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

Billioud, Gaëtan; Pichoud, Christian; Puerstinger, Gerhard; Neyts, Johan; Zoulim, Fabien

doi:10.1016/j.antiviral.2011.08.012

Cited by 75 publications

(59 citation statements)

References 28 publications

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“…4 and 5). Like AT-61 (16,64), the SBAs inhibited wild-type and nucleoside-resistant HBV with similar potencies (Table 3). Furthermore, it is the HBV capsid protein, but not polymerase or pgRNA, that confers the sensitivity of HBV to both AT-61 and SBAs.…”

Section: Discussionmentioning

confidence: 97%

“…Second, due to their distinct antiviral mechanisms, these novel antiviral drugs may be effective against HBV variants that are resistant to the nucleoside analogue viral DNA polymerase inhibitors (5). Third, similar to the highly active antiretroviral therapy (HAART) for human immunodeficiency virus (HIV) infection (15), novel antiviral drugs used in combination with the current DNA polymerase inhibitors may synergistically suppress HBV replication and prevent the emergence of drug resistance, offering a more effective, and possibly curative, treatment for chronic hepatitis B (16).…”

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confidence: 99%

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Sulfamoylbenzamide Derivatives Inhibit the Assembly of Hepatitis B Virus Nucleocapsids

Campagna

Liu

Mao

et al. 2013

J Virol

162

182

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Section: Discussionmentioning

confidence: 97%

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confidence: 99%

Sulfamoylbenzamide Derivatives Inhibit the Assembly of Hepatitis B Virus Nucleocapsids

Campagna

Liu

Mao

et al. 2013

J Virol

162

182

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“…Long-term treatment of chronic hepatitis B with NUCs can lead to the emergence of drug-resistant HBV variants with specific mutations in the polymerase gene and result in treatment failure. Based on their distinct antiviral mechanism, all five previously reported chemotypes of capsid assembly modulators had been demonstrated to effectively inhibit the replication of NUC-resistant HBV (29,52). Not surprisingly, as shown in Table 2, BA-38017 inhibited the replication of wild-type HBV and mutant HBV bearing specific mutations in the polymerase gene conferring resistance to lamivudine, adefovir, and/or entecavir with similar efficacy.…”

mentioning

confidence: 92%

Discovery and Mechanistic Study of Benzamide Derivatives That Modulate Hepatitis B Virus Capsid Assembly

Zhao

Zhang

et al. 2017

J Virol

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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. Interestingly, similar to our previously reported sulfamoylbenzamides (SBAs), the BAs promote the formation of empty capsids through specific interaction with HBV core protein but not other viral and host cellular components. Genetic evidence suggested that both SBAs and BAs inhibited HBV nucleocapsid assembly by binding to the heteroaryldihydropyrimidine (HAP) pocket between core protein dimer-dimer interfaces. However, unlike SBAs, BA compounds uniquely induced the formation of empty capsids that migrated more slowly in native agarose gel electrophoresis from A36V mutant than from the wild-type core protein.Moreover, we showed that the assembly of chimeric capsids from wild-type and drug-resistant core proteins was susceptible to multiple capsid assembly modulators. Hence, HBV core protein is a dominant antiviral target that may suppress the selection of drug-resistant viruses during core protein-targeting antiviral therapy. Our studies thus indicate that BAs are a chemically and mechanistically unique type of HBV capsid assembly modulators and warranted for further development as antiviral agents against HBV.IMPORTANCE HBV core protein plays essential roles in many steps of the viral replication cycle. In addition to packaging viral pregenomic RNA (pgRNA) and DNA polymerase complex into nucleocapsids for reverse transcriptional DNA replication to take place, the core protein dimers, existing in several different quaternary structures in infected hepatocytes, participate in and regulate HBV virion assembly, capsid uncoating, and covalently closed circular DNA (cccDNA) formation. It is anticipated that small molecular core protein assembly modulators may disrupt one or multiple steps of HBV replication, depending on their interaction with the distinct quaternary structures of core protein. The discovery of novel core protein-targeting antivirals, such as benzamide derivatives reported here, and investigation of their antiviral mechanism may lead to the identification of antiviral therapeutics for the cure of chronic hepatitis B.KEYWORDS antiviral agents, capsid assembly, hepatitis B virus

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“…A few non-nucleocapsid molecules have been shown to inhibit the replication of both the wild type virus and of drug resistant variants [78] . These include compounds that belong either to the family of phenylpropenamide (AT-61 and AT-130) and have been reported to prevent RNA encapsidation or to the family of heteroaryldihydropyrimidines (BAY41-4109) that can destabilize nucleocapsids [55,79] .…”

Section: Nucleocapsid Assembly and Stabilitymentioning

confidence: 99%

Current and future antiviral drug therapies of hepatitis B chronic infection

Koumbi¹

2015

WJH

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Despite significant improvement in the management of chronic hepatitis B virus (HBV) it remains a public health problem, affecting more than 350 million people worldwide. The natural course of the infection is dynamic and involves a complex interplay between the virus and the host's immune system. Currently the approved therapeutic regimens include pegylated-interferon (IFN)-α and monotherapy with five nucleos(t)ide analogues (NAs). Both antiviral treatments are not capable to eliminate the virus and do not establish longterm control of infection after treatment withdrawal. IFN therapy is of finite duration and associates with low response rates, liver decompensating and numerous side effects. NAs are well-tolerated therapies but have a high risk of drug resistance development that limits their prolonged use. The imperative for the development of new approaches for the treatment of chronic HBV infection is a challenging issue that cannot be over-sided. Research efforts are focusing on the identification and evaluation of various viral replication inhibitors that target viral replication and a number of immunomodulators that aim to restore the HBV specific immune hyporesponsiveness without inducing liver damage. This review brings together our current knowledge on the available treatment and discusses potential therapeutic approaches in the battle against chronic HBV infection. Core tip: Despite significant improvement in the management of chronic hepatitis B virus (HBV) it remains a public health problem. Current therapeutic regimens include pegylated-interferon (IFN)-α and nucleos(t)ide analogues (NAs). Both treatments do not eradicate the virus and have numerous limitations. IFN therapy is of finite duration and has low response rates while longterm NA therapies have a high risk of drug resistance. The development of new therapeutic approaches is imperative. This review brings together current treatments and the ongoing research efforts on evaluating potential therapeutic strategies that target the suppression of HBV replication the restoration of the weak immune responses against HBV.

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

Cited by 75 publications

References 28 publications

Sulfamoylbenzamide Derivatives Inhibit the Assembly of Hepatitis B Virus Nucleocapsids

Sulfamoylbenzamide Derivatives Inhibit the Assembly of Hepatitis B Virus Nucleocapsids

Discovery and Mechanistic Study of Benzamide Derivatives That Modulate Hepatitis B Virus Capsid Assembly

Current and future antiviral drug therapies of hepatitis B chronic infection

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