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HBV core protein

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https://www.readbyqxmd.com/read/28827084/inhibitory-effects-of-metachromin-a-on-hepatitis-b-virus-production-via-impairment-of-the-viral-promoter-activity
#1
Atsuya Yamashita, Mayumi Tamaki, Hirotake Kasai, Tomohisa Tanaka, Teruhime Otoguro, Akihide Ryo, Shinya Maekawa, Nobuyuki Enomoto, Nicole J de Voogd, Junichi Tanaka, Kohji Moriishi
The currently available antiviral agents for chronic infection with hepatitis B virus (HBV) are pegylated interferon-α and nucleoside/nucleotide analogues, although it has been difficult to completely eliminate covalently closed circular DNA (cccDNA) from patients. To identify an antiviral compound targeting HBV core promoter, 15 terpenes originating from marine organisms were screened using a cell line expressing firefly luciferase under the control of the HBV core promoter. Metachromin A, which is a merosesquiterpene isolated from the marine sponge Dactylospongia metachromia, inhibited the viral promoter activity at the highest level among the tested compounds, and suppressed HBV production with an EC50 value of 0...
August 4, 2017: Antiviral Research
https://www.readbyqxmd.com/read/28795465/a-molecular-breadboard-removal-and-replacement-of-subunits-in-an-hepatitis-b-virus-capsid
#2
Lye Siang Lee, Nicholas Brunk, Daniel G Haywood, David Keifer, Elizabeth Pierson, Panagiotis Kondylis, Joseph Che-Yen Wang, Stephen C Jacobson, Martin F Jarrold, Adam Zlotnick
Hepatitis B virus (HBV) core protein is a model system for studying assembly and disassembly of icosahedral structures. Controlling disassembly will allow re-engineering the 120 subunit HBV capsid, making it a molecular breadboard. We examined removal of subunits from partially crosslinked capsids to form stable incomplete particles. To characterize incomplete capsids, we used two single molecule techniques, resistive-pulse sensing and charge detection mass spectrometry. We expected to find a binomial distribution of capsid fragments...
August 10, 2017: Protein Science: a Publication of the Protein Society
https://www.readbyqxmd.com/read/28792701/predictive-value-of-hepatitis-b-core-related-antigen-hbcrag-during-the-natural-history-of-hepatitis-b-virus-infection
#3
Yu Gou, Yanhua Zhao, Chenli Rao, Shu Feng, Tingting Wang, Dongdong Li, Chuanmin Tao
BACKGROUND: The natural history of HBV infection includes immune tolerance (IT), immune clearance (IC), HBeAg-negative inactive/quiescent carrier (ENQ), and HBeAg-negative hepatitis (ENH) phases. As the current biomarkers for discriminating the four phases still have some weaknesses, additional serological indicators are needed. Hepatitis B core-related antigen (HBcrAg) encoded with the precore/core gene contains denatured HBeAg, HBV core antigen (HBcAg), and a 22-KDa precore protein (p22cr) and has been demonstrated to have a close association with the natural history of hepatitis B infection...
July 1, 2017: Clinical Laboratory
https://www.readbyqxmd.com/read/28768874/pgc1%C3%AE-transcriptional-adaptor-function-governs-hepatitis-b-virus-replication-by-controlling-hbcag-p21-protein-mediated-capsid-formation
#4
Rasha E Shalaby, Saira Iram, Bülent Çakal, Claudia E Oropeza, Alan McLachlan
In the human hepatoma cell line, Huh7, co-expression of the coactivators, peroxisome proliferator-activated receptor gamma coactivator 1α (PGC1α), cAMP responsive element binding protein binding protein (CBP), steroid receptor coactivator 1 (SRC1) and protein arginine methyltransferase 1 (PRMT1) only modestly increase HBV biosynthesis. However, utilizing the human embryonic kidney cell line, HEK293T, it was possible to demonstrate that PGC1α alone can support viral biosynthesis independently of additional coactivator or transcription factor expression...
August 2, 2017: Journal of Virology
https://www.readbyqxmd.com/read/28736196/serological-and-molecular-epidemiological-outcomes-after-two-decades-of-universal-infant-hepatitis-b-virus-hbv-vaccination-in-nunavut-canada
#5
Chris Huynh, Gerald Y Minuk, Julia Uhanova, Maureen Baikie, Thomas Wong, Carla Osiowy
Chronic hepatitis B virus (HBV) infection within the Canadian Arctic is considered endemic (>2% prevalence). Within the Arctic region of Nunavut, a vaccination program targeted at newborn infants was initiated approximately 20years ago, along with interim grade school catch-up programs, with the result that individuals born after 1980 are presumed vaccinated. This study investigates the effectiveness of these programs and is the first seroepidemiological survey to determine HBV prevalence in Nunavut in the post-vaccination era...
August 16, 2017: Vaccine
https://www.readbyqxmd.com/read/28686707/molecular-characterization-of-occult-hepatitis-b-virus-infection-in-patients-with-end-stage-liver-disease-in-colombia
#6
Julio Cesar Rendon, Fabian Cortes-Mancera, Juan Carlos Restrepo-Gutierrez, Sergio Hoyos, Maria-Cristina Navas
BACKGROUND: Hepatitis B virus (HBV) occult infection (OBI) is a risk factor to be taken into account in transfusion, hemodialysis and organ transplantation. The aim of this study was to identify and characterize at the molecular level OBI cases in patients with end-stage liver disease. METHODS: Sixty-six liver samples were obtained from patients with diagnosis of end-stage liver disease submitted to liver transplantation in Medellin (North West, Colombia). Samples obtained from patients who were negative for the surface antigen of HBV (n = 50) were tested for viral DNA detection by nested PCR for ORFs S, C, and X and confirmed by Southern-Blot...
2017: PloS One
https://www.readbyqxmd.com/read/28678685/expression-of-wild-type-or-g1862t-mutant-hbe-antigen-of-subgenotype-a1-of-hepatitis-b-virus-and-the-unfolded-protein-response-in-huh7-cells
#7
Nimisha Harshadrai Bhoola, Anna Kramvis
The G1862T mutation, which occurs most frequently in subgenotype A1 of the hepatitis B virus (HBV), results in a valine to phenylalanine substitution at the -3 position of the signal peptide cleavage site at the amino end of the precore/core (preC/C) precursor protein. The objective of this study was to functionally characterize the G1862T mutation relative to its wild-type counterpart in subgenotype A1. Huh7 cells were transfected with subgenotype A1 replication-competent plasmids, with and without G1862T...
June 2017: Journal of General Virology
https://www.readbyqxmd.com/read/28647474/antiviral-profiling-of-the-capsid-assembly-modulator-bay41-4109-on-full-length-hbv-genotype-a-h-clinical-isolates-and-core-site-directed-mutants-in%C3%A2-vitro
#8
Jan Martin Berke, Ying Tan, Thierry Verbinnen, Pascale Dehertogh, Karen Vergauwen, Ann Vos, Oliver Lenz, Frederik Pauwels
The HBV core protein represents an attractive target for new antiviral therapies due to its multiple functions within the viral life-cycle. Here, we report the antiviral activity of the capsid assembly modulator (CAM) BAY41-4109 and two nucleos(t)ide analogues (NAs) on a diverse panel of 54 HBV clinical isolates from genotype (GT) A-H and assessed the impact of core amino acid (aa) substitutions using site-directed mutants (SDMs). The median EC50 values of BAY41-4109 across genotypes ranged from 26 nM in GT G to 215 nM in GT F irrespective of the presence of NA resistance mutations compared to 43 nM for the GT D reference construct...
June 21, 2017: Antiviral Research
https://www.readbyqxmd.com/read/28635671/rab33b-controls-hepatitis-b-virus-assembly-by-regulating-core-membrane-association-and-nucleocapsid-processing
#9
Christina Bartusch, Tatjana Döring, Reinhild Prange
Many viruses take advantage of cellular trafficking machineries to assemble and release new infectious particles. Using RNA interference (RNAi), we demonstrate that the Golgi/autophagosome-associated Rab33B is required for hepatitis B virus (HBV) propagation in hepatoma cell lines. While Rab33B is dispensable for the secretion of HBV subviral envelope particles, its knockdown reduced the virus yield to 20% and inhibited nucleocapsid (NC) formation and/or NC trafficking. The overexpression of a GDP-restricted Rab33B mutant phenocopied the effect of deficit Rab33B, indicating that Rab33B-specific effector proteins may be involved...
June 21, 2017: Viruses
https://www.readbyqxmd.com/read/28628133/hbv-rna-pre-genome-encodes-specific-motifs-that-mediate-interactions-with-the-viral-core-protein-that-promote-nucleocapsid-assembly
#10
Nikesh Patel, Simon J White, Rebecca F Thompson, Richard Bingham, Eva U Weiß, Daniel P Maskell, Adam Zlotnick, Eric Dykeman, Roman Tuma, Reidun Twarock, Neil A Ranson, Peter G Stockley
Formation of the hepatitis B virus nucleocapsid is an essential step in the viral lifecycle, but its assembly is not fully understood. We report the discovery of sequence-specific interactions between the viral pre-genome and the hepatitis B core protein that play roles in defining the nucleocapsid assembly pathway. Using RNA SELEX and bioinformatics, we identified multiple regions in the pre-genomic RNA with high affinity for core protein dimers. These RNAs form stem-loops with a conserved loop motif that trigger sequence-specific assembly of virus-like particles (VLPs) at much higher fidelity and yield than in the absence of RNA...
June 19, 2017: Nature Microbiology
https://www.readbyqxmd.com/read/28611266/retinoid-x-receptor-%C3%AE-dependent-hbv-minichromosome-remodeling-and-viral-replication
#11
Yan Zhang, Song He, Jin-Jun Guo, Hong Peng, Jia-Hao Fan, Qing-Ling Li
BACKGROUND AND AIM: The HBV covalently closed circular DNA (cccDNA) is organized into a minichromosome in the nuclei of infected hepatocytes through interactions with histone and nonhistone proteins. Retinoid X receptor α (RXRα), a liver-enriched nuclear receptor, participates in regulation of HBV replication and transcription through modulation of HBV enhancer 1 and core promoter activity. MATERIAL AND METHODS: This study investigated RXRα involvement in HBV cccDNA epigenetic modifications...
August 1, 2017: Annals of Hepatology
https://www.readbyqxmd.com/read/28584639/the-evaluation-of-fibrotic-effects-of-the-hepatitis-b-virus-pre-core-in-hepatic-stellate-cells
#12
Seyed Younes Hosseini, Kazem Baesi, Negar Azarpira, Ameneh Pakneiat, Seyedeh Akram Hosseini
The role of the hepatitis B virus (HBV) endogenous pre-core protein in liver fibrosis is controversial. Whether the expression of the pre-core induces the activation of human stellate cells (HSCs) has not yet been reported. Plasmids expressing HBx, or pre-core protein were transfected into LX-2 cells. Subsequently, total RNA extracted and reverse transcription-quantitative polymerase chain reaction was performed to measure the fold change of collagen type I, α1 chain, α-smooth muscle actin and TIMP metalloproteinase inhibitor-1...
June 2017: Biomedical Reports
https://www.readbyqxmd.com/read/28584155/capsid-assembly-modulators-have-a-dual-mechanism-of-action-in-primary-human-hepatocytes-infected-with-hepatitis-b-virus
#13
Jan Martin Berke, Pascale Dehertogh, Karen Vergauwen, Ellen Van Damme, Wendy Mostmans, Koen Vandyck, Frederik Pauwels
Hepatitis B virus (HBV) capsid assembly is a critical step in the propagation of the virus and is mediated by the core protein. Due to its multiple functions in the viral life cycle, core became an attractive target for new antiviral therapies. Capsid assembly modulators (CAMs) accelerate the kinetics of capsid assembly and prevent encapsidation of the polymerase-pregenomic RNA (Pol-pgRNA) complex, thereby blocking viral replication. CAM JNJ-632 is a novel and potent inhibitor of HBV replication in vitro across genotypes A to D...
August 2017: Antimicrobial Agents and Chemotherapy
https://www.readbyqxmd.com/read/28584057/an-rnai-based-high-throughput-screening-assay-to-identify-small-molecule-inhibitors-of-hepatitis-b-virus-replication
#14
Subhanita Ghosh, Abhinav Kaushik, Sachin Khurana, Aditi Varshney, Avishek Kumar Singh, Pradeep Dahiya, Jitendra K Thakur, Shiv Kumar Sarin, Dinesh Gupta, Pawan Malhotra, Sunil K Mukherjee, Raj K Bhatnagar
Persistent or chronic infection with the hepatitis B virus (HBV) represents one of the most common viral diseases in humans. The hepatitis B virus deploys the hepatitis B virus X protein (HBx) as a suppressor of host defenses consisting of RNAi-based silencing of viral genes. Because of its critical role in countering host defenses, HBx represents an attractive target for antiviral drugs. Here, we developed and optimized a loss-of-function screening procedure, which identified a potential pharmacophore that abrogated HBx RNAi suppression activity...
July 28, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28566379/discovery-and-mechanistic-study-of-benzamide-derivatives-that-modulate-hepatitis-b-virus-capsid-assembly
#15
Shuo Wu, Qiong Zhao, Pinghu Zhang, John Kulp, Lydia Hu, Nicky Hwang, Jiming Zhang, Timothy M Block, Xiaodong Xu, Yanming Du, Jinhong Chang, Ju-Tao Guo
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...
August 15, 2017: Journal of Virology
https://www.readbyqxmd.com/read/28559265/hepatitis-b-virus-capsid-assembly-modulators-but-not-nucleoside-analogs-inhibit-the-production-of-extracellular-pregenomic-rna-and-spliced-rna-variants
#16
Angela M Lam, Suping Ren, Christine Espiritu, Mollie Kelly, Vincent Lau, Lingjie Zheng, George D Hartman, Osvaldo A Flores, Klaus Klumpp
The hepatitis B virus (HBV) core protein serves multiple essential functions in the viral life cycle, and antiviral agents that target the core protein are being developed. Capsid assembly modulators (CAMs) are compounds that target core and misdirect capsid assembly, resulting in the suppression of HBV replication and virion production. Besides HBV DNA, circulating HBV RNA has been detected in patient serum and can be associated with the treatment response. Here we studied the effect of HBV CAMs on the production of extracellular HBV RNA using infected HepaRG cells and primary human hepatocytes...
August 2017: Antimicrobial Agents and Chemotherapy
https://www.readbyqxmd.com/read/28499864/role-of-hepatitis-b-core-protein-in-hbv-transcription-and-recruitment-of-histone-acetyltransferases-to-cccdna-minichromosome
#17
Chun Kong Chong, Ching Yan Serene Cheng, Sin Yi Jasmine Tsoi, Fung-Yu Huang, Fen Liu, Wai-Kay Seto, Ching-Lung Lai, Man-Fung Yuen, Danny Ka-Ho Wong
The hepatitis B core protein (HBc) has been suggested to interact with covalently closed circular DNA (cccDNA) and regulate hepatitis B virus (HBV) transcription. However, direct evidence is lacking. We aimed to identify the specific HBc region(s) responsible for transcription regulation and its interaction with cccDNA. Seventeen mutants with mutations at the four arginine-rich clusters of the HBc carboxyl-terminal domain (CTD) were created. The effect of HBc mutations on the levels of HBV DNA, RNA, and hepatitis B surface antigen (HBsAg) were measured...
May 10, 2017: Antiviral Research
https://www.readbyqxmd.com/read/28469174/allosteric-conformational-changes-of-human-hbv-core-protein-transform-its-assembly
#18
Chuang Liu, Guizhen Fan, Zhao Wang, Hong-Song Chen, Chang-Cheng Yin
Hepatitis B Virus core protein (HBc) has multiple roles in the viral lifecycle: viral assembly, compartment for reverse transcription, intracellular trafficking, and nuclear functions. HBc displays assembly polymorphism - it can assemble into icosahedral capsid and aberrant non-capsid structures. It has been hypothesized that the assembly polymorphism is due to allosteric conformational changes of HBc dimer, the smallest assembly unit, however, the mechanism governing the polymorphic assembly of the HBc dimer is still elusive...
May 3, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28445592/polo-like-kinase-1-is-a-proviral-host-factor-for-hepatitis-b-virus-replication
#19
Ahmed M Diab, Adrien Foca, Floriane Fusil, Thomas Lahlali, Pascal Jalaguier, Fouzia Amirache, Lia N'Guyen, Nathalie Isorce, François-Loïc Cosset, Fabien Zoulim, Ourania M Andrisani, David Durantel
Chronic Hepatitis B Virus (HBV) infection is a major risk factor for hepatocellular carcinoma (HCC) and current treatments for CHB and HCC are perfectible. Herein, we identified cellular Serine/Threonine Polo-like-kinase 1 (PLK1) as a positive effector of HBV replication. The aim of this study was to demonstrate the proviral role of PLK1 in HBV biosynthesis and validate PLK1 inhibition a potential antiviral strategy. To this end, we employed physiologically relevant HBV infection models of Primary Human Hepatocytes (PHH) and differentiated HepaRG cells, in conjunction with pharmacologic PLK1 inhibitors, siRNA-mediated knockdown, and overexpression of constitutively active PLK1 (PLK1(CA) )...
April 26, 2017: Hepatology: Official Journal of the American Association for the Study of Liver Diseases
https://www.readbyqxmd.com/read/28401569/influences-on-viral-replication-and-sensitivity-to-gls4-a-hap-compound-of-naturally-occurring-t109-v124-mutations-in-hepatitis-b-virus-core-protein
#20
Jianghua Wang, Haiying Zhang, Yingjun Zhang, Dong Jiang, Jing Li, Siegfried Goldmann, Qingyun Ren, Ran Fei, Xueyan Wang, Lai Wei
Heteroaryldihydropyrimidine (HAP) compounds inhibit HBV replication by binding to a hydrophobic pocket at the interface between hepatitis B virus core protein (HBcAg) dimer, which interrupts capsid assembly by changing the kinetics and thermodynamics during this process. Structure biological studies have identified several amino acids in HBcAg crucial for compound binding. Here, we investigated the polymorphisms of T109 and V124 amino acids in HBV sequences submitted to GenBank database. Naturally occurring T109 and V124 and/or possible compensatory mutations in neighbored amino acids were introduced into HBV-expressing plasmids...
April 12, 2017: Journal of Medical Virology
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