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https://www.readbyqxmd.com/read/27908829/exploring-the-binding-mechanism-of-heteroaryldihydropyrimidines-and-hepatitis-b-virus-capsid-combined-3d-qsar-and-molecular-dynamics
#1
Jing Tu, Jiao Jiao Li, Zhi Jie Shan, Hong Lin Zhai
The non-nucleoside drugs have been developed to treat HBV infection owing to their increased efficacy and lesser side effects, in which heteroaryldihydropyrimidines (HAPs) have been identified as effective inhibitors of HBV capsid. In this paper, the binding mechanism of HAPs targeting on HBV capsid protein was explored through three-dimensional quantitative structure-activity relationship, molecular dynamics and binding free energy decompositions. The obtained models of comparative molecular field analysis and comparative molecular similarity indices analysis enable the sufficient interpretation of structure-activity relationship of HAPs-HBV...
November 28, 2016: Antiviral Research
https://www.readbyqxmd.com/read/27783675/dna-polymerase-%C3%AE%C2%BA-is-a-key-cellular-factor-for-the-formation-of-covalently-closed-circular-dna-of-hepatitis-b-virus
#2
Yonghe Qi, Zhenchao Gao, Guangwei Xu, Bo Peng, Chenxuan Liu, Huan Yan, Qiyan Yao, Guoliang Sun, Yang Liu, Dingbin Tang, Zilin Song, Wenhui He, Yinyan Sun, Ju-Tao Guo, Wenhui Li
Hepatitis B virus (HBV) infection of hepatocytes begins by binding to its cellular receptor sodium taurocholate cotransporting polypeptide (NTCP), followed by the internalization of viral nucleocapsid into the cytoplasm. The viral relaxed circular (rc) DNA genome in nucleocapsid is transported into the nucleus and converted into covalently closed circular (ccc) DNA to serve as a viral persistence reservoir that is refractory to current antiviral therapies. Host DNA repair enzymes have been speculated to catalyze the conversion of rcDNA to cccDNA, however, the DNA polymerase(s) that fills the gap in the plus strand of rcDNA remains to be determined...
October 2016: PLoS Pathogens
https://www.readbyqxmd.com/read/27761438/treatment-for-hepatitis-b-in-patients-with-drug-resistance
#3
Frank Tacke, Daniela C Kroy
Persistent hepatitis B virus (HBV) infections affect about 240 million patients worldwide that are at risk of developing liver cirrhosis or hepatocellular carcinoma. HBV is a small, partially double stranded DNA virus with four overlapping genes and a unique life cycle, which involves the generation of an RNA template for replication via reverse transcription. Mutations occur frequently during chronic infection, and particular selection pressures select distinct mutants. Nucleoside and nucleotide analogues like lamivudine (LMV), entecavir (ETV), telbivudine (LdT), adefovir dipivoxil (ADV) and tenofovir (TDF) are used to achieve long-term suppression of viral replication...
September 2016: Annals of Translational Medicine
https://www.readbyqxmd.com/read/27734898/microrna-mir-204-and-mir-1236-inhibit-hepatitis-b-virus-replication-via-two-different-mechanisms
#4
Jyun-Yuan Huang, Hung-Lin Chen, Chiaho Shih
Hepatitis B virus (HBV) is a major human pathogen. In this study, we found that miR-204 and miR-1236 were down-regulated in HBV-producing cells, and each could suppress HBV replication. Using a bioinformatic approach and a reporter assay, we identified miR-1236, which can reduce HBV replication and protein production by directly targeting at HBV specific mRNA. In contrast, miR-204 was identified by a microarray approach, and had no effect on HBV RNA and protein production. Surprisingly, miR-204 could inhibit HBV pregenomic RNA encapsidation and capsid assembly...
October 13, 2016: Scientific Reports
https://www.readbyqxmd.com/read/27636324/modulators-of-hbv-capsid-assembly-as-an-approach-to-treating-hepatitis-b-virus-infection
#5
Andrew G Cole
The search for a cure for hepatitis B virus infection extends beyond interferon and the existing polymerase inhibitors, and targets different aspects of the virus life cycle to develop agents that operate by alternative mechanisms. Examples of small molecules that disrupt the encapsidation of pgRNA have been known for some time, but recent advances in the understanding of nucleocapsid formation, how compounds interact with core protein, and the development of drug-like molecules have recently progressed the study of capsid assembly modulators to proof of concept in the clinic with respect to reduction of viral load in chronic HBV patients...
September 13, 2016: Current Opinion in Pharmacology
https://www.readbyqxmd.com/read/27581644/molecular-dynamics-simulations-to-determine-the-structure-and-dynamics-of-hepatitis-b-virus-capsid-bound-to-a-novel-anti-viral-drug
#6
Go Watanabe, Shunsuke Sato, Mitsuo Iwadate, Hideaki Umeyama, Michiyo Hayakawa, Yoshiki Murakami, Shigetaka Yoneda
Hepatitis B virus (HBV) chronically infects millions of people worldwide and is a major cause of serious liver diseases, including liver cirrhosis and liver cancer. In our previous study, in silico screening was used to isolate new anti-viral compounds predicted to bind to the HBV capsid. Four of the isolated compounds have been reported to suppress the cellular multiplication of HBV experimentally. In the present study, molecular dynamics simulations of the HBV capsid were performed under rotational symmetry boundary conditions, to clarify how the structure and dynamics of the capsid are affected at the atomic level by the binding of one of the isolated compounds, C13...
2016: Chemical & Pharmaceutical Bulletin
https://www.readbyqxmd.com/read/27518410/importin-%C3%AE-can-bind-hepatitis-b-virus-core-protein-and-empty-core-like-particles-and-induce-structural-changes
#7
Chao Chen, Joseph Che-Yen Wang, Elizabeth E Pierson, David Z Keifer, Mildred Delaleau, Lara Gallucci, Christian Cazenave, Michael Kann, Martin F Jarrold, Adam Zlotnick
Hepatitis B virus (HBV) capsids are found in many forms: immature single-stranded RNA-filled cores, single-stranded DNA-filled replication intermediates, mature cores with relaxed circular double-stranded DNA, and empty capsids. A capsid, the protein shell of the core, is a complex of 240 copies of core protein. Mature cores are transported to the nucleus by a complex that includes both importin α and importin β (Impα and Impβ), which bind to the core protein's C-terminal domains (CTDs). Here we have investigated the interactions of HBV core protein with importins in vitro...
August 2016: PLoS Pathogens
https://www.readbyqxmd.com/read/27458651/design-and-synthesis-of-orally-bioavailable-4-methyl-heteroaryldihydropyrimidine-based-hepatitis-b-virus-hbv-capsid-inhibitors
#8
Zongxing Qiu, Xianfeng Lin, Mingwei Zhou, Yongfu Liu, Wei Zhu, Wenming Chen, Weixing Zhang, Lei Guo, Haixia Liu, Guolong Wu, Mengwei Huang, Min Jiang, Zhiheng Xu, Zheng Zhou, Ning Qin, Shuang Ren, Hongxia Qiu, Sheng Zhong, Yuxia Zhang, Yi Zhang, Xiaoyue Wu, Liping Shi, Fang Shen, Yi Mao, Xue Zhou, Wengang Yang, Jim Z Wu, Guang Yang, Alexander V Mayweg, Hong C Shen, Guozhi Tang
Targeting the capsid protein of hepatitis B virus (HBV) and thus interrupting normal capsid formation have been an attractive approach to block the replication of HBV viruses. We carried out multidimensional structural optimizations based on the heteroaryldihydropyrimidine (HAP) analogue Bay41-4109 (1) and identified a novel series of HBV capsid inhibitors that demonstrated promising cellular selectivity indexes, metabolic stabilities, and in vitro safety profiles. Herein we disclose the design, synthesis, structure-activity relationship (SAR), cocrystal structure in complex with HBV capsid proteins and in vivo pharmacological study of the 4-methyl HAP analogues...
August 25, 2016: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/27440888/hepatitis-b-virus-polymerase-localizes-to-the-mitochondria-and-its-terminal-protein-domain-contains-the-mitochondrial-targeting-signal
#9
Nuruddin Unchwaniwala, Nathan M Sherer, Daniel D Loeb
UNLABELLED: To understand subcellular sites of hepatitis B virus (HBV) replication, we visualized core (Cp), polymerase (Pol), and pregenomic RNA (pgRNA) in infected cells. Interestingly, we found that the majority of Pol localized to the mitochondria in cells undergoing viral replication. The mitochondrial localization of Pol was independent of both the cell type and other viral components, indicating that Pol contains an intrinsic mitochondrial targeting signal (MTS). Neither Cp nor pgRNA localized to the mitochondria during active replication, suggesting a role other than DNA synthesis for Pol at the mitochondria...
October 1, 2016: Journal of Virology
https://www.readbyqxmd.com/read/27334580/distinct-viral-lineages-from-fish-and-amphibians-reveal-the-complex-evolutionary-history-of-hepadnaviruses
#10
Jennifer A Dill, Alvin C Camus, John H Leary, Francesca Di Giallonardo, Edward C Holmes, Terry Fei Fan Ng
UNLABELLED: Hepadnaviruses (hepatitis B viruses [HBVs]) are the only animal viruses that replicate their DNA by reverse transcription of an RNA intermediate. Until recently, the known host range of hepadnaviruses was limited to mammals and birds. We obtained and analyzed the first amphibian HBV genome, as well as several prototype fish HBVs, which allow the first comprehensive comparative genomic analysis of hepadnaviruses from four classes of vertebrates. Bluegill hepadnavirus (BGHBV) was characterized from in-house viral metagenomic sequencing...
September 1, 2016: Journal of Virology
https://www.readbyqxmd.com/read/27203444/complete-spectrum-of-crispr-cas9-induced-mutations-on-hbv-cccdna
#11
Christoph Seeger, Ji A Sohn
Hepatitis B virus (HBV) causes chronic infections that cannot yet be cured. The virus persists in infected hepatocytes, because covalently closed circular DNA (cccDNA), the template for the transcription of viral RNAs, is stable in nondividing cells. Antiviral therapies with nucleoside analogues inhibit HBV DNA synthesis in capsids in the cytoplasm of infected hepatocytes, but do not destroy nuclear cccDNA. Because over 200 million people are still infected, a cure for chronic hepatitis B (CHB) has become one of the major challenges in antiviral therapy...
August 2016: Molecular Therapy: the Journal of the American Society of Gene Therapy
https://www.readbyqxmd.com/read/27139263/the-clinical-implications-of-hepatitis-b-virus-genotypes-and-hbeag-in-pediatrics
#12
REVIEW
Anna Kramvis
Although a successful vaccine against HBV has been implemented in 184 countries, eradication of hepatitis B virus (HBV) is still not on the horizon. There are over 240 million chronic carriers of HBV globally. The risk of developing chronic hepatitis ranges from >90% in newborns of hepatitis Be antigen (HBeAg)-positive mothers, 25%-35% in children under 5 years of age and <5% in adults. HBeAg, a non-particulate viral protein, is a marker of HBV replication. This is the only HBV antigen to cross the placenta, leading to specific unresponsiveness of helper T cells to the capsid protein and HBeAg in newborns...
July 2016: Reviews in Medical Virology
https://www.readbyqxmd.com/read/27084037/intracellular-transport-and-egress-of-hepatitis-b-virus
#13
REVIEW
Marie-Lise Blondot, Volker Bruss, Michael Kann
Hepatitis B virus (HBV) replicates its genomic information in the nucleus via transcription and therefore has to deliver its partially double stranded DNA genome into the nucleus. Like other viruses with a nuclear replication phase, HBV genomes are transported inside the viral capsids first through the cytoplasm towards the nuclear envelope. Following the arrival at the nuclear pore, the capsids are transported through, using classical cellular nuclear import pathways. The arrest of nuclear import at the nucleoplasmic side of the nuclear pore is unique, however, and is where the capsids efficiently disassemble leading to genome release...
April 2016: Journal of Hepatology
https://www.readbyqxmd.com/read/27084032/new-antiviral-targets-for-innovative-treatment-concepts-for-hepatitis-b-virus-and-hepatitis-delta-virus
#14
REVIEW
David Durantel, Fabien Zoulim
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 (NUC) treatments. While viral suppression can be achieved in the majority of patients with the high-barrier-to-resistance new-generation of NUC, i.e. entecavir and tenofovir, HBsAg loss is achieved by PegIFN-α and/or NUC in only 10% of patients, after a 5-year follow-up. Attempts to improve the response by administering two different NUC or a combination of NUC and PegIFN-α have not provided a dramatic increase in the rate of functional cure...
April 2016: Journal of Hepatology
https://www.readbyqxmd.com/read/27076641/cell-free-hepatitis-b-virus-capsid-assembly-dependent-on-the-core-protein-c-terminal-domain-and-regulated-by-phosphorylation
#15
Laurie Ludgate, Kuancheng Liu, Laurie Luckenbaugh, Nicholas Streck, Stacey Eng, Christian Voitenleitner, William E Delaney, Jianming Hu
UNLABELLED: Multiple subunits of the hepatitis B virus (HBV) core protein (HBc) assemble into an icosahedral capsid that packages the viral pregenomic RNA (pgRNA). The N-terminal domain (NTD) of HBc is sufficient for capsid assembly, in the absence of pgRNA or any other viral or host factors, under conditions of high HBc and/or salt concentrations. The C-terminal domain (CTD) is deemed dispensable for capsid assembly although it is essential for pgRNA packaging. We report here that HBc expressed in a mammalian cell lysate, rabbit reticulocyte lysate (RRL), was able to assemble into capsids when (low-nanomolar) HBc concentrations mimicked those achieved under conditions of viral replication in vivo and were far below those used previously for capsid assembly in vitro Furthermore, at physiologically low HBc concentrations in RRL, the NTD was insufficient for capsid assembly and the CTD was also required...
June 15, 2016: Journal of Virology
https://www.readbyqxmd.com/read/26842475/hepatitis-b-virus-capsids-have-diverse-structural-responses-to-small-molecule-ligands-bound-to-the-heteroaryldihydropyrimidine-pocket
#16
Balasubramanian Venkatakrishnan, Sarah P Katen, Samson Francis, Srinivas Chirapu, M G Finn, Adam Zlotnick
UNLABELLED: Though the hepatitis B virus (HBV) core protein is an important participant in many aspects of the viral life cycle, its best-characterized activity is self-assembly into 240-monomer capsids. Small molecules that target core protein (core protein allosteric modulators [CpAMs]) represent a promising antiviral strategy. To better understand the structural basis of the CpAM mechanism, we determined the crystal structure of the HBV capsid in complex with HAP18. HAP18 accelerates assembly, increases protein-protein association more than 100-fold, and induces assembly of nonicosahedral macrostructures...
April 2016: Journal of Virology
https://www.readbyqxmd.com/read/26838678/oxethazaine-inhibits-hepatitis-b-virus-capsid-assembly-by-blocking-the-cytosolic-calcium-signalling-pathway
#17
Lin Zhang, Chunlan Liu, Yu Xiao, Xulin Chen
Chronic hepatitis B virus (HBV) infection is a serious public health problem and may progress to liver fibrosis, cirrhosis and hepatocellular carcinoma. It is currently treated with PEGylated IFN-α2a and nucleoside/nucleotide analogues (NAs). However, PEGylated IFN treatment has problems of high cost, low efficiency and side effects. Long-term administration of NAs is necessary to avoid virus relapse, which can cause drug resistance and side effects. New efforts are now being directed to develop novel anti-HBV drugs targeting either additional viral targets other than viral DNA polymerase or host targets to improve the treatment of chronic hepatitis B...
May 2016: Journal of General Virology
https://www.readbyqxmd.com/read/26725911/the-adventure-of-delta
#18
REVIEW
Mario Rizzetto
The hepatitis D virus (HDV) is unique in animal virology. It has a circular RNA genome that is the smallest of human viruses, requires the HBsAg capsid of the hepatitis B virus to assembly into infectious virions, parasitizes the transcriptional machinery of the host by hijacking cellular RNA polymerases to replicate its RNA genome and is replicated by a rolling circle mechanism unknown to mammalian cells. Hepatitis D is ubiquitous but prevalence varies throughout the world. It is the most severe form of chronic viral liver disorder; carriers of HBsAg superinfected by the HDV are the major victims and the reservoir of the infection...
January 2016: Liver International: Official Journal of the International Association for the Study of the Liver
https://www.readbyqxmd.com/read/26725903/hepatitis-b-virus-new-therapeutic-perspectives
#19
REVIEW
Chih-Lin Lin, Hung-Chih Yang, Jia-Horng Kao
Current antiviral therapies have dramatically improved the long-term outcomes of patients with chronic hepatitis B virus (HBV) infection. Both interferon (IFN) and nucleos(t)ide analogue (NA) treatments have been shown to reduce the progression of liver disease in chronic hepatitis B (CHB) patients. However, persistent covalently closed circular DNA (cccDNA) can result in a viral relapse after discontinuation of antiviral treatment. On the basis of extensive research on the HBV lifecycle and virus-host interactions, several new agents focusing on viral and host targets are under development to cure HBV...
January 2016: Liver International: Official Journal of the International Association for the Study of the Liver
https://www.readbyqxmd.com/read/26719264/subviral-hepatitis-b-virus-filaments-like-infectious-viral-particles-are-released-via-multivesicular-bodies
#20
Bingfu Jiang, Kiyoshi Himmelsbach, Huimei Ren, Klaus Boller, Eberhard Hildt
UNLABELLED: In addition to infectious viral particles, hepatitis B virus-replicating cells secrete large amounts of subviral particles assembled by the surface proteins, but lacking any capsid and genome. Subviral particles form spheres (22-nm particles) and filaments. Filaments contain a much larger amount of the large surface protein (LHBs) compared to spheres. Spheres are released via the constitutive secretory pathway, while viral particles are ESCRT-dependently released via multivesicular bodies (MVBs)...
December 30, 2015: Journal of Virology
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