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https://www.readbyqxmd.com/read/29183719/the-diverse-functions-of-the-hepatitis-b-core-capsid-protein-hbc-in-the-viral-life-cycle-implications-for-the-development-of-hbc-targeting-antivirals
#1
REVIEW
Ahmed Diab, Adrien Foca, Fabien Zoulim, David Durantel, Ourania Andrisani
Virally encoded proteins have evolved to perform multiple functions, and the core protein (HBc) of the hepatitis B virus (HBV) is a perfect example. While HBc is the structural component of the viral nucleocapsid, additional novel functions for the nucleus-localized HBc have recently been described. These results extend for HBc, beyond its structural role, a regulatory function in the viral life cycle and potentially a role in pathogenesis. In this article, we review the diverse roles of HBc in HBV replication and pathogenesis, emphasizing how the unique structure of this protein is key to its various functions...
November 25, 2017: Antiviral Research
https://www.readbyqxmd.com/read/29125756/hepatitis-b-virus-capsid-completion-occurs-through-error-correction
#2
Corinne A Lutomski, Nicholas A Lyktey, Zhongchao Zhao, Elizabeth E Pierson, Adam Zlotnick, Martin F Jarrold
Understanding capsid assembly is important because of its role in virus lifecycles and in applications to drug discovery and nanomaterial development. Many virus capsids are icosahedral, and assembly is thought to occur by the sequential addition of capsid protein subunits to a nucleus, with the final step completing the icosahedron. Almost nothing is known about the final (completion) step because the techniques usually used to study capsid assembly lack the resolution. In this work, charge detection mass spectrometry (CDMS) has been used to track the assembly of the T = 4 hepatitis B virus (HBV) capsid in real time...
November 10, 2017: Journal of the American Chemical Society
https://www.readbyqxmd.com/read/29113909/the-chaperone-dynein-ll1-mediates-cytoplasmic-transport-of-empty-and-mature-hepatitis-b-virus-capsids
#3
Quentin Osseman, Lara Gallucci, Shelly Au, Christian Cazenave, Elodie Berdance, Marie-Lise Blondot, Aurélia Cassany, Dominique Bégu, Jessica Ragues, Cindy Aknin, Irina Sominskaya, Andris Dishlers, Birgit Rabe, Fenja Anderson, Nelly Panté, Michael Kann
BACKGROUND & AIMS: Hepatitis B virus (HBV) has a DNA genome but replicates within nucleus by transcription of an RNA pregenome, which is converted to DNA in cytoplasmic capsids. Capsids in this compartment are correlated with inflammation and epitopes of the capsid protein core (Cp) are the main target for T cell-mediated immune response. We investigated the mechanism of cytoplasmic capsid transport, which is important for infection but also for cytosolic capsid removal. METHODS: We used virion-derived capsids with a mature rcDNA (matC), empty capsids (empC), and RNA containing capsids (rnaC) as control...
November 4, 2017: Journal of Hepatology
https://www.readbyqxmd.com/read/29079518/efficacy-of-nvr-3-778-alone-and-in-combination-with-pegylated-interferon-vs-entecavir-in-upa-scid-mice-with-humanized-livers-and-hbv-infection
#4
Klaus Klumpp, Takashi Shimada, Lena Allweiss, Tassilo Volz, Marc Lütgehetmann, G Hartman, Osvaldo A Flores, Angela M Lam, Maura Dandri
BACKGROUND & AIMS: NVR3-778 is a capsid assembly modulator in clinical development. We determined the in vivo anti-viral efficacy and effects on innate and endoplasmic reticulum (ER) stress responses of NVR3-778 alone or in combination with pegylated interferon alpha (peg-IFN) and compared with entecavir. METHODS: We performed 2 studies, with a total of 61 uPA/SCID mice with humanized livers. Mice were infected with a HBV genotype C preparation; we waited 8 weeks for persistent infection of the human hepatocytes in livers of mice...
October 24, 2017: Gastroenterology
https://www.readbyqxmd.com/read/28947946/design-synthesis-and-evaluation-of-tetrahydropyrrolo-1-2-c-pyrimidines-as-capsid-assembly-inhibitors-for-hbv-treatment
#5
Xiaolin Li, Kai Zhou, Haiying He, Qiong Zhou, Ya Sun, Lijuan Hou, Liang Shen, Xiaofei Wang, Yuedong Zhou, Zhen Gong, Shibo He, Huangtao Jin, Zhengxian Gu, Shuyong Zhao, Long Zhang, Chunyan Sun, Shansong Zheng, Zhe Cheng, Yidong Zhu, Minghui Zhang, Jian Li, Shuhui Chen
The discovery of novel tetrahydropyrrolo[1,2-c]pyrimidines derivatives from Bay41_4109 as hepatitis B virus (HBV) inhibitors is herein reported. The structure-activity relationship optimization led to one highly efficacious compound 28a (IC50 = 10 nM) with good PK profiles and the favorite L/P ratio. The hydrodynamic injection model in mice clearly demonstrated the efficacy of 28a against HBV replication.
September 14, 2017: ACS Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28945802/hbv-core-protein-allosteric-modulators-differentially-alter-cccdna-biosynthesis-from-de-novo-infection-and-intracellular-amplification-pathways
#6
Fang Guo, Qiong Zhao, Muhammad Sheraz, Junjun Cheng, Yonghe Qi, Qing Su, Andrea Cuconati, Lai Wei, Yanming Du, Wenhui Li, Jinhong Chang, Ju-Tao Guo
Hepatitis B virus (HBV) core protein assembles viral pre-genomic (pg) RNA and DNA polymerase into nucleocapsids for reverse transcriptional DNA replication to take place. Several chemotypes of small molecules, including heteroaryldihydropyrimidines (HAPs) and sulfamoylbenzamides (SBAs), have been discovered to allosterically modulate core protein structure and consequentially alter the kinetics and pathway of core protein assembly, resulting in formation of irregularly-shaped core protein aggregates or "empty" capsids devoid of pre-genomic RNA and viral DNA polymerase...
September 2017: PLoS Pathogens
https://www.readbyqxmd.com/read/28893935/tumour-virus-vaccines-hepatitis-b-virus-and-human-papillomavirus
#7
REVIEW
Margaret Stanley
Two of the most important human oncogenic viruses are hepatitis B virus (HBV) and human papillomavirus (HPV). HBV infection has been preventable by vaccination since 1982; vaccination of neonates and infants is highly effective, resulting already in decreased rates of new infections, chronic liver disease and hepato-cellular carcinoma. Nonetheless, HBV remains a global public health problem with high rates of vertical transmission from mother to child in some regions. Prophylactic HPV vaccines composed of virus-like particles (VLPs) of the L1 capsid protein have been licensed since 2006/2007...
October 19, 2017: Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences
https://www.readbyqxmd.com/read/28878350/functional-association-of-cellular-microtubules-with-viral-capsid-assembly-supports-efficient-hepatitis-b-virus-replication
#8
Masashi Iwamoto, Dawei Cai, Masaya Sugiyama, Ryosuke Suzuki, Hideki Aizaki, Akihide Ryo, Naoko Ohtani, Yasuhito Tanaka, Masashi Mizokami, Takaji Wakita, Haitao Guo, Koichi Watashi
Viruses exploit host factors and environment for their efficient replication. The virus-host interaction mechanisms for achieving an optimal hepatitis B virus (HBV) replication have been largely unknown. Here, a single cell cloning revealed that HepAD38 cells, a widely-used HBV-inducible cell line, contain cell clones with diverse permissiveness to HBV replication. The HBV permissiveness was impaired upon treatment with microtubule inhibitor nocodazole, which was identified as an HBV replication inhibitor from a pharmacological screening...
September 6, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28842495/chimeric-rabbit-human-fab-antibodies-against-the-hepatitis-be-antigen-and-their-potential-applications-in-assays-characterization-and-therapy
#9
Xiaolei Zhuang, Norman R Watts, Ira W Palmer, Joshua D Kaufman, Altaira D Dearborn, Joni L Trenbeath, Elif Eren, Alasdair C Steven, Christoph Rader, Paul T Wingfield
Hepatitis B virus (HBV) infection afflicts millions worldwide, causing cirrhosis and liver cancer. HBV e-antigen (HBeAg), a clinical marker for disease severity, is a soluble variant of the viral capsid protein. HBeAg is not required for viral replication but is implicated in establishing immune tolerance and chronic infection. The structure of recombinant e-antigen (rHBeAg) was recently determined, yet to date, the exact nature and quantitation of HBeAg still remain uncertain. Here, to further characterize HBeAg, we used phage display to produce a panel of chimeric rabbit/human monoclonal antibody fragments (both Fab and scFv) against rHBeAg...
October 6, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28795465/a-molecular-breadboard-removal-and-replacement-of-subunits-in-a-hepatitis-b-virus-capsid
#10
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...
November 2017: Protein Science: a Publication of the Protein Society
https://www.readbyqxmd.com/read/28774415/new-treatments-to-reach-functional-cure-virological-approaches
#11
REVIEW
David Durantel
Current therapies of chronic hepatitis B (CHB) remain limited to pegylated-interferon-alpha (pegIFN-α) or any of the five approved nucleos(t)ide analogues (NA). If viral suppression can be achieved in the majority of patients with the high-barrier-to-resistance new-generation of NA, i.e. entecavir and tenofovir, HBsAg loss is achieved by PEG-IFN-α and/or NA in only 10% of patients, after a 5-year follow-up. Attempts to improve the response by administering two different NA or a combination of NA and PEG-IFN-α have not provided a dramatic increase in the rate of "functional cure"...
June 2017: Best Practice & Research. Clinical Gastroenterology
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
#12
Rasha E Shalaby, Saira Iram, Bülent Çakal, Claudia E Oropeza, Alan McLachlan
In the human hepatoma cell line Huh7, the coexpression of the coactivators peroxisome proliferator-activated receptor γ coactivator 1α (PGC1α), cyclic AMP-responsive element binding protein binding protein (CBP), steroid receptor coactivator 1 (SRC1), and protein arginine methyltransferase 1 (PRMT1) only modestly increase hepatitis B virus (HBV) biosynthesis. However, by utilizing the human embryonic kidney cell line HEK293T, it was possible to demonstrate that PGC1α alone can support viral biosynthesis independently of the expression of additional coactivators or transcription factors...
October 15, 2017: Journal of Virology
https://www.readbyqxmd.com/read/28688280/synthesis-of-sulfamoylbenzamide-derivatives-as-hbv-capsid-assembly-effector
#13
Ozkan Sari, Sebastien Boucle, Bryan D Cox, Tugba Ozturk, Olivia Ollinger Russell, Leda Bassit, Franck Amblard, Raymond F Schinazi
The synthesis of novel series of sulfamoylbenzamides as HBV capsid assembly effector is reported. The structure was divided into five parts which were independently modified as part of our lead optimization. All synthesized compounds were evaluated for their anti-HBV activity and toxicity in human hepatocytes, lymphocytes and other cells. Additionally, we assessed their effect on HBV cccDNA formation in an HBeAg reporter cell-based assay. Among the 27 compounds reported, several analogs exhibited submicromolar activities and significant reduction of HBeAg secretion...
September 29, 2017: European Journal of Medicinal Chemistry
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
#14
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/28584155/capsid-assembly-modulators-have-a-dual-mechanism-of-action-in-primary-human-hepatocytes-infected-with-hepatitis-b-virus
#15
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/28566379/discovery-and-mechanistic-study-of-benzamide-derivatives-that-modulate-hepatitis-b-virus-capsid-assembly
#16
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
#17
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/28521532/new-antivirals-for-the-treatment-of-chronic-hepatitis-b
#18
REVIEW
Vincent Soriano, Pablo Barreiro, Laura Benitez, Jose M Peña, Carmen de Mendoza
Current treatment with oral nucleos(t)ides entecavir or tenofovir provide sustained suppression of HBV replication and clinical benefit in most chronic hepatitis B virus (HBV) infected persons. However, HBV rebound generally occurs upon drug discontinuation due to persistence of genomic HBV reservoirs as episomic cccDNA and chromosomic integrated HBV-DNA. There is renewed enthusiasm on HBV drug discovery following recent successes with antivirals for hepatitis C and immunotherapies for some cancers. Areas covered: New drugs that target distinct steps of the HBV life cycle are been developed, including inhibitors of viral entry, new polymerase inhibitors, capsid and assembly inhibitors, virus release blockers, and disruptors of cccDNA formation and transcription...
July 2017: Expert Opinion on Investigational Drugs
https://www.readbyqxmd.com/read/28492809/serum-microrna-30c-levels-are-correlated-with-disease-progression-in-xinjiang-uygur-patients-with-chronic-hepatitis-b
#19
J Zhang, J Ma, H Wang, L Guo, J Li
We aimed to investigate the potential role and mechanism of microRNA-30c (miR-30c) in the pathological development of chronic hepatitis B (CHB). The serum levels of miR-30c in hepatitis B virus (HBV) carrier Xinjiang Uygur patients with inactive, low-replicative, high-replicative and HBe antigen-positive CHB were investigated. HepG2 cells were co-transfected with pHBV1.3 and miR-30c mimic or inhibitor or scramble RNA. The effects of miR-30c dysregulation on HBV replication and gene expression, cell proliferation and cell cycle were then investigated...
May 4, 2017: Brazilian Journal of Medical and Biological Research, Revista Brasileira de Pesquisas Médicas e Biológicas
https://www.readbyqxmd.com/read/28469174/allosteric-conformational-changes-of-human-hbv-core-protein-transform-its-assembly
#20
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
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