Mechanism of CpAM-Induced HBV Core Protein Degradation and Therapeutic Implication
Abstract
Hepatitis B virus (HBV) chronically infects 257 million people worldwide and causes 680 thousand deaths annually due to cirrhosis, hepatocellular carcinoma, and liver failure. The current standard-of-care medicines for chronic HBV infection can significantly reduce viral load and prevent liver disease progression, but rarely induce a functional cure of the viral infection. The failure to achieve a functional cure is attributed to the persistence of viral genome in the infected hepatocytes and dysfunction of host antiviral immune response. Accordingly, novel antiviral therapeutics that can efficiently suppress viral replication and restore a functional antiviral immune response to control the residual HBV infection are urgently needed. HBV core protein allosteric modulators (CpAMs) are a novel type of antiviral agents currently in clinical development for the treatment of chronic hepatitis B. By binding to a hydrophobic pocket at the viral core protein dimer-dimer interface, CpAMs misdirect viral capsid assembly and disassembly to disrupt multiple steps of HBV replication. This project is to discover novel CpAMs that can misdirect core protein to assemble non-capsid polymers for accelerated degradation in hepatocytes by structure-assisted rationale design. The mechanism and potential of the novel CpAM-induced Cp degradation for enhancing the activation of antiviral immune response that can cure the chronic HBV infection will be investigated.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110587
Entities
People
- Ju-Tao Guo
Organizations
- Baruch S. Blumberg Institute
- United States Army