Hepatitis B core protein as a therapeutic target

Abstract

Chronic hepatitis B virus (HBV) infection is difficult to cure, due to the presence of covalently-closed-circular DNA and virus-mediated blunting of host immune response. Existing therapies with nucleos(t)ide analogue or pegylated-interferon are not sufficient to achieve a high rate of HBV surface antigen seroclearance, a more desirable treatment outcome. Novel therapeutic agents targeting alternative viral replication steps are being developed. In this review, we will discuss the hepatitis B core antigen (HBcAg) as a therapeutic target. Areas covered: The basic structure and fundamental functions of HBcAg including nucleocapsid assembly, pre-genomic RNA encapsidation, reverse transcription, virion formation, cccDNA amplification, immune response regulation, and HBx protein interaction will be reviewed. Most of these are identified as therapeutic targets and tested in in vitro and in vivo studies, although clinical trials are scanty. Among the different components, the core protein allosteric modulators (CpAM) have been most widely investigated and appear promising in clinical trials. Expert opinion: The multiple and essential functions of HBcAg for HBV life cycle are important and attractive targets for HBV therapeutic interventions. Controlled trials involving CpAM are awaited. Apart from CpAM, drugs directed against different functions of HBcAg may be further explored to maximize the chance of cure.

Antiviral Activity, Safety, and Pharmacokinetics of Capsid Assembly Modulator NVR 3-778 in Patients with Chronic HBV Infection

“…This mechanism of action inhibits infection of hepatocytes in hepatic lobules and formation of cccDNA via either new cell infection or intracellular cccDNA replenishment cycles in cells that are already HBV-infected, phenomena that depend on the production of HBV DNA-containing nucleocapsids. 5,7,8,[10][11][12]20,21 NVR 3-778 appears to have been the first CAM to complete clinical proof-of-concept studies in HBV-infected patients. The phase 1b study results reported here show consistent and concurrent dose-related reductions in serum HBV DNA and RNA levels, as predicted by its novel mechanism of action (ie, inhibition of pgRNA encapsidation).…”

“…HBc-mediated encapsidation of the viral polymerase and pregenomic HBV RNA (pgRNA) by multimerically assembled viral core (capsid) protein molecules is essential for the production of HBV nucleocapsids and subsequent release of enveloped infectious virus particles from infected cells. [5][6][7] Small molecules have been identified that bind to HBc and can misdirect the assembly of HBc molecules into defective capsid structures, thereby inhibiting pgRNA encapsidation and formation of nucleocapsids and infectious virions. [8][9][10][11] This class of compounds can also inhibit replenishment of intranuclear covalently closed circular DNA (cccDNA) over time, and may have immunomodulatory properties.…”

Guidance for Design and Endpoints of Clinical Trials in Chronic Hepatitis B—Report From the 2019 EASL‐AASLD HBV Treatment Endpoints Conference

“…In comparison to NAs, CpAMs have distinct modes of action; for example, they inhibit pgRNA encapsidation and cccDNA formation, presumably by inhibiting the capsid uncoating step. (73,74) The first compound studied in humans was NVR3-778; in a dose ranging phase Ib study, serum HBV DNA and HBV RNA decreased but a decline in HBsAg was mainly observed when combined with PEG-IFN. (75) Several CpAMs are in preclinical and clinical studies (Table 2).…”

Guidance for design and endpoints of clinical trials in chronic hepatitis B - Report from the 2019 EASL-AASLD HBV Treatment Endpoints Conference‡

“…In comparison to NAs, CpAMs have distinct modes of action; for example, they inhibit pgRNA encapsidation and cccDNA formation, presumably by inhibiting the capsid uncoating step. 77,78 The first compound studied in humans was NVR3-778; in a dose ranging phase Ib study, serum HBV DNA and HBV RNA decreased but a decline in HBsAg was mainly observed when combined with PEG-IFN. 79 Several CpAMs are in preclinical and clinical studies ( Table 2).…”