Inhibition of hepatitis B virus replication by Bay 41-4109 and its association with nucleocapsid disassembly.
The authors investigate the effects and mechanisms of the anti-hepatitis B virus (HBV) agent Bay 41-4109. HepG2.2.15 cells were used to investigate the antiviral effects of Bay 41-4109 by using real-time polymerase chain reaction (PCR), western blotting, and immunofluorescence. The C terminally truncated core protein was expressed and purified. Changes in hepatitis B capsid formation were assayed by dynamic light scattering and transmission electronic microscopy. Bay 41-4109 was found to be a highly selective and potent inhibitor of hepatitis B virus replication in HepG2.2.15 cells. This compound was equally effective at inhibiting HBV DNA release and the cytoplasmic HBcAg level, with 50% inhibitory concentrations of 32.6 and 132 nM, respectively. HBV DNA and HBcAg were inhibited in a dose-dependent manner, indicating that the anti-HBV mechanisms are associated with and dependent on the rate of HBcAg inhibition. Our results indicate that Bay 41-4109 treatment disassembled the core capsids and separated them into monomers or dimers, the form in which they could be further degraded into peptides. The core protein assembled in a misdirected manner cannot function effectively. Our results suggest that, based on its particular activities, Bay 41-4109 is a promising anti-HBV candidate.
Wu
Guo-Yi
GY
Hepatology Institute, People's Hospital, Peking University, Beijing, China.
Zheng
Xiao-Jing
XJ
Yin
Chang-Cheng
CC
Jiang
Dong
D
Zhu
Ling
L
Liu
Yan
Y
Wei
Lai
L
Wang
Yu
Y
Chen
Hong-Song
HS
D000998:Antiviral Agents / Q000494:pharmacology*; D015153:Blotting, Western; D002460:Cell Line; D004279:DNA, Viral / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005455:Fluorescent Antibody Technique; D006512:Hepatitis B Core Antigens / Q000378:metabolism; D006515:Hepatitis B virus / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D019251:Nucleocapsid / Q000187:drug effects* / Q000502:physiology; D016133:Polymerase Chain Reaction; D011725:Pyridines / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D014764:Viral Proteins / Q000096:biosynthesis; D014779:Virus Replication / Q000187:drug effects
D000998:Antiviral Agents; C464059:BAY 41-4109; D004279:DNA, Viral; D006512:Hepatitis B Core Antigens; D011725:Pyridines; D011743:Pyrimidines; D014764:Viral Proteins