Hepatitis B Virus Cure: Targets and Future Therapies

Lee, Hye Won; Lee, Jae Seung; Ahn, Sang Hoon

doi:10.3390/ijms22010213

Cited by 71 publications

(44 citation statements)

References 50 publications

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“…Such effectors would act on the assembled capsids before envelopment in contrast to the established capsid assembly modulators [56]. This is a still unexplored mode of action for HBV antivirals [6], and we believe that exploiting this potential may lead to developing new therapeutics.…”

Section: Discussionmentioning

confidence: 98%

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Conformational Plasticity of Hepatitis B Core Protein Spikes Promotes Peptide Binding Independent of the Secretion Phenotype

et al. 2021

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Hepatitis B virus is a major human pathogen, which forms enveloped virus particles. During viral maturation, membrane-bound hepatitis B surface proteins package hepatitis B core protein capsids. This process is intercepted by certain peptides with an “LLGRMKG” motif that binds to the capsids at the tips of dimeric spikes. With microcalorimetry, electron cryo microscopy and peptide microarray-based screens, we have characterized the structural and thermodynamic properties of peptide binding to hepatitis B core protein capsids with different secretion phenotypes. The peptide “GSLLGRMKGA” binds weakly to hepatitis B core protein capsids and mutant capsids with a premature (F97L) or low-secretion phenotype (L60V and P5T). With electron cryo microscopy, we provide novel structures for L60V and P5T and demonstrate that binding occurs at the tips of the spikes at the dimer interface, splaying the helices apart independent of the secretion phenotype. Peptide array screening identifies “SLLGRM” as the core binding motif. This shortened motif binds only to one of the two spikes in the asymmetric unit of the capsid and induces a much smaller conformational change. Altogether, these comprehensive studies suggest that the tips of the spikes act as an autonomous binding platform that is unaffected by mutations that affect secretion phenotypes.

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Section: Discussionmentioning

confidence: 98%

“…Chronic carriers rely on antivirals, which interfere with the viral maturation cycle to control their viral load. Some antivirals target the virus assembly and are now under clinical trials (for review, see [5,6]).…”

Section: Introductionmentioning

confidence: 99%

Conformational Plasticity of Hepatitis B Core Protein Spikes Promotes Peptide Binding Independent of the Secretion Phenotype

et al. 2021

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“…However, the consensus in the field is that drugs will have to be used in combination in order to achieve an HBV cure. New therapeutic approaches and the results of preclinical/clinicals trials have been discussed in recent reviews [ 107 , 109 , 110 ].…”

Section: Discussionmentioning

confidence: 99%

Early Steps of Hepatitis B Life Cycle: From Capsid Nuclear Import to cccDNA Formation

Dias

Sarica

Neuveut

2021

Viruses

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Hepatitis B virus (HBV) remains a major public health concern, with more than 250 million chronically infected people who are at high risk of developing liver diseases, including cirrhosis and hepatocellular carcinoma. Although antiviral treatments efficiently control virus replication and improve liver function, they cannot cure HBV infection. Viral persistence is due to the maintenance of the viral circular episomal DNA, called covalently closed circular DNA (cccDNA), in the nuclei of infected cells. cccDNA not only resists antiviral therapies, but also escapes innate antiviral surveillance. This viral DNA intermediate plays a central role in HBV replication, as cccDNA is the template for the transcription of all viral RNAs, including pregenomic RNA (pgRNA), which in turn feeds the formation of cccDNA through a step of reverse transcription. The establishment and/or expression of cccDNA is thus a prime target for the eradication of HBV. In this review, we provide an update on the current knowledge on the initial steps of HBV infection, from the nuclear import of the nucleocapsid to the formation of the cccDNA.

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“…Chronic HBV infection accounts for approximately 80% of virus-associated HCC cases and virtually all of childhood HCC, especially in Africa and East Asia, while HCV infection, involved in about 20% of the total HCC cases, seems to be mainly related to HCC development in Western Europe and North America [91]. Prospective cohort studies have shown a significant increase in the risk of developing HCC among persons chronically infected with HBV or HCV [91,93]. Between 70 and 90% of the HBV-infected individuals who develop HCC have cirrhosis secondary to chronic necroinflammation [91,93].…”

Section: Viral Hepatitismentioning

confidence: 99%

“…Prospective cohort studies have shown a significant increase in the risk of developing HCC among persons chronically infected with HBV or HCV [91,93]. Between 70 and 90% of the HBV-infected individuals who develop HCC have cirrhosis secondary to chronic necroinflammation [91,93]. HCV also increases the risk of HCC by inducing fibrosis and, eventually, cirrhosis [91].…”

Section: Viral Hepatitismentioning

confidence: 99%

Endoplasmic Reticulum Stress Signaling and the Pathogenesis of Hepatocarcinoma

Wei

Fang

2021

IJMS

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Hepatocellular carcinoma (HCC), also known as hepatoma, is a primary malignancy of the liver and the third leading cause of cancer mortality globally. Although much attention has focused on HCC, its pathogenesis remains largely obscure. The endoplasmic reticulum (ER) is a cellular organelle important for regulating protein synthesis, folding, modification and trafficking, and lipid metabolism. ER stress occurs when ER homeostasis is disturbed by numerous environmental, physiological, and pathological challenges. In response to ER stress due to misfolded/unfolded protein accumulation, unfolded protein response (UPR) is activated to maintain ER function for cell survival or, in cases of excessively severe ER stress, initiation of apoptosis. The liver is especially susceptible to ER stress given its protein synthesis and detoxification functions. Experimental data suggest that ER stress and unfolded protein response are involved in HCC development, aggressiveness and response to treatment. Herein, we highlight recent findings and provide an overview of the evidence linking ER stress to the pathogenesis of HCC.

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Hepatitis B Virus Cure: Targets and Future Therapies

Cited by 71 publications

References 50 publications

Conformational Plasticity of Hepatitis B Core Protein Spikes Promotes Peptide Binding Independent of the Secretion Phenotype

Conformational Plasticity of Hepatitis B Core Protein Spikes Promotes Peptide Binding Independent of the Secretion Phenotype

Early Steps of Hepatitis B Life Cycle: From Capsid Nuclear Import to cccDNA Formation

Endoplasmic Reticulum Stress Signaling and the Pathogenesis of Hepatocarcinoma

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