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https://www.readbyqxmd.com/read/28094179/synthesis-and-antiviral-evaluation-of-novel-heteroarylpyrimidines-analogs-as-hbv-capsid-effectors
#1
Sebastien Boucle, Xiao Lu, Leda Bassit, Tugba Ozturk, Olivia Ollinger Russell, Franck Amblard, Steven J Coats, Raymond F Schinazi
New modifications to the scaffold of previously reported HBV capsid assembly effectors such as BAY 41-4109, HAP-12 and GLS4 were explored. The anti-HBV activity in the HepAD38 system, and cytotoxicity profiles of each of the new compounds has been assessed. Among them, five new iodo- and bromo-heteroarylpyrimidines analogs displayed anti-HBV activity in the low micromolar range.
January 6, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28061386/characterization-of-the-disassembly-and-reassembly-of-the-hbv-glycoprotein-surface-antigen-a-pliable-nanoparticle-vaccine-platform
#2
John R Gallagher, Udana Torian, Dustin M McCraw, Audray K Harris
While nanoparticle vaccine technology is gaining interest due to the success of vaccines like those for the human papillomavirus that is based on viral capsid nanoparticles, little information is available on the disassembly and reassembly of viral surface glycoprotein-based nanoparticles. One such particle is the hepatitis B virus surface antigen (sAg) that exists as nanoparticles. Here we show, using biochemical analysis coupled with electron microscopy, that sAg nanoparticle disassembly requires both reducing agent to disrupt intermolecular disulfide bonds, and detergent to disrupt hydrophobic interactions that stabilize the nanoparticle...
January 3, 2017: Virology
https://www.readbyqxmd.com/read/28052622/novel-targets-for-hepatitis-b-virus-therapy
#3
REVIEW
Barbara Testoni, David Durantel, Fabien Zoulim
Treatment with either pegylated interferon-alpha (pegIFN-α) or last generation nucleos(t)ide analogues (NAs) successfully leads to serum viral load suppression in most chronically infected hepatitis B (CHB) patients, but HBsAg loss is only achieved in 10% of the cases after a 5-year follow-up. Thus, therapy must be administered long-term and it will not completely eliminate infection because of the persistent hepatitis B virus (HBV) minichromosome in infected cells, and cannot completely abolish the risk of developing severe sequelae such as cirrhosis and hepatocellular carcinoma...
January 2017: Liver International: Official Journal of the International Association for the Study of the Liver
https://www.readbyqxmd.com/read/27989113/optimization-and-synthesis-of-pyridazinone-derivatives-as-novel-inhibitors-of-hepatitis-b-virus-by-inducing-genome-free-capsid-formation
#4
Dong Lu, Feifei Liu, Weiqiang Xing, Xiankun Tong, Lang Wang, Yajuan Wang, Limin Zeng, Chunlan Feng, Li Yang, Jianping Zuo, Youhong Hu
The capsid of hepatitis B virus (HBV) plays a vital role in virus DNA replication. Targeting nucleocapsid function has been demonstrated as an effective approach for anti-HBV drug development. A high-throughput screening and mechanism study revealed the hit compound 4a as an HBV assembly effector (AEf), which could inhibit HBV replication by inducing the formation of HBV DNA-free capsids. The subsequent SAR study and drug-like optimization resulted in the discovery of the lead candidate 4r, with potent antiviral activity (IC50 = 0...
December 29, 2016: ACS Infectious Diseases
https://www.readbyqxmd.com/read/27975317/detection-of-hepatitis-b-virus-particles-released-from-cultured-cells-by-particle-gel-assay
#5
Ran Yan, Dawei Cai, Yuanjie Liu, Haitao Guo
The culture fluid of HBV replicating cells contains a mixture of viral particles with different structural and genetic components, including enveloped infectious virions, genome-free virion, envelope-only subviral particles, and nonenveloped naked capsids. Based on their different physical and chemical properties, the enveloped and nonenveloped particles can be separated by the native agarose gel electrophoresis and transferred onto a positively charged microporous membrane, then the virus particle-associated protein components and nucleic acid content can be detected by antibody-based enzyme immunoassay (EIA) and hybridization, respectively...
2017: Methods in Molecular Biology
https://www.readbyqxmd.com/read/27975314/measuring-changes-in-cytosolic-calcium-levels-in-hbv-and-hbx-expressing-cultured-primary-hepatocytes
#6
Jessica C Casciano, Michael J Bouchard
Chronic infection with hepatitis B virus (HBV) remains a major worldwide health concern and is the leading cause of hepatocellular carcinoma (HCC). The HBV X protein (HBx) is the only regulatory protein encoded in the HBV genome; HBx stimulates HBV replication in vivo and in vitro. HBx also regulates cytosolic Ca(2+) signaling, and altered Ca(2+) signaling is associated with the development of many diseases, including HCC. Importantly, many HBx functions, including HBx modulation of cell proliferation, apoptosis, and transcription pathways, have been linked to changes in cytosolic Ca(2+) signaling...
2017: Methods in Molecular Biology
https://www.readbyqxmd.com/read/27975306/intracytoplasmic-transport-of-hepatitis-b-virus-capsids
#7
Quentin Osseman, Michael Kann
The early steps of HBV entry remain largely unknown despite the recent discovery of an HBV-specific entry receptor. Following entry HBV capsids have to be transported through the cytoplasm to the nuclear periphery, followed by nuclear entry. These steps have to take place in a coordinated manner to allow delivery of the genome into the nucleus. Due to the viscosity of the cytoplasm, the intracytoplasmic translocation has to be active and directed.Here, we describe protocols that can be applied to investigations of the HBV capsid with the cytoplasmic transport systems...
2017: Methods in Molecular Biology
https://www.readbyqxmd.com/read/27958343/hbv-maintains-electrostatic-homeostasis-by-modulating-negative-charges-from-phosphoserine-and-encapsidated-nucleic-acids
#8
Pei-Yi Su, Ching-Jen Yang, Tien-Hua Chu, Chih-Hsu Chang, Chiayn Chiang, Fan-Mei Tang, Chih-Yin Lee, Chiaho Shih
Capsid assembly and stability of hepatitis B virus (HBV) core protein (HBc) particles depend on balanced electrostatic interactions between encapsidated nucleic acids and an arginine-rich domain (ARD) of HBc in the capsid interior. Arginine-deficient ARD mutants preferentially encapsidated spliced viral RNA and shorter DNA, which can be fully or partially rescued by reducing the negative charges from acidic residues or serine phosphorylation of HBc, dose-dependently. Similarly, empty capsids without RNA encapsidation can be generated by ARD hyper-phosphorylation in insect, bacteria, and human hepatocytes...
December 13, 2016: Scientific Reports
https://www.readbyqxmd.com/read/27908829/exploring-the-binding-mechanism-of-heteroaryldihydropyrimidines-and-hepatitis-b-virus-capsid-combined-3d-qsar-and-molecular-dynamics
#9
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...
January 2017: 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
#10
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
#11
REVIEW
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
#12
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
#13
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
#14
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
#15
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
#16
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
#17
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
#18
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
#19
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
#20
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
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