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Influenza Virus Polymerases
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Book Synopsis Viral Polymerases by : Satya Prakash Gupta
Download or read book Viral Polymerases written by Satya Prakash Gupta and published by Academic Press. This book was released on 2018-10-29 with total page 498 pages. Available in PDF, EPUB and Kindle. Book excerpt: Viral Polymerases: Structures, Functions and Roles as Antiviral Drug Targets presents in-depth study information on the structure and functions of polymerases and their roles in the lifecycle of viruses, and as drug targets. Viral polymerases constitute a vital component in the lifecycle of many viruses, such as human immunodeficiency virus (HIV), hepatitis viruses, influenza virus, and several others. They are essentially required for the replication of viruses. Thus, the polymerases that can be found in viruses (called viral polymerases) represent favorable targets for the design and development of antiviral drugs. Provides comprehensive, state-of-the-art coverage on virus infections, the virus lifecycle, and mechanisms of polymerase inhibition Analyzes the structure-activity relationships of inhibitors of each viral polymerase Presents a consistent and comprehensive coverage of all aspects of viral polymerases, including structure, function and their role as antiviral drug targets
Book Synopsis Viral Molecular Machines by : Michael G. Rossmann
Download or read book Viral Molecular Machines written by Michael G. Rossmann and published by Springer Science & Business Media. This book was released on 2012-02-02 with total page 685 pages. Available in PDF, EPUB and Kindle. Book excerpt: This book will contain a series of solicited chapters that concern with the molecular machines required by viruses to perform various essential functions of virus life cycle. The first three chapters (Introduction, Molecular Machines and Virus Architecture) introduce the reader to the best known molecular machines and to the structure of viruses. The remainder of the book will examine in detail various stages of the viral life cycle. Beginning with the viral entry into a host cell, the book takes the reader through replication of the genome, synthesis and assembly of viral structural components, genome packaging and maturation into an infectious virion. Each chapter will describe the components of the respective machine in molecular or atomic detail, genetic and biochemical analyses, and mechanism. Topics are carefully selected so that the reader is exposed to systems where there is a substantial infusion of new knowledge in recent years, which greatly elevated the fundamental mechanistic understanding of the respective molecular machine. The authors will be encouraged to simplify the detailed knowledge to basic concepts, include provocative new ideas, as well as design colorful graphics, thus making the cutting-edge information accessible to broad audience.
Book Synopsis Influenza A Virus: A Role for the RNA Polymerase in Viral Particle Assembly by : John F. Regan
Download or read book Influenza A Virus: A Role for the RNA Polymerase in Viral Particle Assembly written by John F. Regan and published by . This book was released on 2005 with total page 660 pages. Available in PDF, EPUB and Kindle. Book excerpt: Influenza is an RNA virus whose segmented genome is encapsidated into viral ribonucleoprotein complexes (vRNPs). Upon infection, the vRNPs migrate into the nucleus where transcription and replication take place. The vRNPs contain a RNA-dependent RNA polymerase that is responsible for viral transcription and replication. The polymerase is composed of three subunits, PB1, PB2, and PA. PBI has polymerase activity and PB2 is involved in viral transcription. The function of PA is unclear. To help elucidate the role of PA in the viral life cycle, 16 conserved regions of PA were targeted for alanine substitution. A plasmid-based transfection system was used to generate recombinant influenza particles bearing each mutation, which were tested for viral viability and the ability of each mutant polymerase to transcribe and replicate a reporter. Mutations in the N-terminus were not well tolerated and resulted in either non-viable or attenuated viruses. One of the mutants, J10, was capable of RNA synthesis, yet did not create viral particles capable of plaque formation in MDCK cells. Specifically, when compared to wild-type, this mutant synthesized 50+/-7% vRNA, 86+/-12% mRNA, and 128+/-18% cRNA. These levels are compatible with viability, as mutants J8 (27%) and J12 (23%), produced significantly less vRNA than J10, yet were viable by plaque assay. The mRNAs generated from J10 polymerase were found to be translationally-active, and both the mutant protein and its RNA products were appropriately localized in the cytoplasm, where influenza assembly occurs. Nevertheless, J10 failed to generate infectious particles from cells in a plasmid-based influenza assembly assay, and hemagglutinating material from the supernatants of such cells contained little or no nuclease-resistant genomic RNA. These findings suggest that PA has a previously unrecognized role in assembly or release of influenza virions, perhaps influencing core structure or the packaging of vRNAs or other essential components into nascent influenza particles.
Book Synopsis The RNA Polymerase Activity of Influenza Virus by : William J. Bean
Download or read book The RNA Polymerase Activity of Influenza Virus written by William J. Bean and published by . This book was released on 1974 with total page 272 pages. Available in PDF, EPUB and Kindle. Book excerpt:
Download or read book Influenza Virus written by Yohei Yamauchi and published by Humana. This book was released on 2019-09-11 with total page 663 pages. Available in PDF, EPUB and Kindle. Book excerpt: This book provides researchers with widely used techniques for the study of virology, focusing on molecular biology and imaging to encourage mechanistic investigation of virus-host interactions. Chapters detail a broad range of methods from diagnosis, virus propagation, proteomics, haploid screening, lentiviral screening, virus entry, single molecule RNA imaging, correlative light and electron microscopy (CLEM), EM, light-sheet microscopy, biochemistry, viral transcription, physiological infection models, animal models, in vivo imaging, antigenic evolution, immunology to mathematical modelling. Reviews cover general influenza, clinical trials, both sides of the gain-of-function debate, and computational modelling. Written in the highly successful Methods in Molecular Biology series format, chapters include introductions to their respective topics, lists of the necessary materials and reagents, step-by-step, readily reproducible laboratory protocols, and tips on troubleshooting and avoiding known pitfalls. Cutting-edge and thorough, Influenza Virus: Methods and Protocols aims to motivate experienced researchers and newcomers in the field and improve our overall understanding of influenza.
Book Synopsis Conserved Polymerase Structural Features and Ubiquitination Regulate the Influenza Virus RNA Replication Machinery by :
Download or read book Conserved Polymerase Structural Features and Ubiquitination Regulate the Influenza Virus RNA Replication Machinery written by and published by . This book was released on 2016 with total page 158 pages. Available in PDF, EPUB and Kindle. Book excerpt: The influenza A virus polymerase is essential for the virus life cycle. The polymerase is a trimeric complex composed of subunits PA, PB1, and PB2 and associates with viral RNAs and nucleoprotein (NP) to form higher order ribonucleoprotein (RNP) complexes. In the context of these RNPs, the polymerase expresses viral genes and replicates the viral genome. The polymerase is also a major determinant of influenza virus host tropism and pathogenicity. It is a target for species-specific restriction of influenza viruses in mammals. Polymerases encoded by avian influenza viruses do not function efficiently in mammals. This restriction has been mapped to position 627 in the PB2 subunit, which is normally a glutamic acid in avian isolates. Conversely, a lysine is present at position 627 in most mammalian viral isolates and creates a basic face on the domain surface that confers high activity in mammals. In addition to species-specific regulation, the polymerase is also regulated temporally over the course of infection to ensure coordinated expression of viral genes as well as replication of the viral genome. Various host factors and processes have been implicated in regulation of the IAV polymerase function, including post-translational modifications, however the mechanisms are not fully understood. We created a series of mutants in the 627 domain of the PB2 subunit to alter the conserved “P[F/P]AAAPP” sequence motif and a number of conserved basic residues that give the domain surface a basic face. Mutating the basic face or the P[F/P]AAAP motif impaired polymerase activity, assembly of replication complexes and viral replication. We found that the P[F/P]AAAP motif residues were important for polymerase function in both human and chicken cells, suggesting that they play a structural role and are essential for overall polymerase function. We also identified PB2 positions 586 and 589 on the basic surface of the 627 domain to be species-specific determinants of polymerase function that are preferentially required for function in human versus avian cells. Thus, we identified new residues in the 627 domain that regulate overall polymerase function and those that function in a species-specific fashion. This work highlights the importance of the surface charge and structure of the PB2 627 domain for virus replication and host adaptation. We assessed the ubiquitination status of the RNP complex and investigated the effect of ubiquitin expression on polymerase function. We show that all protein subunits in the RNP complex are ubiquitinated and that their levels are not significantly affected, despite the well known activity of ubiquitin-mediated protein degradation. Instead, we found that ubiquitination and an active proteasome enhance polymerase activity. Ubiquitin expression up-regulates polymerase function causing increased accumulation of vRNA, cRNA and mRNA and enhanced viral gene expression during infection. We show that ubiquitin expression enhances polymerase activity independent of NP or RNP assembly. Ubiquitination and the proteasome pathway play multiple roles in the influenza virus cycle, and we now demonstrate that ubiquitination also modulates polymerase activity independent of protein degradation. Overall, we describe here key features of the influenza virus polymerase that regulate its function in a species-specific fashion and a new way in which a host cell process can be co-opted by the virus to enhance its polymerase function.
Book Synopsis DEVELOPMENT OF ANTIVIRAL AGENT by : Shuofeng Yuan
Download or read book DEVELOPMENT OF ANTIVIRAL AGENT written by Shuofeng Yuan and published by Open Dissertation Press. This book was released on 2017-01-26 with total page 220 pages. Available in PDF, EPUB and Kindle. Book excerpt: This dissertation, "Development of Antiviral Agents Targeting the RNA Polymerase of Influenza Virus" by Shuofeng, Yuan, 袁碩峰, was obtained from The University of Hong Kong (Pokfulam, Hong Kong) and is being sold pursuant to Creative Commons: Attribution 3.0 Hong Kong License. The content of this dissertation has not been altered in any way. We have altered the formatting in order to facilitate the ease of printing and reading of the dissertation. All rights not granted by the above license are retained by the author. Abstract: The rapid mutability of influenza virus in conjunction with genomic reassortment between viral strains promotes the virus' ability to evade vaccines and to become resistant to antiviral drugs. Therefore, novel anti-influenza therapeutics utilizing new targets and creative strategies are essential. The RNA-dependent RNA polymerase of the virus consists of PA, PB1, and PB2 subunits. Biological and structural investigations of the functional domains of these subunits have broadened the target reservoir for drug screening. With the wealth of knowledge from these studies, identification of small-molecule inhibitors that specifically disrupt the polymerase assembly or abrogate polymerase activities has emerged as an innovative and promising approach. In an attempt to facilitate the discovery of antiviral agents that target viral polymerase, isolated functional domains such as the PA endonuclease domain, the PB2 cap-binding domain, and the PA-PB1 interaction domains were expressed as screening targets. Based on the biochemical and structural properties of individual targets, a variety of platforms were established for the effective screening of inhibitors, including systematic evolution of ligands by exponential enrichment (SELEX), fluorescence resonance energy transfer (FRET) assay, fluorescence polarization (FP) assay, and enzyme-linked immunosorbent assay (ELISA). The antiviral efficacies of selected inhibitors were examined in vitro and in vivo, followed by verification of their antiviral mechanisms. Clinical merits of selected inhibitors were further evaluated, focusing mainly on their cross-protection abilities among influenza virus subtypes and their potential synergetic antiviral effects when used in combination with other drugs. A number of small-molecule compounds, i.e. PA-30, ANA-0, PB2-19, PAC-3 and ANA-1, together with the aptamer PAN-2, were identified as potent inhibitors against the replication of multiple subtypes of influenza A virus, including H1N1, H3N2, H5N1, H7N7, H7N9, and H9N2, in Madin-Darby canine kidney (MDCK) cell cultures. The intranasal administration of the identified compounds enhanced survival rates and reduced lung viral loads in BALB/c mice infected with H1N1 virus. The docking analyses predicted the compounds targeting PA or PB2 interacted with enzyme active sites to abolish endonuclease or cap-binding activity of the polymerase, whereas the compound targeting the PA-PB1 interaction likely induced configurational changes that impeded polymerase assembly. In addition, the combined treatment of zanamivir with the PA- or PB2-targeted compounds exerted synergistic antiviral effects in vitro. This study underscores the medical importance of polymerase functional domains as druggable targets, which may be due to the fact that these targeted areas are not only highly conserved among virus subtypes but also key to viral fitness. The identified antivirals exhibit substantial promise for clinical applications and provide new additions to the arsenal of drugs that are already used for chemoprophylaxis and treatment of influenza. Importantly, the established screening platforms for PA endonuclease inhibitors, PB2 cap-binding inhibitors, and PA-PB1 interaction disrupters should advance the development of a category of anti-influenza drugs that target viral polymerase. DOI: 10.5353/th_b5699888 Subjects: Antiviral agents RNA po
Book Synopsis The Molecular Basis of Host Range Restriction of Avian Influenza Virus Polymerases in Mammalian Hosts by : Olivier Moncorgé
Download or read book The Molecular Basis of Host Range Restriction of Avian Influenza Virus Polymerases in Mammalian Hosts written by Olivier Moncorgé and published by . This book was released on 2013 with total page pages. Available in PDF, EPUB and Kindle. Book excerpt: Influenza A virus adaptation to humans is a rare but recurrent event that can result in a pandemic. The influenza polymerase, composed of the viral proteins PB1, PB2 and PA, is responsible for transcription and replication of the viral genome. Typical avian-origin influenza polymerases are restricted in human cells and polymerase subunit PB2 is particularly involved in this restriction. Residue 627 of PB2 is a glutamic acid in almost all avian influenza viruses, and mutation to a lysine is a potent enhancer of avian polymerase function in human cells. However, the underlying molecular mechanism and the cellular factors modulating avian-origin influenza replication in mammals are not known. Using a cell based replication assay in heterokaryons formed between avian and human cells, we concluded that the restriction is not due to a dominant human inhibitory factor. We also showed that supply of avian factors to human cells stimulated the activity of an avian-origin influenza polymerase and a functional screen was set up to attempt to isolate such chicken co-factor(s). We hypothesised that PB2 E627K mutation enhances the viral polymerase activity by optimizing an interaction with a human co-factor. A biochemical approach was used to try to identify this factor. Pigs are thought to be more susceptible to avian influenza than other mammalian species and are a supposed "mixing vessel" for influenza A viruses. To compare the replicative capacity of different influenza polymerases in pig, human and avian cells, an influenza polymerase assay in pig cells was set up. This assay was also used to study the impact in pig cells of known PB2 mammalian adaptive mutations. No obvious difference in the capacity of pig and human cells to support influenza polymerase activity was found, questioning the suggested susceptibility of pigs to influenza. Viruses from the avian H9N2 G1 lineage have been responsible for some human infections. Despite having none of the known mammalian signatures, we found the H9N2 G1 polymerase was active in human and pig cells. This study identified H9N2 G1 PA protein as being particularly mammalian adapted, highlighting the role of PA in influenza mammalian adaptation.
Book Synopsis Studies on the Influenza Virus RNA Polymerase by : K. W. Tibbles
Download or read book Studies on the Influenza Virus RNA Polymerase written by K. W. Tibbles and published by . This book was released on 1987 with total page 0 pages. Available in PDF, EPUB and Kindle. Book excerpt:
Book Synopsis Polymerase Activity of Chimeric Polymerase by : Wing-Hong Chin
Download or read book Polymerase Activity of Chimeric Polymerase written by Wing-Hong Chin and published by Open Dissertation Press. This book was released on 2017-01-26 with total page pages. Available in PDF, EPUB and Kindle. Book excerpt: This dissertation, "Polymerase Activity of Chimeric Polymerase: a Determining Factor for an Influenza Virus to Be a Pandemic Strain" by Wing-hong, Chin, 錢永康, was obtained from The University of Hong Kong (Pokfulam, Hong Kong) and is being sold pursuant to Creative Commons: Attribution 3.0 Hong Kong License. The content of this dissertation has not been altered in any way. We have altered the formatting in order to facilitate the ease of printing and reading of the dissertation. All rights not granted by the above license are retained by the author. Abstract: The influenza polymerase is a complex of three subunits, polymerase basic protein 2 (PB2), polymerase basic protein 1 (PB1) and polymerase acidic protein (PA). It associates with the viral RNA segment and nucleoprotein (NP) to form a viral ribonucleoprotein (vRNP) complex which is important for transcription and replication of the viral genome. Concurrently, the previous three influenza pandemics viruses contain reassorted vRNP of different origins. This leads to the aim of study to investigate the role of polymerase in the pandemic viruses. By reconstitution of vRNPs in human cells, it was demonstrated that vRNPs of H2N2 and H3N2 pandemic viruses had higher polymerase activity than the H2N2 seasonal viruses in-between them. The recombinant virus with H2N2 pandemic vRNP also showed faster growth kinetics in the early stage of viral replication and better adaptability to the selective environment with neuraminidase inhibitor than the recombinant virus with H2N2 seasonal vRNP, which had a lower polymerase activity. Reconstitution of chimeric vRNPs of H2N2 pandemic and seasonal viruses revealed that PB2, PB1 and PA were responsible for the difference in polymerase activity between them. Five residues, one in PB2, three in PB1 and one in PA were identified to be significant for the polymerase activity change. These polymerase subunits and residues may act as part of the determining factors for the H2N2 pandemic virus. Furthermore, PB2-627 has been shown to have stringent host specificity and affect polymerase activity and viral replication. Recombinant viruses in mammalian and avian cells with random mutation were generated at this position. It showed that the amino acids at this position are not restricted to those appear in the nature for generating viable viruses. It was also observed that the avian-derived viruses generally had lower polymerase activity and reduced growth kinetics in mammalian cells, while part of the mammalian-derived viruses had lower polymerase activity and reduced growth kinetics in avian cells. This consolidated the role of PB2-627 on host specificity and demonstrated the possibility of some novel amino acids for this position, which may play a role in the future influenza pandemic. The 2009 H1N1 pandemic virus contains a reassorted vRNP with subunits of avian, human and swine origins. This prompts me to compare the polymerase activity of all the 81 possible combinations of chimeric vRNPs of three different origins. The results were statistically analyzed and several single subunit factors and interactions between vRNP subunits were identified to significantly affect the polymerase activity. In order to reduce the effort and resources required, a fractional factorial design of 27 experimental runs was developed to substitute the 81-combination full factorial design for identifying the significant single subunit factors that affect the polymerase activity. Overall, this study identified some factors that may contribute to a pandemic virus and allows us to have better understanding of the role of polymerase in a pandemic virus. These findings may contribute to evaluating the pandemic potential of the novel virus that emerges or may emerge in the nature and enhances the preparedness towards the next pandemic influenza. DOI: 10.5353/th_b4979918 Subjects: RNA polymerases Influenza viruses Nucleoproteins
Book Synopsis Studies of the Influenza Virus RNA Polymerase by : Vivian Carol Blok
Download or read book Studies of the Influenza Virus RNA Polymerase written by Vivian Carol Blok and published by . This book was released on 1988 with total page pages. Available in PDF, EPUB and Kindle. Book excerpt:
Book Synopsis Interactions Between the Influenza Virus RNA Polymerase and Cellular RNA Polymerase II by : Annie Yee-Man Chan
Download or read book Interactions Between the Influenza Virus RNA Polymerase and Cellular RNA Polymerase II written by Annie Yee-Man Chan and published by . This book was released on 2007 with total page 328 pages. Available in PDF, EPUB and Kindle. Book excerpt:
Book Synopsis Influenza Virus by : Yoshihiro Kawaoka
Download or read book Influenza Virus written by Yoshihiro Kawaoka and published by Humana Press. This book was released on 2016-08-23 with total page 234 pages. Available in PDF, EPUB and Kindle. Book excerpt: Reports of influenza-like illnesses date back to the Middle Ages, and outbreaks of influenza likely afflicted humans long before that. Over the last half century, influenza virus research has led to the development of two classes of antivirals – ion channel and neuraminidase inhibitors. Recently, a method of the artificial generation of an influenza virus was established. This system has been instrumental in the development of novel influenza vaccines and in the understanding of viral pathogenicity and the functions of viral proteins. Influenza Virus: Methods and Protocols summarizes the current techniques that have made this progress possible, ranging from protocols for virus isolation, growth, and subtyping to procedures for the efficient generation of any influenza virus. Written in the successful Methods in Molecular BiologyTM series format, chapters include introductions to their respective topics, lists of the necessary materials and reagents, step-by-step, readily reproducible protocols, and notes on troubleshooting and avoiding known pitfalls. Authoritative and easily accessible, Influenza Virus: Methods and Protocols seeks to serve both professionals and novices with the techniques used in numerous laboratories around the world that are, thus, the building blocks that underpin almost all influenza virus research.
Book Synopsis Influenza Polymerase Subunit Compatibility Between Human H1 and H5 Viruses by : Tin-Wai Olive Li
Download or read book Influenza Polymerase Subunit Compatibility Between Human H1 and H5 Viruses written by Tin-Wai Olive Li and published by . This book was released on 2017-01-28 with total page pages. Available in PDF, EPUB and Kindle. Book excerpt: This dissertation, "Influenza Polymerase Subunit Compatibility Between Human H1 and H5 Viruses" by Tin-wai, Olive, Li, 李天慧, was obtained from The University of Hong Kong (Pokfulam, Hong Kong) and is being sold pursuant to Creative Commons: Attribution 3.0 Hong Kong License. The content of this dissertation has not been altered in any way. We have altered the formatting in order to facilitate the ease of printing and reading of the dissertation. All rights not granted by the above license are retained by the author. DOI: 10.5353/th_b4189689 Subjects: Influenza A virus - Reproduction RNA polymerases RNA - Synthesis RNA viruses Host-virus relationships
Book Synopsis Structure of the RNA-dependent RNA Polymerase from Influenza C Virus by : Narin Hengrung
Download or read book Structure of the RNA-dependent RNA Polymerase from Influenza C Virus written by Narin Hengrung and published by . This book was released on 2014 with total page pages. Available in PDF, EPUB and Kindle. Book excerpt:
Book Synopsis Study of the Structure and Function of the Influenza Virus RNA-dependent RNA Polymerase by : Itziar Serna Martin
Download or read book Study of the Structure and Function of the Influenza Virus RNA-dependent RNA Polymerase written by Itziar Serna Martin and published by . This book was released on 2017 with total page pages. Available in PDF, EPUB and Kindle. Book excerpt:
Book Synopsis Primary Structure of the Polymerase Acidic (PA) Gene of an Influenza B Virus (B/SING/222/79) by : Emmanuel Kwesi Akoto-Amanfu
Download or read book Primary Structure of the Polymerase Acidic (PA) Gene of an Influenza B Virus (B/SING/222/79) written by Emmanuel Kwesi Akoto-Amanfu and published by . This book was released on 1987 with total page 78 pages. Available in PDF, EPUB and Kindle. Book excerpt:
