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:2.7.7.7 (DNA polymerase)
17,007 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Autoantibodies to nuclear and smooth muscle are common in hepatitis B virus (HBV) infection. To understand their origin, we scanned protein databases and found that HBV-DNA polymerase (HBV-pol) shares 7-9 amino acid sequences with nuclear (MHC II trans-activator, nuclear pore core protein, nuclear mitotic apparatus, and polymyositis sclerosis Ag) and smooth muscle proteins (caldesmon and myosin). Twenty-mer peptides with relevant homologues and an irrelevant control peptide were constructed and ELISAs were established. Sixty-five children with chronic HBV infection, 104 patients with other chronic liver diseases (CLD), 36 patients with extrahepatic autoimmune diseases, and 24 healthy controls were investigated. Double reactivity to HBV-pol peptides and corresponding self homologues was observed in 40% of HBV-positive patients as compared with four (4%) with other chronic liver diseases, two (6%) with extrahepatic autoimmune diseases, and in none of the healthy controls (p < 0.001 for all). Double reactivity to myosin or caldesmon peptides and their HBV-pol homologues was associated with anti-smooth muscle Ab positivity by immunofluorescence (p < 0.05 for both). HBV-positive sera double reactive for myosin or caldesmon and their homologous HBV-pol peptides also reacted with the native proteins on immunoblot. Fifty to ninety percent Ab inhibition to individual HBV-pol and HBV-pol99-118 peptides was noted by preincubation with individual HBV-pol/self homologue peptide and native proteins, respectively, but not with control peptide. Our results show that cross-reactive immunity targeting homologous sequences of viral and self proteins may partly account for autoantibody production in HBV infection.
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PMID:Mimicry between the hepatitis B virus DNA polymerase and the antigenic targets of nuclear and smooth muscle antibodies in chronic hepatitis B virus infection. 997 45

We have shown that highly proofreading DNA polymerase is required for the polymerase chain reaction in the genetic analysis of hepatitis C virus (HCV). To clarify the status of HCV quasispecies in hepatic tissue using proofreading DNA polymerase, we performed a genetic analysis of the HCV core protein-encoding region in cancerous and noncancerous lesions derived from 4 patients with hepatocellular carcinoma. In contrast to the previously published data, we observed neither deletions nor stop codons in the analyzed region and no significant difference in the complexity of HCV quasispecies between cancerous and noncancerous lesions. This result suggests that the HCV core gene is never structurally defective in hepatic tissues, including cancerous lesions. However, in 3 of the patients, the consensus HCV species differed between cancerous and noncancerous lesions, suggesting that the predominant replicating HCV species differs between these 2 types of lesions. Moreover, during the course of the study, we obtained several interesting variants possessing a substitution at codon 9 of the core gene, whose substitution has been shown to induce the production of the F protein synthesized by a - 2/+1 ribosomal frameshift.
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PMID:Hepatitis C virus quasispecies in cancerous and noncancerous hepatic lesions: the core protein-encoding region. 1210 85

Synthesis of hepadnaviral DNA is dependent upon both the viral DNA polymerase and the viral core protein, the subunit of the nucleocapsids in which viral DNA synthesis takes place. In a study of natural isolates of duck hepatitis B virus (DHBV), we cloned full-length viral genomes from a puna teal. One of the clones failed to direct viral DNA replication in transfected cells, apparently as a result of a 3 nt inframe deletion of histidine 107 in the core protein. Histidine 107 is located in the center of a predicted helical region of the "insertion domain", a stretch of 45 amino acids which appears to be at the tip of a spike on the surface of the nucleocapsid. The mutation was introduced into a well-characterized strain of DHBV for further analysis. Core protein accumulated in cells transfected with the mutant DHBV but was partially degraded, suggesting that it was unstable. Assembled nucleocapsids were not detected by capsid gel electrophoresis. Interestingly, the mutant protein appeared to form chimeric nucleocapsids with wild-type core protein. The chimeric nucleocapsids supported viral DNA replication. These results suggest that the insertion domain of the spike may play a role either in assembly of stable nucleocapsids, possibly in formation of the dimer subunits, or in triggering nucleocapsid disintegration, required during initiation of new rounds of infection.
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PMID:The insertion domain of the duck hepatitis B virus core protein plays a role in nucleocapsid assembly. 1683 20

Nucleos(t)ide analogue antiviral therapy for chronic hepatitis B has proven to be effective in the short term but the frequent development of resistance limits its clinical utility. Agents targeting other stages of viral replication are needed in order to develop improved combination therapies. The phenylpropenamide derivatives AT-61 and AT-130 have been shown to inhibit HBV replication in vitro, but the mechanism of action of these compounds remains undefined. The aim of this study was to determine the mechanism of action of AT-130, a non-nucleoside inhibitor of HBV in several in vitro models of replication. These studies found that AT-130 inhibited HBV DNA replication in hepatoma cells but had no effect on viral DNA polymerase activity or core protein translation. Total HBV RNA production was also unaffected in the presence of the drug whilst the amount of encapsidated RNA was significantly reduced, thereby inhibiting subsequent viral reverse transcription. These studies have established that the inhibition of HBV genome replication by a non-nucleoside analogue acting at the level of viral encapsidation and packaging is a potentially useful strategy for future therapeutic drug development in the management of chronic hepatitis B.
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PMID:The phenylpropenamide derivative AT-130 blocks HBV replication at the level of viral RNA packaging. 1770 47

Removal of genome-bound viral DNA polymerase ought to be an essential step in the formation of hepadnavirus covalently closed circular DNA (cccDNA). We previously demonstrated that deproteinized (DP) relaxed circular DNA (rcDNA) of hepatitis B virus (HBV) existed in both the cytoplasm and nuclei of infected cells and the vast majority of cytoplasmic DP rcDNA was associated with DNase I-permeable nucleocapsids. In our efforts to investigate the role of the cytoplasmic DP rcDNA in cccDNA formation, we demonstrated that rcDNA deproteinization could occur in an endogenous DNA polymerase reaction with either virion-derived or intracellular nucleocapsids. As observed in the cytoplasm of virally infected cells, in vitro deproteinization requires the maturation of plus-strand DNA and results in changes in nucleocapsid structure that render the DP rcDNA susceptible to DNase I digestion. Remarkably, we found that the cytoplasmic DP rcDNA-containing nucleocapsids could be selectively immunoprecipitated with an antibody against the carboxyl-terminal peptide of HBV core protein and are associated with cellular nuclear transport receptors karyopherin-alpha and -beta. Moreover, transfection of small interfering RNA targeting karyopherin-beta1 mRNA or expression of a dominant-negative karyopherin-beta1 in a stable cell line supporting HBV replication resulted in the accumulation of DP rcDNA in cytoplasm and reduction of nuclear DP rcDNA and cccDNA. Our results thus favor a hypothesis that completion of plus-strand DNA synthesis triggers the genomic DNA deproteinization and structural changes of nucleocapsids, which leads to the exposure of nuclear localization signals in the C terminus of core protein and mediates the nuclear transportation of DP rcDNA via interaction with karyopherin-alpha and -beta.
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PMID:Production and function of the cytoplasmic deproteinized relaxed circular DNA of hepadnaviruses. 1986 87

We report a case of repeated seroconversion to anti-HBe antibody in a patient with chronic hepatitis B. We amplified and cloned sections of the hepatitis B virus (HBV) genes by polymerase chain reaction (PCR), and sequenced the PCR products. The results were analyzed by connecting all of the sequences to generate complete genomes. As a result, we confirmed the coexistence of two different HBV clones, both of which had the same subtype (adr) and genotype (C2). Neither clone had mutations in the S gene region in sequences involved in gene expression or in sequences involved in drug resistance. However, both clones had mutations in the core promoter(A1762T, G1764A). In one HBe antibody-positive clone, a pre-core mutation associated with HBe antigen negativity (G1896A) was found. In addition, pre-S2 deletion and 6 amino acid substitutions in the core protein gene were detected in this clone. The other HBe antigen-positive clone was essentially wild-type. Interestingly, this clone had accumulated mutations, which participated in DNA polymerase inactivation in the P gene region. Therefore, it is expected that this clone cannot replicate its own DNA polymerase. Consequently, this repeated seroconversion phenomenon was suggested to be responsible for the observed findings. In conclusion, analysis of the complete HBV genome has greatly expanded the number of mutations identified, and this method is useful for understanding the causes of rare cases of hepatitis B.
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PMID:[Analysis of the complete hepatitis B virus genomes in a patient for repeated seroconversion to anti-HBe antibody due to co-infection with two virus clones]. 2268 39

Poxvirus infections have been found in 230 species of wild and domestic birds worldwide in both terrestrial and marine environments. This ubiquity raises the question of how infection has been transmitted and globally dispersed. We present a comprehensive global phylogeny of 111 novel poxvirus isolates in addition to all available sequences from GenBank. Phylogenetic analysis of the Avipoxvirus genus has traditionally relied on one gene region (4b core protein). In this study we expanded the analyses to include a second locus (DNA polymerase gene), allowing for a more robust phylogenetic framework, finer genetic resolution within specific groups, and the detection of potential recombination. Our phylogenetic results reveal several major features of avipoxvirus evolution and ecology and propose an updated avipoxvirus taxonomy, including three novel subclades. The characterization of poxviruses from 57 species of birds in this study extends the current knowledge of their host range and provides the first evidence of the phylogenetic effect of genetic recombination of avipoxviruses. The repeated occurrence of avian family or order-specific grouping within certain clades (e.g., starling poxvirus, falcon poxvirus, raptor poxvirus, etc.) indicates a marked role of host adaptation, while the sharing of poxvirus species within prey-predator systems emphasizes the capacity for cross-species infection and limited host adaptation. Our study provides a broad and comprehensive phylogenetic analysis of the Avipoxvirus genus, an ecologically and environmentally important viral group, to formulate a genome sequencing strategy that will clarify avipoxvirus taxonomy.
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PMID:Worldwide phylogenetic relationship of avian poxviruses. 2340 35

There are only two currently approved classes of hepatitis B virus (HBV) antiviral agents, pegylated interferon (Peg-IFN), and nucleos(t)ide analogs (NAs) for chronic HBV infection. Although Peg-IFN is used for a finite 48-week duration and offers a greater chance of sustained off-treatment virological response, it is poorly tolerated and can only be offered to selected patients. The NAs are well tolerated but require prolonged therapy due to risk of relapse with treatment cessation. There is evolving data that novel virological assays (e.g., quantitative hepatitis B surface antigen, quantitative hepatitis B core antigen, quantitative antibody to core protein) in combination with hepatitis B genotype and more sensitive HBV DNA polymerase chain reaction (PCR) assays may be useful to predict response to IFN as well as off-treatment NA durability. Utilization of these clinical laboratory tests may be important given the development of novel anti-HBV therapies, hoping to achieve a cure for chronic hepatitis B infection.
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PMID:Review of Laboratory Tests used in Monitoring Hepatitis B Response to Pegylated Interferon and Nucleos(t)ide Analog Therapy. 2754 27

Avipoxvirus (APV) infections have been observed in a wide variety of wild, captive and domestic avian hosts, recently including a range of island endemic and endangered species. However, not enough is known about genome diversity and phylogenetic relationships of APVs, as well as their host-range specificity. A wild stone curlew (Burhinus oedicnemus) was recovered in Sardinia (Italy), showing large wart-like lesions and nodules on both legs and toes, which resulted positive to poxvirus by PCR. Histopathological examination of the lesions showed ballooning degeneration and large intracytoplasmic inclusion bodies consistent with APV infection. A multiple gene sequencing approach was applied to highlight the phylogenetic relationships of this virus with a panel of selected APVs at the clade and subclade levels. This novel isolate was characterized by sequencing partial 4b core protein, P35 (locus fpv140) and DNA polymerase genes and phylogenetic analyses assigned it to clade A, (Fowlpox virus, FWPV), subclade A2. Conservation implications of avian pox presence in Sardinian stone curlews and possibly in other island bird species are discussed.
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PMID:Multiple gene typing and phylogeny of avipoxvirus associated with cutaneous lesions in a stone curlew. 2805 22

Chronic hepatitis B virus (HBV) infection is a global public health problem. Although the currently approved medications can reliably reduce the viral load and prevent the progression of liver diseases, they fail to cure the viral infection. In an effort toward discovery of novel antiviral agents against HBV, a group of benzamide (BA) derivatives that significantly reduced the amount of cytoplasmic HBV DNA were discovered. The initial lead optimization efforts identified two BA derivatives with improved antiviral activity for further mechanistic studies. Interestingly, similar to our previously reported sulfamoylbenzamides (SBAs), the BAs promote the formation of empty capsids through specific interaction with HBV core protein but not other viral and host cellular components. Genetic evidence suggested that both SBAs and BAs inhibited HBV nucleocapsid assembly by binding to the heteroaryldihydropyrimidine (HAP) pocket between core protein dimer-dimer interfaces. However, unlike SBAs, BA compounds uniquely induced the formation of empty capsids that migrated more slowly in native agarose gel electrophoresis from A36V mutant than from the wild-type core protein. Moreover, we showed that the assembly of chimeric capsids from wild-type and drug-resistant core proteins was susceptible to multiple capsid assembly modulators. Hence, HBV core protein is a dominant antiviral target that may suppress the selection of drug-resistant viruses during core protein-targeting antiviral therapy. Our studies thus indicate that BAs are a chemically and mechanistically unique type of HBV capsid assembly modulators and warranted for further development as antiviral agents against HBV.IMPORTANCE HBV core protein plays essential roles in many steps of the viral replication cycle. In addition to packaging viral pregenomic RNA (pgRNA) and DNA polymerase complex into nucleocapsids for reverse transcriptional DNA replication to take place, the core protein dimers, existing in several different quaternary structures in infected hepatocytes, participate in and regulate HBV virion assembly, capsid uncoating, and covalently closed circular DNA (cccDNA) formation. It is anticipated that small molecular core protein assembly modulators may disrupt one or multiple steps of HBV replication, depending on their interaction with the distinct quaternary structures of core protein. The discovery of novel core protein-targeting antivirals, such as benzamide derivatives reported here, and investigation of their antiviral mechanism may lead to the identification of antiviral therapeutics for the cure of chronic hepatitis B.
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PMID:Discovery and Mechanistic Study of Benzamide Derivatives That Modulate Hepatitis B Virus Capsid Assembly. 2856 79


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