Past, Current, and Future Developments of Therapeutic Agents for Treatment of Chronic Hepatitis B Virus Infection

Abstract

For decades, treatment of hepatitis B virus (HBV) infection has been relying on interferon (IFN)-based therapies and nucleoside/nucleotide analogues (NAs) that selectively target the viral polymerase reverse transcriptase (RT) domain and thereby disrupt HBV viral DNA synthesis. We have summarized here the key steps in the HBV viral life cycle, which could potentially be targeted by novel anti-HBV therapeutics. A wide range of next-generation direct antiviral agents (DAAs) with distinct mechanisms of actions are discussed, including entry inhibitors, transcription inhibitors, nucleoside/nucleotide analogues, inhibitors of viral ribonuclease H (RNase H), modulators of viral capsid assembly, inhibitors of HBV surface antigen (HBsAg) secretion, RNA interference (RNAi) gene silencers, antisense oligonucleotides (ASOs), and natural products. Compounds that exert their antiviral activities mainly through host factors and immunomodulation, such as host targeting agents (HTAs), programmed cell death protein 1 (PD-1)/programmed death ligand 1 (PD-L1) inhibitors, and Toll-like receptor (TLR) agonists, are also discussed. In this Perspective, we hope to provide an overview, albeit by no means being comprehensive, for the recent development of novel therapeutic agents for the treatment of chronic HBV infection, which not only are able to sustainably suppress viral DNA but also aim to achieve functional cure warranted by HBsAg loss and ultimately lead to virus eradication and cure of hepatitis B.

Solid-state [13C–15N] NMR resonance assignment of hepatitis B virus core protein

“…However, a comparison with the solution-NMR chemical shifts reported for the Cp149 dimer (Freund et al 2008) highlights conformational differences in three distinct regions of the protein, suggesting they are structurally affected by the transition from the dimer state to the capsid state. In summary, the work presented here sets the stage for future high resolution NMR studies of the HBV core protein which is central in HBV infection and thus is also becoming a highly attractive target for novel anti-HBV therapeutics (Zlotnick et al 2015;Durantel and Zoulim 2016;Pei et al 2017).…”

2′‐Fluoro‐6′‐methylene carbocyclic adenosine and its phosphoramidate prodrug: A novel anti‐HBV agent, active against drug‐resistant HBV mutants

“…Recent drug discovery efforts by biotech firms include (a) direct inhibition of viral replication using entry inhibitors; (b) targeting cccDNA; (c) inhibitors of nucleocapsid assembly (e.g., inhibition of capsid formation); (d) siRNA targeting viral transcription; (e) approaches to target the secretion of viral envelope proteins; (f) restoration of immune responses; (g) RNase H inhibitors . Most of these approaches are in different preclinical and clinical stages (Figure ) . Most of these anti‐HBV agents reduce the viral load up to 95%.…”

“…47,62,63 Most of these approaches are in different preclinical and clinical stages ( Figure 2). 64,65 Most of these anti-HBV agents reduce the viral load up to 95%. Regardless of the availability of effective prophylactic vaccines and/or antiviral agents, chronic HBV remains a challenging global health problem because of the multifaceted process of HBV infection, progression, and frequent mutations.…”

Hepatitis B: Standard and Novel Treatment Options

“…HBV has a complex life cycle involving viral proteins and host factors, which are potential targets of therapeutic intervention. A wide range of next‐generation direct antiviral agents with distinct mechanisms are currently in development, which include viral entry inhibitors, transcription inhibitors, inhibitors of viral RNase H, modulators of capsid assembly, inhibitors of HBsAg secretion, RNA interference gene silencers, and antisense oligonucleotides . Compounds that exert antiviral activities through host factors and immunomodulation, such as host targeting agents, programmed cell death protein 1/programmed death ligand‐1 inhibitors, and Toll‐like receptor agonists, are also being studied …”

“…1,2,8 This class includes lamivudine (LAM), telbivudine, entecavir (ETV), adefovir dipivoxil (ADV), tenofovir disoproxil fumarate (TDF), and the very recently approved tenofovir alafenamide fumarate (TAF). 1,8 Overall, NAs are administered orally, have negligible adverse effects, and can be used in decompensated cirrhosis or acute liver failure, which make them preferred over PEG-IFN in most cases. However, the requirement for indefinite therapy in many cases is associated with concerns regarding long-term costs, risk for nonadherence, and adverse effects.…”