Treatment of Chronic Hepatitis B Virus Infection Using Small Molecule Modulators of Nucleocapsid Assembly: Recent Advances and Perspectives

Abstract

On the basis of the recent advance of basic research on molecular biology of hepatitis B virus (HBV) infection, novel antiviral drugs targeting various steps of the HBV life cycle have been developed in recent years. HBV nucleocapsid assembly is now recognized as a hot target for anti-HBV drug development. Structural and functional analysis of HBV nucleocapsid allowed rational design and improvement of small molecules with the ability to interact with the components of HBV nucleocapsid and modulate the viral nucleocapsid assembly process. Prototypes of small molecule modulators targeting HBV nucleocapsid assembly are being preclinically tested or have moved forward in clinical trials, with promising results. This Review summarizes the recent advances in the approach to develop antiviral drugs based on the modulation of HBV nucleocapsid assembly. The antiviral mechanisms of small molecule modulators beyond the capsid formation and the potential implications will be discussed.

Host Genetic Determinants of Hepatitis B Virus Infection

“…Attempts to improve the response by administering two different NUCs or a combination of NUCs and IFN-α failed to increase the rate of “functional cure.” New drug candidates targeting different steps of HBV life cycle including entry, cccDNA formation, viral transcription, capsid assembly, and secretion of viral envelope proteins were developed and partly tested in clinical trials (Qazi et al, 2018; Tu and Urban, 2018; Yang and Lu, 2018; Yang et al, 2019). Immunotherapeutic approaches to enhance antiviral immunity using IL-15, TLR agonists, retinoic acid inducible gene I (RIG-I) agonist, stimulator of IFN genes (STING) agonist or based on engineered T cells are also under investigation (Ma et al, 2015; Zhang and Lu, 2015; Guo et al, 2017; Koh et al, 2018).…”

Solid-State NMR for Studying the Structure and Dynamics of Viral Assemblies

“…With the proton resonances assigned, this approach can now be used for further interaction studies, with cellular partners that are available in small quantities, as well as with antivirals like the capsid assembly modulators (CAMs, also called core protein allosteric modulators, CpAMs). CAMs are currently under pharmaceutical development for targeting viral nucleocapsid assembly [ 107 , 108 ]; they act by either promoting assembly of regularly appearing but genome-less capsids, or they induce the formation of aberrantly shaped irregular multimers, which are not functional in viral replication; notably, recent data suggest that this distinction is not always strict in that the concentration of a compound and the time it is in contact can affect the morphological outcome [ 109 ]. In this context, the use of cell-free synthesis systems for sample preparation is particularly interesting as assembly modulators can act directly on the capsid protein exiting from the ribosome, and hence in a preassembly state.…”

Mechanism of action of HBV capsid assembly modulators predicted from binding to early assembly intermediates

“…It is characterized by a persistent presence of covalently closed circular DNA (cccDNA) in the infected hepatocytes, which is not eliminated by presently approved therapies [2][3][4] . A promising orthogonal approach for eliminating the infection is to target HBV nucleocapsid [5][6][7][8][9][10][11][12][13] . Capsid assembly modulators (CAMs) are small molecules that affect capsid assembly by interacting with the capsid proteins 5-10, 12, 13 .…”

“…Capsid assembly modulators (CAMs) are small molecules that affect capsid assembly by interacting with the capsid proteins 5-10, 12, 13 . Different assembly effects, such as acceleration or misdirection, have been achieved by different CAMs [5][6][7][8][9][10][11][12][13] . It was also discovered that CAMs can both inhibit virus replication and interfere with cccDNA synthesis, suggesting that they could help eliminate the virus from hepatocytes more efficiently 5,6 .…”