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https://www.readbyqxmd.com/read/29555628/preclinical-profile-of-ab-423-an-inhibitor-of-hepatitis-b-virus-pgrna-encapsidation
#1
Nagraj Mani, Andrew G Cole, Janet R Phelps, Andrzej Ardzinski, Kyle D Cobarrubias, Andrea Cuconati, Bruce D Dorsey, Ellen Evangelista, Kristi Fan, Fang Guo, Haitao Guo, Ju-Tao Guo, Troy O Harasym, Salam Kadhim, Steven G Kultgen, Amy C H Lee, Alice H L Li, Quanxin Long, Sara A Majeski, Richeng Mao, Kevin D McClintock, Stephen P Reid, Rene Rijnbrand, Nicholas M Snead, Holly M Micolochick Steuer, Kim Stever, Sunny Tang, Xiaohe Wang, Qiong Zhao, Michael J Sofia
AB-423 is a sulfamoylbenzamide (SBA) class of HBV capsid inhibitor in Phase 1 clinical trials. In cell culture models AB-423 showed potent inhibition of HBV replication (EC50 /EC90 = 0.08-0.27 μM/0.33-1.32 μM) with no significant cytotoxicity (CC50 >10 μM). Addition of 40% human serum resulted in a 5-fold increase in the EC50 values. AB-423 inhibited HBV genotypes A through D and nucleos/tide-resistant variants in vitro Treatment of HepDES19 cells with AB-423 resulted in capsid particles devoid of encapsidated pgRNA and rcDNA indicating it is a class II capsid inhibitor...
March 19, 2018: Antimicrobial Agents and Chemotherapy
https://www.readbyqxmd.com/read/29542854/localizing-conformational-hinges-by-nmr-where-do-hbv-core-proteins-adapt-for-capsid-assembly
#2
Lauriane Lecoq, Shishan Wang, Thomas Wiegand, Stéphane Bressanelli, Michael Nassal, Beat H Meier, Anja Böckmann
The hepatitis B virus (HBV) icosahedral nucleocapsid is assembled from 240 chemically identical core protein molecules and, structurally, comprises four groups of symmetrically nonequivalent subunits. We show here that this asymmetry is reflected in solid-state NMR spectra of the capsids in which peak splitting is observed for a subset of residues. We compare this information to dihedral angle variations from available 3D structures, and also to computational predictions of dynamic domains and molecular hinges...
March 15, 2018: Chemphyschem: a European Journal of Chemical Physics and Physical Chemistry
https://www.readbyqxmd.com/read/29500037/hepatitis-b-virus
#3
Chiaho Shih, Ching-Chun Yang, Gansukh Choijilsuren, Chih-Hsu Chang, An-Ting Liou
This infographic about hepatitis B virus explores its replication cycle, natural history of infection and pathogenesis, and how this can be controlled and treated. Hepatitis B virus (HBV) is a common worldwide blood-borne pathogen. Chronic hepatitis B can progress to an inactive carrier state, and then, in some patients, give rise to cirrhosis and cancer of the liver, leading to death. An HBV surface-antigen vaccine is effective, but treatments are currently not curative. HBV replicates via reverse transcription...
February 27, 2018: Trends in Microbiology
https://www.readbyqxmd.com/read/29491156/asymmetric-modification-of-hbv-genomes-by-an-endogenous-cytidine-deaminase-inside-hbv-cores-informs-a-model-of-reverse-transcription
#4
Smita Nair, Adam Zlotnick
Cytidine deaminases inhibit replication of broad range of DNA viruses by deaminating cytidines on single stranded DNA to generate uracil. While several lines of evidence have revealed HBV genome editing by deamination, it is still unclear which nucleic acid intermediate of HBV is modified. Hepatitis B virus has a relaxed circular double-stranded DNA (rcDNA) genome that is reverse transcribed within virus cores from a RNA template. The HBV genome also persists as covalently closed circular DNA (cccDNA) in the nucleus of an infected cell...
February 28, 2018: Journal of Virology
https://www.readbyqxmd.com/read/29447911/fluorescent-protein-tagged-hepatitis-b-virus-capsid-protein-with-long-glycine-serine-linker-that-supports-nucleocapsid-formation
#5
Jiang-Yan Chen, Chun-Yang Gan, Xue-Fei Cai, Wen-Lu Zhang, Quan-Xin Long, Xia-Fei Wei, Yuan Hu, Ni Tang, Juan Chen, Haitao Guo, Ai-Long Huang, Jie-Li Hu
Fusion core proteins of Hepatitis B virus can be used to study core protein functions or capsid trafficking. A problem in constructing fusion core proteins is functional impairment of the individual domains in these fusion proteins, might due to structural interference. We reported a method to construct fusion proteins of Hepatitis B virus core protein (HBc) in which the functions of fused domains were partially kept. This method follows two principles: (1) fuse heterogeneous proteins at the N terminus of HBc; (2) use long Glysine-serine linkers between the two domains...
February 12, 2018: Journal of Virological Methods
https://www.readbyqxmd.com/read/29427479/towards-hbv-curative-therapies
#6
REVIEW
Raymond F Schinazi, Maryam Ehteshami, Leda Bassit, Tarik Asselah
Tremendous progress has been made over the last 2 decades to discover and develop approaches to control hepatitis B virus (HBV) infections and to prevent the development of hepatocellular carcinoma using various interferons and small molecules as antiviral agents. However, none of these agents have significant impact on eliminating HBV from infected cells. Currently the emphasis is on silencing or eliminating cccDNA, which could lead to a cure for HBV. Various approaches are being developed including the development of capsid effectors, CRISPR/Cas9, TALENS, siRNA, entry and secretion inhibitors, as well as immunological approaches...
February 2018: Liver International: Official Journal of the International Association for the Study of the Liver
https://www.readbyqxmd.com/read/29381358/3-r-4-r-6-2-bromo-4-fluorophenyl-5-ethoxycarbonyl-2-thiazol-2-yl-3-6-dihydropyrimidin-4-yl-methyl-morpholin-2-yl-propanoic-acid-hec72702-a-novel-hepatitis-b-virus-capsid-inhibitor-based-on-clinical-candidate-gls4
#7
Qingyun Ren, Xinchang Liu, Guanghua Yan, Biao Nie, Zhifu Zou, Jing Li, Yunfu Chen, Yu Wei, Jianzhou Huang, Zhonghua Luo, Baohua Gu, Siegfried Goldmann, Jiancun Zhang, Yingjun Zhang
The inhibition of hepatitis B virus (HBV) capsid assembly is a novel strategy for the development of chronic hepatitis B (CHB) therapeutics. On the basis of the preclinical properties and clinical results of GLS4, we carried out further investigation to seek a better candidate compound with appropriate anti-HBV potency, reduced hERG activity, decreased CYP enzyme induction, and improved pharmacokinetic (PK) properties. To this end, we have successfully found that morpholine carboxyl analogues with comparable anti-HBV activities to that of GLS4 showed decreased hERG activities, but they displayed strong CYP3A4 induction in a concentration-dependent manner, except for morpholine propionic acid analogues...
January 30, 2018: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/29377794/hepatitis-b-virus-core-protein-allosteric-modulators-can-distort-and-disrupt-intact-capsids
#8
Christopher John Schlicksup, Joseph Che-Yen Wang, Samson Francis, Balasubramanian Venkatakrishnan, William W Turner, Michael VanNieuwenhze, Adam Zlotnick
Defining mechanisms of direct-acting antivirals facilitates drug development and our understanding of virus function. Heteroaryldihydropyrimidines (HAPs) inappropriately activate assembly of hepatitis B virus (HBV) core protein (Cp), suppressing formation of virions. We examined a fluorophore-labeled HAP, HAP-TAMRA. HAP-TAMRA induced Cp assembly and also bound pre-assembled capsids. Kinetic and spectroscopic studies imply that HAP-binding sites are usually not available but are bound cooperatively. Using cryo-EM, we observed that HAP-TAMRA asymmetrically deformed capsids, creating a heterogeneous array of sharp angles, flat regions, and outright breaks...
January 29, 2018: ELife
https://www.readbyqxmd.com/read/29353039/withdrawn-cetylpyridinium-chloride-as-a-novel-inhibitor-of-hepatitis-b-viral-capsid-assembly
#9
Hyun Wook Seo, Joon Pyung Seo, Yoon Jun Kim, Guhung Jung
This article has been withdrawn at the request of the author(s) and/or editor. The Publisher apologizes for any inconvenience this may cause. The full Elsevier Policy on Article Withdrawal can be found at https://www.elsevier.com/about/our-business/policies/article-withdrawal.
January 17, 2018: Biochemical and Biophysical Research Communications
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
#10
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...
January 2018: Antiviral Research
https://www.readbyqxmd.com/read/29125756/hepatitis-b-virus-capsid-completion-occurs-through-error-correction
#11
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 22, 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
#12
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 the nucleus by reverse 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 a major target for T cell-mediated immune responses. We investigated the mechanism of cytoplasmic capsid transport, which is important for infection but also for cytosolic capsid removal...
March 2018: 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
#13
Klaus Klumpp, Takashi Shimada, Lena Allweiss, Tassilo Volz, Marc Lütgehetmann, George 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 antiviral 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 hepatitis B virus (HBV) genotype C preparation; we waited 8 weeks for persistent infection of the human hepatocytes in livers of mice...
February 2018: Gastroenterology
https://www.readbyqxmd.com/read/28947946/design-synthesis-and-evaluation-of-tetrahydropyrrolo-1-2-c-pyrimidines-as-capsid-assembly-inhibitors-for-hbv-treatment
#14
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
#15
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
#16
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
#17
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
#18
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
#19
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
#20
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
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