Development of Direct-acting Antiviral and Host-targeting Agents for Treatment of Hepatitis B Virus Infection

Abstract

Hepatitis B virus (HBV) infection affects approximately 300 million people worldwide. Although antiviral therapies have improved the long-term outcomes, patients often require life-long treatment and there is no cure for HBV infection. New technologies can help us learn more about the pathogenesis of HBV infection and develop therapeutic agents to reduce its burden. We review recent advances in development of direct-acting antiviral and host-targeting agents, some of which have entered clinical trials. We also discuss strategies for unbiased high-throughput screens to identify compounds that inhibit HBV and for repurposing existing drugs.

Keywords: Direct-acting Antivirals; Drug; Functional Cure; Screening.

Figure 1.. HBV Life Cycle and Therapeutic Targets

The HBV cycle includes virus attachment, entry, uncoating, trafficking to nucleus, cccDNA formation, transcription, translation, encapsulation, secretion, and integration. HBV infection is initiated via interaction with heparan sulfate proteoglycans (HSGP), resulting in a large envelope protein that binds NTCP. After internalization, viral capsids are released and then directed to the nucleus, where the HBV genomes are released. In the nucleus, relaxed circular DNA genomes are converted into cccDNAs, which can persist in the nucleus of infected cells as a mini-chromosome and serve as template for viral RNA transcription. Viral mRNAs are transported to the cytoplasm, where they are translated into viral proteins. Together with the viral polymerase, the pgRNA is encapsulated and reverse transcribed within the nucleocapsid into progeny rcDNA. Mature nucleocapsids are then either directed to the MVB pathway for envelopment with HBV envelope proteins or re-directed to the nucleus to establish a cccDNA pool. dslDNA that contains capsid is also produced that can be integrated into the cellular genome or released as defective virion. Drugs or antiviral agents designed to target different steps of the HBV life cycle are shown in red.

Figure 2.. Types and Structures of HBV Capsid Inhibitors

(A) Representative compounds belong to phenylpropenamide, heteroaryldihydropyrimidine, or sulfamoylbenzamide family. (B) The targets of different compounds are: phenylpropenamide chemicals, which interfere with pgRNA packaging; heteroaryldihydropyrimidine compounds, which induce abnormal assembly of capsid; and sulfamoylbenzamide family serials, which target both. The target side of heteroaryldihydropyrimidine is shown with a black arrow. (Figure adapted from Wynne et al. Mol Cell 1999. with permission from Cell Press)

Figure 3.. High-throughput Screen for Anti-HBV Compounds

A high-throughput screen for compounds that inhibit HBV involves culture of HBV-susceptible hepatocytes, followed by infection with HBV and addition of compound library. Compounds found to block HBV entry or replication in this assay can be validated in additional assays and for their effects on cell viability.