These proteins play a pivotal role in the virus life cycle; thus they are potential targets for the development of new anti-influenza agents. In this study, we produced human monoclonal antibodies that bound to the influenza A polymerase proteins by using a human antibody phage display library. Complementary DNA was prepared from the total RNA of a highly pathogenic avian influenza (HPAI) virus: A/duck/Thailand/144/2005(H5N1). The cDNA synthesized from the total virus RNA was used as template for the amplification of the gene segments encoding the N-terminal halves of the PB1, PB2 and PA polymerase proteins which encompassed the biologically active portions of the respective proteins. The cDNA amplicons were individually cloned into appropriate vectors and the recombinant vectors were introduced into Escherichia coli bacteria. Transformed E. coli clones were selected, and induced to express the recombinant proteins. Individually purified proteins were used as antigens in bio-panning to select the phage clones displaying specific human monoclonal single chain variable fragments (HuScFv) from a human antibody phage display library constructed from Thai blood donors in our laboratory. The purified HuScFv that bound specifically to the recombinant polymerase proteins were prepared. The inhibitory effects on the biological functions of the respective polymerase proteins should be tested. We envisage the use of the HuScFv in their cell penetrating version (transbodies) as an alternative influenza therapeutic to current anti-virus drugs.
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PMID:Human monoclonal single chain antibodies (HuScFv) that bind to the polymerase proteins of influenza A virus. 1859 27

Accumulating evidence supports the use of specific diagnostic tests and antiviral therapies for seriously ill patients with influenza. Among available diagnostic tests, reverse-transcriptase polymerase chain reaction is faster than culture and more sensitive than commercial antigen assays. Current neuraminidase inhibitors were approved on the basis of their efficacy in ambulatory patients, but seriously ill patients who receive these agents are less likely to die, even when treatment is initiated >48 h after symptom onset. For patients hospitalized with suspected influenza, it is unclear which circumstances warrant diagnostic testing and which warrant the use of empirical therapy. Rapid antigen assays may reduce the unnecessary use of other tests and medications but are relatively insensitive, thus eliminating many patients with influenza as candidates for treatment. Empirical antiviral therapy ensures that all patients receive treatment promptly, at a cost equivalent to that of diagnostic tests alone, but results in the receipt of treatment by many patients without influenza. For patients hospitalized with suspected influenza, clinicians need to combine these approaches in order to optimize patient care.
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PMID:Diagnostic testing or empirical therapy for patients hospitalized with suspected influenza: what to do? 1906 10

Reverse transcriptase PCR designed to amplify the N1 to N9 neuraminidase (NA) genes of avian influenza viruses detected 118 of the 119 NA genes tested (99.2%) in a subtype-specific manner. This technique successfully subtyped all 167 recent avian influenza viruses isolated from birds. Subtype specificity was confirmed by sequence analyses of all 285 PCR products.
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PMID:Use of reverse transcriptase PCR to subtype N1 to N9 neuraminidase genes of avian influenza viruses. 1940 72

During the 2007-2008 influenza season global strain surveillance for antiviral resistance revealed the sudden emergence of oseltamivir resistance in influenza A H1N1 isolates. Although oseltamivir resistance rates vary from region to region, 16% of isolates tested globally were found to be oseltamivir resistant by a histidine to tyrosine mutation of residue 275 of the neuraminidase gene of influenza A. In order to implement effective resistance testing locally a novel real-time reverse-transcriptase PCR (RT-PCR) assay was developed for the detection of the H275Y mutation. To evaluate this method, 40 oseltamivir resistant and 61 oseltamivir sensitive H1N1 influenza isolates were tested using Sanger sequencing, which is the reference method for detection of resistance, pyrosequencing and the novel H275Y RT-PCR assay. In comparison to Sanger sequencing, the sensitivity and specificity of the H275Y RT-PCR assay were 100% (40/40) and 100% (61/61) respectively, while the sensitivity and specificity of pyrosequencing were 100% (40/40) and 97.5% (60/61) respectively. Although all three methods were effective in detecting the H275Y mutation associated with oseltamivir resistance, the H275Y RT-PCR assay was the most rapid and could easily be incorporated into an influenza subtyping protocol.
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PMID:Development of a novel real-time reverse-transcriptase PCR method for the detection of H275Y positive influenza A H1N1 isolates. 1942 89

Influenza, especially pandemic influenza, poses great threat to health and humans life of. Due to the antigenic drift and shift of the influenza virus, there is a constant requirement to accurately adjust contents of the vaccine to current subtype of the virus. As there is always a long period of time between the moment of detection of a new kind of influenza virus till a new vaccine is produced, the only protection for the people are antiviral drugs. Some examples of antiviral compounds that can be used in treatment in near future have been presented. A review of the researches on the substances that are active against influenza viruses has been carried out and their mechanism of action was described. We have taken into account the chemical compounds that seem to be active in the process of virus adsorption; hemagglutinin and neuraminidase inhibitors; M2 ion channel blockers; polymerase, endonuclease, transcriptase, proteine kinase and signaling cascade inhibitors. The potential of oligonucleotide antiviral therapeutics and the substances that are extracted from different plants were presented. The future direction of research were shown.
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PMID:[The substances active against influenza virus. Possibilities and prospects of application]. 2012 Sep 45

Influenza A viruses are a major cause of morbidity and mortality worldwide and affect large segments of the population every year. The nature of their genome, formed by eight segments of single-stranded RNA, favors the constant evolution of the virus by two main mechanisms: the accumulation of single nucleotide mutations in the viral genes introduced by an error-prone viral RNA polymerase and the reassortment of genes between two strains of different origin. The viral genome encodes 11 proteins. Most have been shown to play a role in shaping the virulence scenario of influenza A viruses, including the adaptation of infection and transmission into new host species, the ability to modulate the host immune response, and the capacity to replicate efficiently at low temperature. On the surface of the virus particles there are two principal polypeptides, the hemagglutinin (HA) and the neuraminidase (NA), which are the target for the neutralizing antibodies immune response. There are 16 HA and 9 NA different subtypes in the influenza A virus that circulate in humans and animals. When a virus strain with a new HA or NA subtype appears in the human population by genetic reassortment, it usually causes a pandemic because there is no preexisting immunity against the new virus. This was the case for the three pandemics that occurred during the last century (1918, 1957, and 1968) and also for the first pandemic of the 21(st) century, caused by the currently circulating A (H1N1) 2009 virus, which was generated by gene reassortment between a virus present in pigs of North America and a virus that circulates in the swine population of Euroasia.
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PMID:Molecular anatomy of 2009 influenza virus A (H1N1). 2030 51

Avian influenza virus (AIV) is an infectious agent of birds and mammals. AIV is causing huge economic loss and can be a threat to human health. Reverse transcriptase polymerase chain reaction (RT-PCR) has been used as a method for the detection and identification of AIV virus. Although RT-PCR is a sensitive method for detection of AIV, it requires sample preparation including separation and purification of AIV and concentrate viral RNA. It is laborious and complex process especially for diagnosis using faecal sample. In this study, magnetic beads were used for immunoseparation of AIV in chicken faecal sample by a magnetic microsystem. Using this system, all the 16 hemagglutinin (H) and 9 neuraminidase (N) subtypes of AIV were separated and detected in spiked faecal samples using RT-PCR, without an RNA extraction step. This rapid sample preparation method can be integrated with a total analysis microsystem and used for diagnosis of AIV.
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PMID:Rapid sample preparation for detection and identification of avian influenza virus from chicken faecal samples using magnetic bead microsystem. 2067 Jun 56

Against pandemic influenza A (H1N1) 2009, anti-influenza drugs were useful to save the disease aggravation and reduce the mortality. In addition to the existing anti-influenza drugs, novel drugs, including neuraminidase inhibitors (peramivir and laninamivir) and RNA polymerase inhibitors (favipiravir), also have clinical potentials to suppress pandemic influenza A (H1N1) 2009 virus as well as seasonal influenza virus.
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PMID:[Present and future in development of new anti-influenza drugs]. 2084 48

Following viral infection, cells rapidly present peptides from newly synthesized viral proteins on MHC class I molecules, likely from rapidly degraded forms of nascent proteins. The nature of these defective ribosomal products (DRiPs) remains largely undefined. Using inhibitors of RNA polymerase II that block influenza A virus neuraminidase (NA) mRNA export from the nucleus and inhibit cytoplasmic NA translation, we demonstrate a surprising disconnect between levels of NA translation and generation of SIINFEKL peptide genetically inserted into the NA stalk. A 33-fold reduction in NA expression is accompanied by only a 5-fold reduction in K(b)-SIINFEKL complex cell-surface expression, resulting in a net 6-fold increase in the overall efficiency of Ag presentation. Although the proteasome inhibitor MG132 completely blocked K(b)-SIINFEKL complex generation, we were unable to biochemically detect a MG132-dependent cohort of NA DRiPs relevant for Ag processing, suggesting that a minute population of DRiPs is a highly efficient source of antigenic peptides. These data support the idea that Ag processing uses compartmentalized translation, perhaps even in the nucleus itself, to increase the efficiency of the generation of class I peptide ligands.
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PMID:RNA polymerase II inhibitors dissociate antigenic peptide generation from normal viral protein synthesis: a role for nuclear translation in defective ribosomal product synthesis? 2104 11


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