1. Academic Validation
  2. The novel compound Z060228 inhibits assembly of the HBV capsid

The novel compound Z060228 inhibits assembly of the HBV capsid

  • Life Sci. 2015 Jul 15:133:1-7. doi: 10.1016/j.lfs.2015.04.011.
Hua Guan 1 Guoming Zhao 2 Wei Chen 2 Guoyi Wu 3 Hongying Liu 2 Xingkai Jiang 2 Song Li 4 Li-li Wang 5
Affiliations

Affiliations

  • 1 Beijing Institute of Pharmacology and Toxicology, Beijing 100850, People's Republic of China; Department of Radiation Toxicology and Oncology, Beijing Key Laboratory for Radiobiology, Beijing Institute of Radiation Medicine, Beijing 100850, People's Republic of China.
  • 2 Beijing Institute of Pharmacology and Toxicology, Beijing 100850, People's Republic of China.
  • 3 Peking University, Beijing 100871, People's Republic of China.
  • 4 Beijing Institute of Pharmacology and Toxicology, Beijing 100850, People's Republic of China. Electronic address: lisong_amms@yahoo.cn.
  • 5 Beijing Institute of Pharmacology and Toxicology, Beijing 100850, People's Republic of China. Electronic address: wangll63@126.com.
Abstract

Aims: The effective anti-HBV drugs on the market are mainly immunomodulators or nucleoside analogs. The uses of INF-α and lamivudine (3TC) are considerably limited by their low response rate, side effects, drug resistance and HBV recurrence. Thus, new mechanism-based drugs remain in urgent need. This study aimed to investigate the anti-HBV effects of the novel compound Z060228 and to confirm its anti-HBV mechanisms.

Main methods: HepG2.2.15 cells and HBV-transgenic mice were used to evaluate the anti-HBV activity of Z060228. Conformational changes of the capsid structure induced by Z060228 were detected with high-resolution electron microscopy (EM), size-exclusion chromatography (SEC), and atomic force microscopy (AFM).

Key findings: The HBV DNA replication in the supernatants of the HepG2.2.15 cells was effectively inhibited by Z060228 and Bay41-4109. In the liver of HBV-transgenic mice, the HBcAg content was significantly decreased and HBV DNA replication was also inhibited after high-dose (30 mg/kg) Z060228 treatment. Z060228 and Bay41-4109 exhibited similar effects on the self-assembly of Cp149. SEC data revealed that Z060228 altered the equilibrium (a state of stability) of Cp149 assembly. EM data further demonstrated that Z060228 could prevent Cp149 from self-assembling to the correct core particles. Additionally, AFM results showed that a low concentration of Z060228 caused Cp149 syncretizing, whereas a high concentration caused Cp149 to polymerize.

Significance: Z060228 was demonstrated to be a potential capsid targeting anti-HBV drug candidate. The methods employed here could be used as a general strategy to study mechanisms of self-assembling protein-targeted drugs.

Keywords

Capsid; Cp149; HAPs; HBV; Z060228.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-109969
    Anti-HBV Agent
    HBV