What are HBV core protein modulators and how do they work?

Hepatitis B virus (HBV) is a major global health concern, infecting over 250 million people worldwide and leading to serious conditions such as liver cirrhosis and hepatocellular carcinoma. The virus is a complex pathogen with a sophisticated lifecycle, making it challenging to treat and manage. One promising avenue of treatment is the use of HBV core protein modulators. These agents offer a new approach to combatting HBV by targeting the virus's core protein, which is crucial for its replication and persistence.

HBV core protein modulators, also known as capsid assembly modulators, are designed to interfere with the formation and function of the HBV nucleocapsid, a structure essential to the virus's lifecycle. The HBV core protein plays several roles, including packaging the viral pregenomic RNA (pgRNA) and the DNA polymerase enzyme into the nucleocapsid, which is then converted into relaxed circular DNA (rcDNA). The rcDNA is eventually converted into covalently closed circular DNA (cccDNA), a stable form that resides in the nucleus of infected cells and serves as a template for the production of new viral particles. By disrupting these processes, HBV core protein modulators aim to inhibit the replication and propagation of the virus.

The mechanism of action of HBV core protein modulators involves binding to the core protein, altering its conformation and assembly dynamics. There are two primary categories of these modulators: Class I and Class II. Class I modulators, also known as capsid assembly accelerators, induce the formation of empty capsids, which are non-infectious and unable to encapsulate the viral genome. This premature assembly prevents the proper packaging of pgRNA and the DNA polymerase, thereby inhibiting the production of new virions. Class II modulators, on the other hand, disrupt the formation of the capsid entirely, leading to the degradation of core protein and preventing the assembly of any nucleocapsid structures. Both classes ultimately reduce the levels of cccDNA, thereby decreasing viral persistence and replication.

HBV core protein modulators have several potential applications in the treatment of chronic hepatitis B. One of the primary uses is in combination therapy with existing antiviral agents such as nucleos(t)ide analogues (NAs) and interferons. While NAs are effective at suppressing viral replication by inhibiting the reverse transcription of pgRNA to DNA, they do not eliminate cccDNA, which can persist in the liver and cause viral rebound once treatment is stopped. By targeting the core protein and reducing cccDNA levels, core protein modulators can enhance the efficacy of NAs and potentially lead to a functional cure, characterized by sustained suppression of HBV DNA without the need for ongoing treatment.

Another significant use of HBV core protein modulators is in the context of drug-resistant HBV strains. Resistance to NAs can develop over time, particularly in patients who require long-term therapy. Core protein modulators, with their distinct mechanism of action, offer an alternative strategy to suppress these resistant strains. Their use could be particularly beneficial in patients who have failed multiple lines of antiviral therapy.

In addition to their therapeutic potential, HBV core protein modulators also provide valuable tools for research into the HBV lifecycle and pathogenesis. By selectively targeting specific stages of the viral replication process, these agents can help elucidate the roles of different viral components and identify new targets for drug development. This could ultimately lead to the discovery of additional therapeutic strategies and a better understanding of how to eradicate HBV infection.

In conclusion, HBV core protein modulators represent a promising advancement in the fight against chronic hepatitis B. By interfering with the assembly and function of the viral nucleocapsid, these agents have the potential to enhance existing treatments, address drug-resistant strains, and contribute to a functional cure. As research and clinical trials continue, HBV core protein modulators hold the potential to significantly impact the management and outcome of HBV infection, offering hope to millions of affected individuals worldwide.