Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.7.48 (transcriptase)
 9,479 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Virus-specific protein and RNA syntheses have been analyzed in chicken embryo fibroblast cells infected with two group IV temperature-sensitive (ts) mutants of influenza A (fowl plague) virus in which the ts lesion maps in RNA segment 8 (J. W. Almond, D. McGeoch, and R. D. Barry, Virology 92:416-427, 1979), known to code to code for two nonstructural proteins, NS1 and NS2. Both mutants induced the synthesis of similar amounts of all the early virus-specific proteins (P1, P2, P3, NP, and NS1) at temperatures that were either permissive (34 degrees C) or nonpermissive (40.5 degrees C) for replication. However, the synthesis of M protein, which normally accumulates late in infection, was greatly reduced in ts mutant-infected cells at 40.5 degrees C compared to 34 degrees C. The NS2 protein was not detected at either temperature in cells infected with one mutant (mN3), and was detected only at the permissive temperature in cells infected with mutant ts47. There was no overall reduction in polyadenylated (A+) complementary RNA, which functions as mRNA, in cells infected with these mutants at 40.5 degrees C compared to 34 degrees C, nor was there any evidence of selective accumulation of this type of RNA within the nucleus at the nonpermissive temperature. No significant differences in ts mutant virion RNA transcriptase activity were detected by assays in vitro at 31 and 40.5 degrees C compared to wild-type virus. Virus-specific non-polyadenylated (A-) complementary RNA, which is believed to act as the template for new virion RNA production, accumulated normally in cells at both 34 and 40.5 degrees C, but at 40.5 degrees C accumulation of new virion RNA was reduced by greater than 90% when compared to accumulation at 34 degrees C.
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PMID:Influenza virus-specific RNA and protein syntheses in cells infected with temperature-sensitive mutants defective in the genome segment encoding nonstructural proteins. 644 1

Oligodeoxyribonucleotides targeted against respiratory syncytial virus (RSV) genomic RNA inhibited RSV replication in cell culture by an apparent antisense mechanism. HEp-2 cells were infected with RSV strain A2 and incubated in the presence of oligonucleotides. Virus replication was measured by enzyme-linked immunosorbent assay (ELISA), virus yield assay, or production of specific RSV mRNAs. Using ELISA, 50% effective concentration (EC50) values were about 0.5-1 microM for an antisense oligonucleotide targeted to the start of the NS2 gene. All oligonucleotides inhibited virus antigen production as measured by ELISA. In all assays, this antisense oligonucleotide was more potent than: (1) a control oligonucleotide containing the reverse sequence; (2) oligonucleotides targeted at RSV mRNA; (3) a random sequence oligonucleotide; and (4) ribavirin. Reverse transcriptase polymerase chain reaction (PT-PCR) showed sequence specific depletion of the genomic RNA target following treatment of cells with the antisense oligonucleotide. Specific cleavage of the genomic target RNA has been detected at the antisense oligonucleotide binding site, suggesting that cellular Rnase H participates in the reaction. These results indicate that antisense oligonucleotides targeted against RSV genomic RNA can effectively inhibit RSV replication and may have therapeutic value.
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PMID:Inhibition of respiratory syncytial virus replication by antisense oligodeoxyribonucleotides. 903 76

The hepatitis C virus is the major causative agent of nonA-nonB hepatitis worldwide. Although this virus cannot be cultivated in cell culture, several of its features have been elucidated in the past few years. The viral genome is a single-stranded, 9.5kb long RNA molecule of positive polarity. The viral genome is translated into a single polyprotein of about 3000 amino acids. The virally encoded polyprotein undergoes proteolytic processing by a combination of cellular and viral proteolytic enzymes in order to yield all the mature viral gene products. The gene order of HCV has been determined to be C-E1-E2-p7-NS2-NS3-NS4A-NS4B-NS5A-NS5B. The mature structural proteins, C, E1 and E2 have been shown to arise from the viral polyprotein via proteolytic processing by host signal peptidases. Conversely, generation of the mature nonstructural proteins relies on the activity of viral proteases. Thus, cleavage at the NS2/NS3 junction is accomplished by a metal-dependent autoprotease encoded within NS2 and the N-terminus of NS3. The remaining cleavages downstream from this site are effected by a serine protease contained within the N-terminal region of NS3. Besides the protease domain, NS3 also contains an RNA helicase domain at its C-terminus. NS3 forms a heterodimeric complex with NS4A. The latter is a membrane protein that has been shown to act as a cofactor of the protease. Whereas the NS5B protein has been shown to be the viral RNA-dependent RNA polymerase, no function has yet been attributed to NS4B and NS5A. The latter is a cytoplasmic phosphoprotein and appears to be involved in mediating the resistance of the hepatitis C virus to the action of interferon.
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PMID:The nonstructural proteins of the hepatitis C virus: structure and functions. 922 25

The hepatitis C virus (HCV) was identified as the major causative agent of posttransfusion and community-acquired non-A, non-B hepatitis throughout the world. It is an enveloped virus with a plus-strand RNA genome encoding a polyprotein of about 3,010 amino acids. This polyprotein is cleaved co- and posttranslationally into mature viral proteins by host cell signal peptidases and 2 viral enzymes designated the NS2-3 proteinase and the NS3/4A proteinase complex. It is assumed that virus replication takes place in a membrane-associated complex containing at least 2 viral enzymatic activities: the NS3 nucleoside triphosphatase (NTPase)/helicase and the NS5B RNA-dependent RNA polymerase (RdRp). Based on their important role for the viral life cycle and the wealth of information available for related cellular and viral proteins, the NS3/4A serine-type proteinase complex, the NS3 NTPase/helicase and the NS5B RdRp are the most attractive targets for development of HCV-specific antiviral therapies. This review will summarize our current knowledge about structure and function of these proteins and describe approaches pursued to identify effective antiviral compounds.
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PMID:Candidate targets for hepatitis C virus-specific antiviral therapy. 967 42

Four bovine viral diarrhea virus type 2 (BVDV-2) pairs consisting of cytopathogenic (cp) and noncp BVDV-2 were isolated during an outbreak of mucosal disease. Comparative sequence analysis showed that the four noncp BVDV-2 isolates were almost identical. For the cp BVDV-2 isolates, viral subgenomic RNAs were shown by Northern blot to have a length of about 8 kb, which is about 4.3 kb shorter than the genome of noncp BVDV. Cytopathogenicity and the expression of NS3 were both strictly correlated to the presence of viral subgenomic RNAs. By reverse transcription-PCR, Southern blot analysis, and nucleotide sequencing, a set of 11 unique subgenomes was identified with up to 5 different subgenomes isolated from one animal. To our knowledge, this is the first report on isolation of a set of pestiviral subgenomes from individual animals. Common features of the BVDV-2 subgenomic RNAs include (i) deletion of most of the genomic region encoding the structural proteins, as well as the nonstructural proteins p7 and NS2, and (ii) insertion of cellular (poly)ubiquitin coding sequences. Three subgenomes also comprised 15 to 75 nucleotides derived from the 5' part of the NS2 gene. Comparisons of the obtained nucleotide sequences revealed that the different BVDV-2 subgenomes evolved from the respective noncp BVDV-2 by RNA recombination. The presence of short regions of sequence similarity at several crossing-over sites suggests that base pairing between the nascent RNA strand and the acceptor RNA template facilitates template switching of the BVDV RNA-dependent RNA polymerase.
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PMID:Nonhomologous RNA recombination in bovine viral diarrhea virus: molecular characterization of a variety of subgenomic RNAs isolated during an outbreak of fatal mucosal disease. 1036 14

Hepatitis C virus (HCV) has a positive-stranded RNA genome of about 9.5 kb and a large open reading frame encoding a precursor polyprotein of ca. 3,000 amino acids (aa). This polyprotein is cleaved by host cellular signalase(s) and viral proteases into 10 viral proteins in the order of NH(2)-Core-E1-E2-p7-NS2-NS3-NS4A-NS4B-NS5A-NS 5B-COOH. Core and E1/E2 are considered to be a capsid protein and envelope glycoproteins, respectively. NS2-NS5B are putative nonstructural proteins involved in the replication of HCV. NS2/3 is a metalloprotease which cleaves in cis at the NS2/3 junction. NS3 possesses serine protease and RNA helicase activities and is responsible for the cleavage of the remaining nonstructural proteins. NS4A is suggested to be a cofactor for NS3 protease. Although the function of p7, NS4B and NS5A are still unknown, an association of a mutation in NS5A with a susceptibility to interferon (IFN) has been reported. NS5B possesses an RNA-dependent RNA polymerase activity. Most of the current findings in HCV proteins depend on expression studies of HCV cDNA clones because of the lack of an efficient replication system in cell cultures. Therefore, a final assignment of cleavages and functions of HCV proteins has to await the propagation of HCV in cell cultures.
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PMID:Processing and functions of Hepatitis C virus proteins. 1051 68

Infection with the hepatitis C virus (HCV) is the major cause of nonA-nonB hepatitis worldwide. Although this virus cannot be cultivated in vitro, several of its key features have been elucidated in the past few years. The viral genome is a positive-sense, single-stranded, 9.6 kb long RNA molecule. The viral genome is translated into a single polyprotein of about 3000 amino acids. The viral polyprotein is proteolytically processed by the combination of cellular and viral proteinases in order to yield all the mature viral gene products. The genomic order of HCV has been shown to be C-E1-E2-p7-NS2-NS3-NS4A-NS4B-NS5A-NS5B. C, E1 and E2 are the virion.structural proteins. The function of p7 is currently unknown. These proteins have been shown to arise from the viral polyprotein via proteolytic processing by the host signal peptidases. Generation of the mature nonstructural proteins, NS2 to NS5B, relies on the activity of viral proteinases. Cleavage at the NS2/NS3 junction is accomplished by a metal-dependent autocatalytic proteinase encoded within NS2 and the N-terminus of NS3. The remaining cleavages downstream from this site are effected by a serine proteinase also contained within the N-terminal region of NS3. NS3 also contains an RNA helicase domain at its C-terminus. NS3 forms a heterodimeric complex with NS4A. The latter is a membrane protein that has been shown to act as a cofactor of the proteinase. While no function has yet been attributed to NS4B, it has recently been suggested that NS5A is involved in mediating the resistance of the hepatitis C virus to the action of interferon. Finally, the NS5B protein has been shown to be the viral RNA-dependent RNA polymerase.
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PMID:Molecular virology of the hepatitis C virus. 1062 60

Hepatitis C virus (HCV), a positive-strand enveloped RNA virus, is a major cause of chronic liver disease worldwide. Cis-acting RNA elements and virus-encoded polypeptides required for HCV replication represent attractive targets for the development of antiviral therapies. Internal ribosome entry site-directed translation of HCV genome RNA produces a long polyprotein which is co- and post-translationally processed to yield at least 10 viral proteins. A host signal peptidase is responsible for maturation of the structural proteins located in the N-terminal one-third of the polyprotein. Thus far, four enzymatic activities encoded by the non-structural (NS) proteins have been reported. The NS2-3 region encodes an autoproteinase responsible for cleavage at the 2/3 site. The N-terminal one-third of NS3 functions as the catalytic subunit of a serine proteinase which cleaves at the 3/4A, 4A/4B, 4B/5A and 5A/5B sites, and NS4A is an essential cofactor for some of these cleavages. NS3 also encodes an RNA-stimulated NTPase/RNA helicase at its C terminus, and NS5B has been shown to possess an RNA-dependent RNA polymerase activity. To date, no functions have been reported for NS4B or NS5A in RNA replication, however, NS5A has been implicated in modulating the sensitivity of HCV to interferon. Sequence and structural conservation within the 3' terminal 98 bases of genomic RNA suggest a functional importance in the virus life-cycle and hence another target for antiviral intervention. Recently, HCV infection was shown to be initiated in chimpanzees following intrahepatic inoculation of RNA transcribed from cloned HCV cDNA. The ability to generate large quantities of infectious HCV RNA may facilitate the development of reliable cell culture replication systems useful for the evaluation of antiviral drugs.
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PMID:Molecular virology of hepatitis C virus: an update with respect to potential antiviral targets. 1072 57

Infection with the hepatitis C virus (HCV) is the major cause of non-A, non-B hepatitis worldwide. The viral genome, a positive-sense, single-stranded, 9.6-kb long RNA molecule, is translated into a single polyprotein of about 3,000 amino acids. The viral polyprotein is proteoytically processed to yield all the mature viral gene products. The genomic order of HCV has been determined to be C-->E1-->E2-->p7-->NS2-->NS3-->NS4A-->NS4B-->NS5A++ +-->NS5B. C, E1, and E2 are the virion structural proteins. Whereas the function of p7 is currently unknown, NS2 to NS5B are thought to be the nonstructural proteins. Generation of the mature nonstructural proteins relies on the activity of viral proteinases. Cleavage at the NS2-NS3 junction is accomplished by a metal-dependent autocatalytic proteinase encoded within NS2 and the N-terminus of NS3. The remaining downstream cleavages are effected by a serine proteinase contained also within the N-terminal region of NS3. NS3, in addition, contains an RNA helicase domain at its C-terminus. NS3 forms a heterodimeric complex with NS4A. The latter is a membrane protein that acts as a cofactor of the proteinase. Although no function has yet been attributed to NS4B, NS5A has been recently suggested to be involved in mediating the resistance of the HCV to the action of interferon. Finally, the NS5B protein has been shown to be the viral RNA-dependent RNA polymerase. This article reviews the current understanding of the structure and the function of the various HCV nonstructural proteins with particular emphasis on their potential as targets for the development of novel antiviral agents and vaccines.
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PMID:Biochemical and immunologic properties of the nonstructural proteins of the hepatitis C virus: implications for development of antiviral agents and vaccines. 1089 33

Rotaviruses, members of family Reoviridae, are a major cause of acute gastroenteritis of infants and young children. The rotavirus genome consists of 11 segments of double-stranded (ds)RNA and the virion is an icosahedron composed of multiple layers of protein. The virion core is formed by a layer of VP2 and contains multiple copies of the RNA-dependent RNA polymerase VP1 and the mRNA-capping enzyme VP3. Double-layered particles (DLPs), representing cores surrounded by a layer of VP6, direct the synthesis of viral mRNAs. Rotavirus core- and DLP-like replication intermediates (RIs) catalyze the synthesis of dsRNA from viral template mRNAs coincidentally with the packaging of the mRNAs into the pre-capsid structures of RIs. In addition to structural proteins, the nonstructural proteins NSP2 and NSP5 are components of RIs with replicase activity. NSP2 self assembles into octameric structures that have affinity for ssRNA and NTPase and helix-destabilizing activites. Its interaction with nucleotides induces a conformational shift in the octamer to a more condensed form. Phosphate residues generated by the NTPase activity are believed to be transferred from NSP2 to NSP5, leading to the hyperphosphorylation of the latter protein. It is suspected that the transfer of the phosphate group to NSP5 allows NSP2 to return to its noncondensed state and, thus, to accept another NTP molecule. The NSP5-mediated cycling of NSP2 from condensed to noncondensed combined with its RNA binding and helix-destabilizing activities are consistent with NSP2 functioning as a molecular motor to facilitate the packaging of template mRNAs into the pre-capsid structures of RIs. Similarities with the bluetongue virus protein NS2 and the reovirus proteins sigmaNS and micro2 suggest that they may be functional homologs of rotavirus NSP2 and NSP5.
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PMID:Nonstructural proteins involved in genome packaging and replication of rotaviruses and other members of the Reoviridae. 1501 Feb 17


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