2. Academic Validation
  3. SRPKIN-1 as an inhibitor against hepatitis B virus blocking the viral particle formation and the early step of the viral infection

SRPKIN-1 as an inhibitor against hepatitis B virus blocking the viral particle formation and the early step of the viral infection

  • Antiviral Res. 2023 Dec:220:105756. doi: 10.1016/j.antiviral.2023.105756.
Xiaofang Li 1,  Kenji Nakashima 1,  Masahiko Ito 1,  Mami Matsuda 2,  Takeshi Chida 3,  Kazumasa Sekihara 1,  Hirotaka Takahashi 4,  Takanobu Kato 5,  Tatsuya Sawasaki 4,  Tetsuro Suzuki 6
Affiliations

Affiliations

  • 1 Department of Microbiology and Immunology, Hamamatsu University School of Medicine, Shizuoka, Japan.
  • 2 Department of Virology II, National Institute of Infectious Diseases, Musashi-murayama, Japan.
  • 3 Department of Internal Medicine II, Hamamatsu University School of Medicine, Shizuoka, Japan; Department of Regional Medical Care Support, Hamamatsu University School of Medicine, Shizuoka, Japan.
  • 4 Division of Cell-Free Science, Proteo-Science Center, Ehime University, Matsuyama, Ehime, Japan.
  • 5 Department of Virology II, National Institute of Infectious Diseases, Tokyo, Japan.
  • 6 Department of Microbiology and Immunology, Hamamatsu University School of Medicine, Shizuoka, Japan. Electronic address: [email protected].
PMID: 37992764 DOI: 10.1016/j.antiviral.2023.105756
Abstract

New Antiviral agents are needed for the treatment of hepatitis B virus (HBV) Infection because currently available drugs do not completely eradicate chronic HBV in patients. Phosphorylation dynamics of the HBV core protein (HBc) regulate several processes in the HBV life cycle, including nucleocapsid formation, cell trafficking, and virus uncoating after entry. In this study, the SRPK inhibitors SPHINX31, SRPIN340, and SRPKIN-1 showed concentration-dependent anti-HBV activity. Detailed analysis of the effects of SRPKIN-1, which exhibited the strongest inhibitory activity, on the HBV replication process showed that it inhibits the formation of infectious particles by inhibiting pregenomic RNA packaging into capsids and nucleocapsid envelopment. Mass spectrometry analysis combined with cell-free translation system experiments revealed that hyperphosphorylation of the C-terminal domain of HBc is inhibited by SRPKIN-1. Further, SRPKIN-1 exhibited concentration-dependent inhibition of HBV Infection not only in HepG2-hNTCP-C4 cells but also in fresh human hepatocytes (PXB cells) and in the single-round Infection system. Treatment with SRPKIN-1 at the time of Infection reduced the nuclease sensitivity of HBV DNA in the nuclear fraction. These results suggest that SRPKIN-1 has the potential to not only inhibit the HBV particle formation process but also impair the early stages of viral Infection.

Keywords

Antiviral; HBc; Hepatitis B virus; Phosphorylation; SRPK inhibitor.

Figures
Products