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Accepted (AM)Open Access (License Unspecified), Open
Journal article
Targeting the multifunctional HBV core protein as a potential cure for chronic hepatitis B
Antiviral research, v 182, 104917
01 Oct 2020
PMID: 32818519
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
The core (capsid) protein of hepatitis B virus (HBV) is the building block of nucleocapsids where viral DNA reverse transcriptional replication takes place and mediates virus-host cell interaction important for the persistence of HBV infection. The pleiotropic role of core protein (Cp) in HBV replication makes it an attractive target for antiviral therapies of chronic hepatitis B, a disease that affects more than 257 million people worldwide without a cure. Recent clinical studies indicate that core protein allosteric modulators (CpAMs) have a great promise as a key component of hepatitis B curative therapies. Particularly, it has been demonstrated that modulation of Cp dimer-dimer interactions by several chemical series of CpAMs not only inhibit nucleocapsid assembly and viral DNA replication, but also induce the disassembly of double-stranded DNA-containing nucleocapsids to prevent the synthesis of cccDNA. Moreover, the different chemotypes of CpAMs modulate Cp assembly by interaction with distinct amino acid residues at the HAP pocket between Cp dimer-dimer interfaces, which results in the assembly of Cp dimers into either non-capsid Cp polymers (type I CpAMs) or empty capsids with distinct physical property (type II CpAMs). The different CpAMs also differentially modulate Cp metabolism and subcellular distribution, which may impact cccDNA metabolism and host antiviral immune responses, the critical factors for the cure of chronic HBV infection. This review article highlights the recent research progress on the structure and function of core protein in HBV replication cycle, the mode of action of CpAMs, as well as the current status and perspectives on the discovery and development of core protein-targeting antivirals. This article forms part of a symposium in Antiviral Research on “Wide-ranging immune and direct-acting antiviral approaches to curing HBV and HDV infections."
•Core protein is a building block of nucleocapsids and involved in multiple steps of the HBV replication.•CpAMs bind to a hydrophobic pocket between core protein dimers to misdirect nucleocapsid assembly and disassembly.•CpAMs not only block viral DNA replication, but also inhibit de novo cccDNA formation.•Targeting the multi-functional core protein is an effective antiviral approach against HBV infection.
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Details
- Title
- Targeting the multifunctional HBV core protein as a potential cure for chronic hepatitis B
- Creators
- Usha Viswanathan - Baruch S. Blumberg InstituteNagraj Mani - Arbutus Biopharma (Canada)Zhanying Hu - Baruch S. Blumberg InstituteHaiqun Ban - Baruch S. Blumberg InstituteYanming Du - Baruch S. Blumberg InstituteJin Hu - Baruch S. Blumberg InstituteJinhong Chang - Baruch S. Blumberg InstituteJu-Tao Guo - Baruch S. Blumberg Institute
- Publication Details
- Antiviral research, v 182, 104917
- Publisher
- Elsevier
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Microbiology and Immunology
- Web of Science ID
- WOS:000576075400004
- Scopus ID
- 2-s2.0-85089817526
- Other Identifier
- 991020547446904721
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InCites Highlights
Data related to this publication, from InCites Benchmarking & Analytics tool:
- Web of Science research areas
- Pharmacology & Pharmacy
- Virology