Novel therapeutic strategies for chronic hepatitis B

Abstract

The last few years have seen a resurgence of activity in the hepatitis B drug pipeline, with many compounds in various stages of development. This review aims to provide a comprehensive overview of the latest advances in therapeutics for chronic hepatitis B (CHB). We will discuss the broad spectrum of direct-acting antivirals in clinical development, including capsids inhibitors, siRNA, HBsAg and polymerase inhibitors. In addition, host-targeted therapies (HTT) will be extensively reviewed, focusing on the latest progress in immunotherapeutics such as toll-like receptors and RIG-1 agonists, therapeutic vaccines and immune checkpoints modulators. A growing number of HTT in pre-clinical development directly target the key to HBV persistence, namely the covalently closed circular DNA (cccDNA) and hold great promise for HBV cure. This exciting area of HBV research will be highlighted, and molecules such as cyclophilins inhibitors, APOBEC3 deaminases and epigenetic modifiers will be discussed.

A Semi‐mechanistic Model to Characterize the Long‐Term Dynamics of Hepatitis B Virus Markers During Treatment With Lamivudine and Pegylated Interferon

“…6,10,11 Despite encouraging results obtained with these new agents, the complexity of the host-pathogen interaction makes it likely that NUC and Peg-IFN will remain the backbone of many future treatments. 12 With complex combinations targeting different aspects of the viral lifecycle, the evaluation of new treatment strategies will be particularly challenging. Following the example of hepatitis C virus, mathematical modeling could play a key role to optimize therapy, in terms of dosing regimens and treatment duration.…”

“…Despite encouraging results obtained with these new agents, the complexity of the host‐pathogen interaction makes it likely that NUC and Peg‐IFN will remain the backbone of many future treatments 12 . With complex combinations targeting different aspects of the viral lifecycle, the evaluation of new treatment strategies will be particularly challenging.…”

Discovery of 4,5,6,7-Tetrahydropyrazolo[1.5-a]pyrizine Derivatives as Core Protein Allosteric Modulators (CpAMs) for the Inhibition of Hepatitis B Virus

“…Recent progress in interfering with the viral replication cycle has led to the development of versatile novel therapeutic options for HBV treatment . HBV core protein allosteric modulators (CpAMs) have recently demonstrated excellent inhibitory effects of HBV replication in both preclinical and clinical settings .…”

Design, Synthesis and Evaluation of Novel 4‐(4‐Chlorobenzyl)‐6‐methylpyridazin‐3(2H)‐one Derivatives as Hepatitis B Virus Inhibitors

“…Although viral suppression can be achieved by these drugs, HBV infection cannot be cured. Because of their limitation in the clinical context, new mechanisms of action against HBV infection are being researched to reach new generation anti‐HBV drugs [3–7] …”

“…Because of their limitation in the clinical context, new mechanisms of action against HBV infection are being researched to reach new generation anti-HBV drugs. [3][4][5][6][7] Targeting the nucleocapsid is a promising strategy for this purpose due to not only the capsid of HBV playing a vital role in virus DNA replication by packaging of the HBV pregenomic RNA (pgRNA) and DNA polymerase but also has no human homolog. [8,9] This class of anti-HBV drugs is referred to as core inhibitors, capsid inhibitors, nucleocapsid assembly inhibitors, or core protein assembly modulators (CpAMs).…”