Capsid Assembly Modulators as Antiviral Agents against HBV: Molecular Mechanisms and Clinical Perspectives

Taverniti, Valério; Ligat, Gaëtan; Debing, Yannick; Kum, Dieudonné Buh; Baumert, Thomas F.

doi:10.3390/jcm11051349

Cited by 43 publications

(31 citation statements)

References 79 publications

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“…For example, the reduction in RNA levels was consistently higher in patients treated with CAMs in combination with NUCs than in those treated with NUCs alone 112 . The reduction of serum HBV RNA during treatment with CAMs is consistent with their mechanism, which blocks pgRNA packaging into capsids as required for their secretion into blood 113 . In this case, serum RNA will no longer correlate with cccDNA levels or transcriptional activity but can serve to monitor target engagement.…”

Section: Hbv Biomarkers During Treatmentsupporting

confidence: 60%

A roadmap for serum biomarkers for hepatitis B virus: current status and future outlook

Kramvis

Chang

Dandri

et al. 2022

Nat Rev Gastroenterol Hepatol

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Globally, 296 million people are infected with hepatitis B virus (HBV), and approximately one million people die annually from HBV-related causes, including liver cancer. Although there is a preventative vaccine and antiviral therapies suppressing HBV replication, there is no cure. Intensive efforts are under way to develop curative HBV therapies. Currently, only a few biomarkers are available for monitoring or predicting HBV disease progression and treatment response. As new therapies become available, new biomarkers to monitor viral and host responses are urgently needed. In October 2020, the International Coalition to Eliminate Hepatitis B Virus (ICE-HBV) held a virtual and interactive workshop on HBV biomarkers endorsed by the International HBV Meeting. Various stakeholders from academia, clinical practice and the pharmaceutical industry, with complementary expertise, presented and participated in panel discussions. The clinical utility of both classic and emerging viral and immunological serum biomarkers with respect to the course of infection, disease progression, and response to current and emerging treatments was appraised. The latest advances were discussed, and knowledge gaps in understanding and interpretation of HBV biomarkers were identified. This Roadmap summarizes the strengths, weaknesses, opportunities and challenges of HBV biomarkers.

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Section: Hbv Biomarkers During Treatmentsupporting

confidence: 60%

A roadmap for serum biomarkers for hepatitis B virus: current status and future outlook

Kramvis

Chang

Dandri

et al. 2022

Nat Rev Gastroenterol Hepatol

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“…NUCs inhibit viral DNA synthesis, which reduces the amount of newly productive viruses and slows the synthesis of downstream cccDNA. Capsid protein assembly modulators (CpAM) interfere with pregenomic RNA (pgRNA) encapsidation into the capsid [ 78 , 79 , 80 , 81 ], which also reduces viral production and cccDNA replenishment. Entry inhibitors of various types, including peptides, monoclonal antibodies and compounds [ 82 , 83 , 84 ], suppress cccDNA replenishment by preventing viruses from entering the cells.…”

Section: Considering Chb Treatments In Light Of Cccdna Dynamicsmentioning

confidence: 99%

Dynamics of Hepatitis B Virus Covalently Closed Circular DNA: A Mini-Review

Huang

2023

Microorganisms

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Eradication of cccDNA is an ideal goal of chronic hepatitis B (CHB) therapy. Understanding the changes in the cccDNA pool during therapy provides a basis for developing CHB treatment strategies. On the other hand, the shift in the balance of the cccDNA pool following therapies allowed researchers to investigate the dynamics of cccDNA. Central to the description of cccDNA dynamics is a parameter called cccDNA half-life. CccDNA half-life is not an intrinsic property of cccDNA molecules, but a description of an observed phenomenon characterized by cccDNA pool decline. Since cccDNA has to be in the nuclei of host cells to function, the half-life of cccDNA is determined by the state and destiny of the host cells. The major factors that drive cccDNA decay include noncytopathic effects and hepatocyte turnover (death and division). In some cases, the determining factor is not the half-life of cccDNA itself, but rather the half-life of the hepatocyte. The main purpose of this review is to analyze the major factors affecting cccDNA half-life and determine the areas requiring further study. In addition, the discrepancy in cccDNA half-life between short-term and long-term nucleot(s)ide analog (NUC) therapy was reported. Hypotheses were proposed to explain the multi-phasic decline of cccDNA during NUC therapy, and a framework based on cccDNA dynamics was suggested for the consideration of various anti-HBV strategies.

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“…Currently, drug development for anti-HBV treatment is focused on CAMs. In addition to the small molecules mentioned above, there are some other small molecules currently being studied in clinical or preclinical studies, such as EDP-514 ( Feld et al., 2022 ), RG7907 ( Gonçalves et al., 2021 ), ABI-H3733 ( Taverniti et al., 2022 ), ALG-000184 ( Taverniti et al., 2022 ), GLP-26 ( Amblard et al., 2021 ), and SHR5133 ( Li et al., 2022 ).…”

Section: The Development Of Drugs Affecting the Hbv Life Cyclementioning

confidence: 99%

“…In more than half of patients administered with JNJ-56136379, an obvious reduction of the HBV DNA and RNA levels was observed (Zoulim et al, 2020). However, JNJ-56136379 did not have an effect on the levels of HBsAgs and HBeAgs, and viral rebound was observed after the end of treatment (Gane et al, 2022;Taverniti et al, 2022).…”

Section: Capsid Assembly Modulatorsmentioning

confidence: 99%

The progress of molecules and strategies for the treatment of HBV infection

Pan

Xia

et al. 2023

Front. Cell. Infect. Microbiol.

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Hepatitis B virus infections have always been associated with high levels of mortality. In 2019, hepatitis B virus (HBV)-related diseases resulted in approximately 555,000 deaths globally. In view of its high lethality, the treatment of HBV infections has always presented a huge challenge. The World Health Organization (WHO) came up with ambitious targets for the elimination of hepatitis B as a major public health threat by 2030. To accomplish this goal, one of the WHO’s strategies is to develop curative treatments for HBV infections. Current treatments in a clinical setting included 1 year of pegylated interferon alpha (PEG-IFNα) and long-term nucleoside analogues (NAs). Although both treatments have demonstrated outstanding antiviral effects, it has been difficult to develop a cure for HBV. The reason for this is that covalently closed circular DNA (cccDNA), integrated HBV DNA, the high viral burden, and the impaired host immune responses all hinder the development of a cure for HBV. To overcome these problems, there are clinical trials on a number of antiviral molecules being carried out, all -showing promising results so far. In this review, we summarize the functions and mechanisms of action of various synthetic molecules, natural products, traditional Chinese herbal medicines, as clustered regularly interspaced short palindromic repeats and their associated proteins (CRISPR/Cas)-based systems, zinc finger nucleases (ZFNs), and transcription activator-like effector nucleases (TALENs), all of which could destroy the stability of the HBV life cycle. In addition, we discuss the functions of immune modulators, which can enhance or activate the host immune system, as well some representative natural products with anti-HBV effects.

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Capsid Assembly Modulators as Antiviral Agents against HBV: Molecular Mechanisms and Clinical Perspectives

Cited by 43 publications

References 79 publications

A roadmap for serum biomarkers for hepatitis B virus: current status and future outlook

A roadmap for serum biomarkers for hepatitis B virus: current status and future outlook

Dynamics of Hepatitis B Virus Covalently Closed Circular DNA: A Mini-Review

The progress of molecules and strategies for the treatment of HBV infection

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