Novel Hepatitis B Virus Capsid Assembly Modulator Induces Potent Antiviral Responses in Vitro and in Humanized Mice (original) (raw)
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NVR 3-778 is the first Capsid Assembly Modulator (CAM) that has demonstrated antiviral activity in HBV infected patients. NVR 3-778 inhibited the generation of infectious HBV DNA containing virus particles with a mean antiviral EC of 0.40 µM in HepG2.2.15 cells. The antiviral profile of NVR 3-778 indicates pan-genotypic antiviral activity and lack of cross-resistance with nucleos(t)ide inhibitors of HBV replication. The combination of NVR 3-778 with nucleos(t)ide analogs resulted in additive or synergistic antiviral activity. Mutations within the hydrophobic pocket at the dimer-dimer interface of the core protein could confer resistance to NVR 3-778, which is consistent with the ability of the compound to bind to core and to induce capsid assembly. By targeting core, NVR 3-778 inhibits pgRNA encapsidation, viral replication and the production of HBV DNA- and HBV RNA-containing particles. NVR 3-778 also inhibited infection and viral replication in primary human hepatocytes with EC va...
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Around 257 million people worldwide have chronic hepatitis B virus (HBV) infection, which leads to almost 1 million deaths per year from complications, mainly decompensated cirrhosis and hepatocellular carcinoma. The development of effective treatments for hepatitis C virus has led to hope for a cure for HBV. Current treatments for HBV infection include pegylated interferon-alfa, which is associated with modest efficacy and poor tolerability, or nucleoside analogues, which require lifelong administration and rarely achieve hepatitis B surface antigen (HBsAg) loss. Understanding the HBV lifecycle is essential to develop new approaches, since each step is a potential target for drug development. New direct-acting antivirals for HBV in development include entry inhibitors, capsid assembly modulators, and drugs targeting cccDNA or HBV RNA, and HBsAg secretion inhibitors. In this Review, we discuss potential targets and direct-acting antiviral approaches in development.
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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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