scholarly journals Novel Hepatitis B Virus Capsid Assembly Modulator Induces Potent Antiviral Responses In Vitro and in Humanized Mice

2019 ◽  
Vol 64 (2) ◽  
Author(s):  
Franck Amblard ◽  
Sebastien Boucle ◽  
Leda Bassit ◽  
Bryan Cox ◽  
Ozkan Sari ◽  
...  
Keyword(s):  
Hepatitis B Virus ◽  
Hepatitis B ◽  
Nucleoside Analogs ◽  
Humanized Mouse Model ◽  
Single Digit ◽  
Viral Loads ◽  
Antiviral Responses ◽  
B Virus

ABSTRACT Hepatitis B virus (HBV) affects an estimated 250 million chronic carriers worldwide. Though several vaccines exist, they are ineffective for those already infected. HBV persists due to the formation of covalently closed circular DNA (cccDNA)—the viral minichromosome—in the nucleus of hepatocytes. Current nucleoside analogs and interferon therapies rarely clear cccDNA, requiring lifelong treatment. Our group identified GLP-26, a novel glyoxamide derivative that alters HBV nucleocapsid assembly and prevents viral DNA replication. GLP-26 exhibited single-digit nanomolar anti-HBV activity, inhibition of HBV e antigen (HBeAg) secretion, and reduced cccDNA amplification, in addition to showing a promising preclinical profile. Strikingly, long term combination treatment with entecavir in a humanized mouse model induced a decrease in viral loads and viral antigens that was sustained for up to 12 weeks after treatment cessation.

scholarly journals Phosphorothioate Di- and Trinucleotides as a Novel Class of Anti-Hepatitis B Virus Agents

2004 ◽  
Vol 48 (6) ◽  
pp. 2199-2205 ◽  
Author(s):  
Radhakrishnan P. Iyer ◽  
Yi Jin ◽  
Arlene Roland ◽  
John D. Morrey ◽  
Samir Mounir ◽  
...  
Keyword(s):  
Hepatitis B Virus ◽  
Hepatitis B ◽  
Nucleoside Analogs ◽  
Hbv Dna ◽  
Parallel Synthesis ◽  
Hbv Replication ◽  
Long Term Treatment ◽  
B Virus ◽  
Dna Strand

ABSTRACT Several nucleoside analogs are under clinical development for use against hepatitis B virus (HBV). Lamivudine (3TC), a nucleoside analog, and adefovir dipivoxil (ADV), an acyclonucleotide analog, are clinically approved. However, long-term treatment can induce viral resistance, and following the cessation of therapy, viral rebound is frequently observed. There continues to be a need for new antiviral agents with novel mechanisms of action. A library of more than 600 di- and trinucleotide compounds synthesized by parallel synthesis using a combinatorial strategy was screened for potential inhibitors of HBV replication using the chronically HBV-producing cell line 2.2.15. Through an iterative process of synthesis, lead optimization, and screening, three analogs were identified as potent inhibitors of HBV replication: dinucleotides ORI-7246 (drug concentration at which a 10-fold reduction of HBV DNA was observed [EC90], 1.4 μM) and ORI-9020 (EC90, 1.2 μM) and trinucleotide ORI-7170 (EC90, 7.2 μM). These analogs inhibited the replication of both strands of HBV DNA. No suppression of HBV protein synthesis or intracellular core particle formation by these analogs was observed. No inhibition of HBV DNA strand elongation by the analogs or their 5′-triphosphate versions was apparent in in vitro polymerase assays. Although the exact mechanism of action is not yet identified, present data are consistent with an inhibition of the HBV reverse transcriptase-directed priming step prior to elongation of the first viral DNA strand. In transient-transfection assays, these analogs inhibited the replication of 3TC-resistant HBV. Synergistic interactions in combination treatments between the analogs and either 3TC or ADV were observed. These compounds represent a novel class of anti-HBV molecules and warrant further investigation as potential therapeutic agents.

scholarly journals Interaction between ganciclovir and foscarnet as inhibitors of duck hepatitis B virus replication in vitro.

1996 ◽  
Vol 40 (5) ◽  
pp. 1180-1185 ◽  
Author(s):  
G Civitico ◽  
T Shaw ◽  
S Locarnini
Keyword(s):  
Hepatitis B Virus ◽  
Hepatitis B ◽  
Hbv Dna ◽  
Duck Hepatitis ◽  
Chronic Hepatitis B Virus ◽  
B Virus ◽  
Dose Limiting Toxicity

Safe and effective treatments for chronic hepatitis B virus (HBV) infection have yet to be developed. Both ganciclovir (9-[1,3-dihydroxy-2-propoxymethyl]guanine) and foscarnet (trisodium phosphonoformate hexahydrate) are potent inhibitors of hepadnavirus replication when used individually in vitro and in vivo. However, the clinical usefulness of each drug is reduced by dose-limiting toxicity, especially during long-term monotherapy. Here we demonstrate additive inhibition of duck HBV DNA replication in cultures of primary duck hepatocytes congenitally infected with duck HBV by combinations of ganciclovir and foscarnet at low, clinically achievable concentrations. These results suggest that the effects of ganciclovir and foscarnet against HBV may be additive in vivo.

Telbivudine Prevents Vertical Transmission of Hepatitis B Virus From Women With High Viral Loads: A Prospective Long-Term Study

2015 ◽  
Vol 13 (6) ◽  
pp. 1170-1176 ◽  
Author(s):  
Quanxin Wu ◽  
Hongfei Huang ◽  
Xiaowen Sun ◽  
Meimin Pan ◽  
Yun He ◽  
...  
Keyword(s):  
Hepatitis B Virus ◽  
Hepatitis B ◽  
Vertical Transmission ◽  
Term Study ◽  
Viral Loads ◽  
Long Term Study ◽  
B Virus

scholarly journals Identification of BMS-200475 as a potent and selective inhibitor of hepatitis B virus.

1997 ◽  
Vol 41 (7) ◽  
pp. 1444-1448 ◽  
Author(s):  
S F Innaimo ◽  
M Seifer ◽  
G S Bisacchi ◽  
D N Standring ◽  
R Zahler ◽  
...  
Keyword(s):  
Hepatitis B Virus ◽  
Hepatitis B ◽  
Cell Line ◽  
Nucleoside Analogs ◽  
Hbv Replication ◽  
Mitochondrial Dna Content ◽  
B Virus ◽  
Antiviral Activities ◽  
Replicative Intermediates

BMS-200475 is a novel carbocyclic 2'-deoxyguanosine analog found to possess potent and selective anti-hepatitis B virus (anti-HBV) activity. BMS-200475 is distinguished from guanosine by replacement of the natural furanose oxygen on the sugar moiety with an exo carbon-carbon double bond. In the HepG2 stably transfected cell line 2.2.15, BMS-200475 had a 50% effective concentration (EC50) of 3.75 nM against HBV, as determined by analysis of secreted HBV DNA. Structurally related compounds with adenine, iodouracil, or thymine base substitutions were significantly less potent or were inactive. Direct comparison of the antiviral activities of BMS-200475 with those of a variety of other nucleoside analogs, including lamivudine (EC50 = 116.26 nM), demonstrated the clearly superior in vitro potency of BMS-200475 in 2.2.15 cells. Intracellular HBV replicative intermediates were uniformly reduced when cells were treated with BMS-200475, but rebounded after treatment was terminated. The concentration of BMS-200475 causing 50% cytotoxicity in 2.2.15 cell cultures was 30 microM, approximately 8,000-fold greater than the concentration required to inhibit HBV replication in the same cell line. Treatment with BMS-200475 resulted in no apparent inhibitory effects on mitochondrial DNA content.

The main Hepatitis B virus (HBV) mutants resistant to nucleoside analogs are susceptible in vitro to non-nucleoside inhibitors of HBV replication

2011 ◽  
Vol 92 (2) ◽  
pp. 271-276 ◽  
Author(s):  
Gaëtan Billioud ◽  
Christian Pichoud ◽  
Gerhard Puerstinger ◽  
Johan Neyts ◽  
Fabien Zoulim
Keyword(s):  
Hepatitis B Virus ◽  
Hepatitis B ◽  
Nucleoside Analogs ◽  
Hbv Replication ◽  
B Virus ◽  
Nucleoside Inhibitors

scholarly journals Identification and Characterization of Clevudine-Resistant Mutants of Hepatitis B Virus Isolated from Chronic Hepatitis B Patients

2010 ◽  
Vol 84 (9) ◽  
pp. 4494-4503 ◽  
Author(s):  
So Young Kwon ◽  
Yong Kwang Park ◽  
Sung Hyun Ahn ◽  
Eun Sook Cho ◽  
Won Hyeok Choe ◽  
...  
Keyword(s):  
Chronic Hepatitis ◽  
Hepatitis B Virus ◽  
Hepatitis B ◽  
Chronic Hepatitis B ◽  
Drug Susceptibility ◽  
Compensatory Mutation ◽  
B Virus ◽  
Resistant Mutants

ABSTRACT Clevudine (CLV) is a nucleoside analog with potent antiviral activity against chronic hepatitis B virus (HBV) infection. Viral resistance to CLV in patients receiving CLV therapy has not been reported. The aim of this study was to characterize CLV-resistant HBV in patients with viral breakthrough (BT) during long-term CLV therapy. The gene encoding HBV reverse transcriptase (RT) was analyzed from chronic hepatitis B patients with viral BT during CLV therapy. Sera collected from the patients at baseline and at the time of viral BT were studied. To characterize the mutations of HBV isolated from the patients, we subjected the HBV mutants to in vitro drug susceptibility assays. Several conserved mutations were identified in the RT domain during viral BT, with M204I being the most common. In vitro phenotypic analysis showed that the mutation M204I was predominantly associated with CLV resistance, whereas L229V was a compensatory mutation for the impaired replication of the M204I mutant. A quadruple mutant (L129M, V173L, M204I, and H337N) was identified that conferred greater replicative ability and strong resistance to both CLV and lamivudine. All of the CLV-resistant clones were lamivudine resistant. They were susceptible to adefovir, entecavir, and tenofovir, except for one mutant clone. In conclusion, the mutation M204I in HBV RT plays a major role in CLV resistance and leads to viral BT during long-term CLV treatment. Several conserved mutations may have a compensatory role in replication. Drug susceptibility assays reveal that adefovir and tenofovir are the most effective compounds against CLV-resistant mutants. These data may provide additional therapeutic options for CLV-resistant patients.

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