Phenylpropenamide Derivatives AT-61 and AT-130 Inhibit Replication of Wild-Type and Lamivudine-Resistant Strains of Hepatitis B Virus In Vitro

Delaney, William E.; Edwards, Rosalind; Colledge, Danni; Shaw, Timothy J.; Furman, Phil; Painter, George R.; Locarnini, Stephen

doi:10.1128/aac.46.9.3057-3060.2002

Cited by 146 publications

(116 citation statements)

References 33 publications

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“…For instance, in the case of hepatitis B virus (HBV), several inhibitors targeting the core protein have been reported, and at least two classes of HBV assembly effectors, the heteroaryldihydropyrimidines (HAPs) and phenylpropenamides, have been extensively characterized (53,54,55,56). For the HAPs, elegant work from Zlotnick and colleagues demonstrated that these compounds can increase the kinetics of assembly and strengthen dimer-dimer association to stabilize capsids (57,58).…”

Section: Discussionmentioning

confidence: 99%

Characterization of the Mode of Action of a Potent Dengue Virus Capsid Inhibitor

Scaturro

Trist

Paul

et al. 2014

J Virol

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Dengue viruses (DV) represent a significant global health burden, with up to 400 million infections every year and around 500,000 infected individuals developing life-threatening disease. In spite of attempts to develop vaccine candidates and antiviral drugs, there is a lack of approved therapeutics for the treatment of DV infection. We have previously reported the identification of ST-148, a small-molecule inhibitor exhibiting broad and potent antiviral activity against DV in vitro and in vivo (C. M. Byrd et al., Antimicrob. Agents Chemother. 57:15-25, 2013, doi:10.1128/AAC.01429-12). In the present study, we investigated the mode of action of this promising compound by using a combination of biochemical, virological, and imaging-based techniques. We confirmed that ST-148 targets the capsid protein and obtained evidence of bimodal antiviral activity affecting both assembly/ release and entry of infectious DV particles. Importantly, by using a robust bioluminescence resonance energy transfer-based assay, we observed an ST-148-dependent increase of capsid self-interaction. These results were corroborated by molecular modeling studies that also revealed a plausible model for compound binding to capsid protein and inhibition by a distinct resistance mutation. These results suggest that ST-148-enhanced capsid protein self-interaction perturbs assembly and disassembly of DV nucleocapsids, probably by inducing structural rigidity. Thus, as previously reported for other enveloped viruses, stabilization of capsid protein structure is an attractive therapeutic concept that also is applicable to flaviviruses. Dengue virus (DV) belongs to the genus Flavivirus, a large group of emerging pathogens capable of causing severe human diseases. Among these, DV represents the most prevalent mosquito-borne human-pathogenic virus worldwide, comprising 4 serotypes that are transmitted mainly by infected Aedes mosquitoes during a blood meal. DV infections can lead to a wide range of clinical manifestations, ranging from asymptomatic infections to life-threatening dengue hemorrhagic fever and shock syndrome. A recent study estimated around 390 million DV infections each year, resulting in approximately 100 million symptomatic cases and around 25,000 deaths (1). Despite intense efforts and growing public interest, no licensed antiviral drug against DV infection is available, and the most advanced DV vaccine candidate did not meet expectations in a recent large clinical trial (2).DV has a single-stranded RNA genome of positive polarity that codes for a polyprotein, which is co-and posttranslationally processed into three structural proteins (capsid, prM, and envelope) and seven nonstructural proteins (NS1, NS2A, NS2B, NS3, NS4A, NS4B, and NS5) (3). The virus enters mammalian cells via receptor-mediated endocytosis. In the endosomal compartment, the low pH induces a conformational change in the envelope (E) protein, triggering membrane fusion and nucleocapsid release into the cytoplasm (4, 5). Disassembly of the nucleocapsid occur...

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Section: Discussionmentioning

confidence: 99%

Characterization of the Mode of Action of a Potent Dengue Virus Capsid Inhibitor

Scaturro

Trist

Paul

et al. 2014

J Virol

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“…AEfs such as HAPs and phenylpropenamides have been suggested as antiviral agents (18,19,27,44). A caveat to their use as therapy would be the emergence of resistant mutants.…”

Section: Discussionmentioning

confidence: 99%

Genetically Altering the Thermodynamics and Kinetics of Hepatitis B Virus Capsid Assembly Has Profound Effects on Virus Replication in Cell Culture

Tan

Maguire

Loeb

et al. 2013

J Virol

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b Capsid (core) assembly is essential for hepatitis B virus (HBV) replication. We hypothesize that assembly kinetics and stability are tuned for optimal viral replication, not maximal assembly. Assembly effectors (AEfs) are small molecules proposed to disrupt this balance by inappropriately enhancing core assembly. Guided by the structure of an AEf-bound core, we designed a structural mimic of AEf-bound core protein, the V124W mutant. In biochemical studies, the V124W mutant recapitulated the effects of AEfs, with fast assembly kinetics and a strong protein-protein association energy. Also, the mutant was resistant to exogenous AEfs. In cell culture, the V124W mutant behaved like a potent AEf: expression of HBV carrying the V124W mutant was defective for genome replication. Critically, the V124W mutant interfered with replication of wild-type HBV in a dose-dependent manner, mimicking AEf activity. In addition, the V124W mutant was shown to adopt a more compact conformation than that of the wild type, confirming the allosteric regulation in capsid assembly. These studies show that the heteroaryldihydropyrimidine (HAP) binding pocket is a promiscuous target for inducing assembly. Suppression of viral replication by the V124W mutant suggests that mutations that fill the HAP site are not a path for HBV to escape from AEfs.

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“…These includes myristilated pre-S1 peptides to compete with the interaction of the virion envelope proteins and the hepatocyte receptor , peptides or recombinant core proteins exhibiting a trans dominant negative effect on nucleocapsid assembly (von Weizsacker et al, 1999), non nucleosides inhibitors that inhibit the correct assembly and packaging of pregenomic RNA, iminosugars to inhibit the correct glycosylation process of viral envelope proteins and the maturation of virions. For instance, phenylpropenamide derivatives were shown to inhibit HBV replication independently of an interference with the viral polymerase activity (Delaney et al, 2002;King et al, 1998). It was suggested that these compounds may inhibit the packaging of pregenomic RNA, which in turn may explain their antiviral activity on both wild type and lamivudine resistant strains.…”

Section: Perspectivementioning

confidence: 99%

Mechanism of viral persistence and resistance to nucleoside and nucleotide analogs in chronic Hepatitis B virus infection

Zoulim

2004

Antiviral Research

106

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Phenylpropenamide Derivatives AT-61 and AT-130 Inhibit Replication of Wild-Type and Lamivudine-Resistant Strains of Hepatitis B Virus In Vitro

Cited by 146 publications

References 33 publications

Characterization of the Mode of Action of a Potent Dengue Virus Capsid Inhibitor

Characterization of the Mode of Action of a Potent Dengue Virus Capsid Inhibitor

Genetically Altering the Thermodynamics and Kinetics of Hepatitis B Virus Capsid Assembly Has Profound Effects on Virus Replication in Cell Culture

Mechanism of viral persistence and resistance to nucleoside and nucleotide analogs in chronic Hepatitis B virus infection

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