Preclinical Profile and Characterization of the Hepatitis B Virus Core Protein Inhibitor ABI-H0731

Huang, Qi; Yan, Ran; Li, Lichun; Zong, Yu; Guo, Lida; Mercier, Alexandre; Zhou, Yi; Tang, Ariel; Henne, Kirk R.; Colonno, Richard J.

doi:10.1128/aac.01463-20

Cited by 44 publications

(30 citation statements)

References 40 publications

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“…Not surprisingly, many of the CpAM-resistant Cp mutations severely compromised pgRNA encapsidation and viral DNA synthesis [32,54,60] (Fig 1). Moreover, while single amino acid mutations at the HAP pocket usually confer resistance to selected chemotypes of CpAMs [20,32,60,61], our systematic mutagenesis study of 25 amino acid residues at the wall of HAP pocket identified that several mutations of residue P25, T33 or I105 conferred strong resistance to the inhibition of HBV DNA replication by heteroaryldihydropyrimidines (HAP) as well as four chemotypes of type II CpAMs [26]. Importantly, seven out of the nine mutations supported relatively high levels of pgRNA packaging and DNA synthesis, which allowed investigating the role and mechanism of these residues in other steps of viral replication.…”

Section: Plos Pathogensmentioning

confidence: 99%

Amino acid residues at core protein dimer-dimer interface modulate multiple steps of hepatitis B virus replication and HBeAg biogenesis

et al. 2021

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The core protein (Cp) of hepatitis B virus (HBV) assembles pregenomic RNA (pgRNA) and viral DNA polymerase to form nucleocapsids where the reverse transcriptional viral DNA replication takes place. Core protein allosteric modulators (CpAMs) inhibit HBV replication by binding to a hydrophobic “HAP” pocket at Cp dimer-dimer interfaces to misdirect the assembly of Cp dimers into aberrant or morphologically “normal” capsids devoid of pgRNA. We report herein that a panel of CpAM-resistant Cp with single amino acid substitution of residues at the dimer-dimer interface not only disrupted pgRNA packaging, but also compromised nucleocapsid envelopment, virion infectivity and covalently closed circular (ccc) DNA biosynthesis. Interestingly, these mutations also significantly reduced the secretion of HBeAg. Biochemical analysis revealed that the CpAM-resistant mutations in the context of precore protein (p25) did not affect the levels of p22 produced by signal peptidase removal of N-terminal 19 amino acid residues, but significantly reduced p17, which is produced by furin cleavage of C-terminal arginine-rich domain of p22 and secreted as HBeAg. Interestingly, p22 existed as both unphosphorylated and phosphorylated forms. While the unphosphorylated p22 is in the membranous secretary organelles and the precursor of HBeAg, p22 in the cytosol and nuclei is hyperphosphorylated at the C-terminal arginine-rich domain and interacts with Cp to disrupt capsid assembly and viral DNA replication. The results thus indicate that in addition to nucleocapsid assembly, interaction of Cp at dimer-dimer interface also plays important roles in the production and infectivity of progeny virions through modulation of nucleocapsid envelopment and uncoating. Similar interaction at reduced p17 dimer-dimer interface appears to be important for its metabolic stability and sensitivity to CpAM suppression of HBeAg secretion.

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Section: Plos Pathogensmentioning

confidence: 99%

Amino acid residues at core protein dimer-dimer interface modulate multiple steps of hepatitis B virus replication and HBeAg biogenesis

et al. 2021

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“…ABI-H0731 marked the beginning of a new category of compounds. It is a dibenzo-thiazepine-2-carboxamide derivative, and it has been shown to cause a significant reduction in HBV DNA and RNA levels in phase I clinical trials, as a core protein modulator [ 39 , 205 ].…”

Section: Novel Therapeutic Strategiesmentioning

confidence: 99%

Recent Advances in Hepatitis B Treatment

et al. 2021

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Hepatitis B virus infection affects over 250 million chronic carriers, causing more than 800,000 deaths annually, although a safe and effective vaccine is available. Currently used antiviral agents, pegylated interferon and nucleos(t)ide analogues, have major drawbacks and fail to completely eradicate the virus from infected cells. Thus, achieving a “functional cure” of the infection remains a real challenge. Recent findings concerning the viral replication cycle have led to development of novel therapeutic approaches including viral entry inhibitors, epigenetic control of cccDNA, immune modulators, RNA interference techniques, ribonuclease H inhibitors, and capsid assembly modulators. Promising preclinical results have been obtained, and the leading molecules under development have entered clinical evaluation. This review summarizes the key steps of the HBV life cycle, examines the currently approved anti-HBV drugs, and analyzes novel HBV treatment regimens.

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“…Interference with capsid assembly and inhibition of pgRNA encapsidation (the so‐called primary mechanism) is the most important instrument of inhibition. An additive check on HBV replication has been shown on ultra‐sensitive HBV DNA tests 27 by the turnover of cccDNA and by the monitoring of emergence of signature mutations 28 . A reduction in pgRNA encapsidation is shown by a reduction in particles containing HBV RNA.…”

Section: Inhibitors Of Hbv Replicationmentioning

confidence: 99%

Hepatitis B cure: How and when

Dusheiko

2021

Liver International

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Background First‐ and second‐ generation new treatments are being evaluated to provide a cure for hepatitis B. The life cycle of HBV includes several well‐ categorized steps that are targets for new treatments. A cure remains a major challenge even if it is measured by HBsAg seroclearance alone. The notion of a functional cure of hepatitis B has been accepted, while a partial functional cure has been more tentatively defined as a decline in HBsAg concentrations to lower levels after finite treatment. Methods More profound suppression of hepatitis B replication through the addition of capsid inhibitors with nucleoside analogues could improve patient prognosis and a sustained treatment response. Several strategies are being evaluated to achieve a cure: (a) deepening inhibition of HBV replication or (b) a reduction in HBsAg presentation for HBsAg seroclearance. Results Fortunately, there are signs of important progress in the treatment of hepatitis B including improved on‐ treatment reductions or seroclearance of HBsAg in phase 2 studies that was not achieved with chain terminators and inhibitors of initiation of DNA synthesis. Progress in immunomodulatory therapy has lagged behind that of antiviral therapy. Conclusions Increasing the multilayered impaired and dysfunctional immune response in hepatitis B is perhaps more likely and feasible after a reduction in host antigen burden. Other potential experimental strategies include CRISPR‐ Cas9 genome‐ editing nucleases to specifically target and cleave cccDNA or novel monoclonal antibodies.

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Preclinical Profile and Characterization of the Hepatitis B Virus Core Protein Inhibitor ABI-H0731

Cited by 44 publications

References 40 publications

Amino acid residues at core protein dimer-dimer interface modulate multiple steps of hepatitis B virus replication and HBeAg biogenesis

Amino acid residues at core protein dimer-dimer interface modulate multiple steps of hepatitis B virus replication and HBeAg biogenesis

Recent Advances in Hepatitis B Treatment

Hepatitis B cure: How and when

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