A novel synthetic bile acid derivative inhibits hepatitis B virus infection at entry step by interfering with the oligomerization of sodium taurocholate co-transporting polypeptide

  • Antiviral Res. 2025 Aug 30:243:106267. doi: 10.1016/j.antiviral.2025.106267.
Gede Ngurah Rsi Suwardana  1 ,  Takayuki Abe  2 ,  Lin Deng  3 ,  Chieko Matsui  3 ,  Takashi Okitsu  4 ,  Takeshi Yamada  5 ,  Manabu Hatano  5 ,  Pattama Wiriyasermkul  6 ,  Shushi Nagamori  7 ,  Sameh A Gad  8 ,  Hussein H Aly  8 ,  Hironori Nishitsuji  9 ,  Kunitada Shimotohno  10 ,  Ikuo Shoji  11
Affiliations
  • 1. Division of Infectious Disease Control, Center for Infectious Diseases, Kobe University Graduate School of Medicine, Kobe, Japan; Department of Microbiology, Faculty of Medicine, Udayana University, Bali, Indonesia.
  • 2. Department of Virology, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan.
  • 3. Division of Infectious Disease Control, Center for Infectious Diseases, Kobe University Graduate School of Medicine, Kobe, Japan.
  • 4. Faculty of Pharmaceutical Sciences, University of Toyama, Toyama, Japan.
  • 5. Faculty of Pharmaceutical Sciences, Kobe Pharmaceutical University, Kobe, Japan.
  • 6. Department of Biological Chemistry and Food Science, Iwate University Faculty of Agriculture, Iwate, Japan; Center for SI Medical Research, The Jikei University School of Medicine, Tokyo, Japan.
  • 7. Center for SI Medical Research, The Jikei University School of Medicine, Tokyo, Japan.
  • 8. Japan Institute for Health Security (JIHS)-National Institute of Infectious Diseases (NIID), Department of Virology II, Tokyo, Japan.
  • 9. Department of Virology, Fujita Health University School of Medicine, Toyoake, Japan.
  • 10. Laboratory of Microbial Carcinogenesis, Institute of Microbial Chemistry, Tokyo, Japan.
  • 11. Division of Infectious Disease Control, Center for Infectious Diseases, Kobe University Graduate School of Medicine, Kobe, Japan. Electronic address: [email protected].
PMID: 40889532 DOI: 10.1016/j.antiviral.2025.106267
Abstract

Hepatitis B virus (HBV) Infection is a major global health burden worldwide despite the availability of an effective vaccine and effective anti-HBV drugs. The currently approved anti-HBV drugs-i.e., nucleos(t)IDE analogues and pegylated interferon α-can effectively suppress HBV replication, but rarely achieve a functional cure. Accordingly, new anti-HBV agents targeting different aspects of the HBV life cycle are needed. In this study, we screened for anti-HBV agents using the recombinant HBV expressing NanoLuc (NL) reporter gene (HBV/NL) and our original synthetic heterocyclic compound library. As a result, we identified a synthetic bile acid derivative, SO-145, as a potential novel anti-HBV agent, and investigated its effects in several cellular models of HBV. Treatment of HepG2-NTCP-C4 cells with SO-145 suppressed their NL activity following Infection with HBV/NL. SO-145 suppressed HBV replication in PXB-cells infected with HBV genotype D, but did not show any inhibitory effect on HBV replication in Hep38.7-Tet cells. These results suggest that SO-145 specifically inhibits the early phase of the HBV life cycle. In Other experiments, SO-145 was also shown to inhibit hepatitis D virus Infection. Immunofluorescence analysis using fluorescent-labeled preS1 peptide revealed that SO-145 does not inhibit the preS1 attachment to the NTCP, but does markedly inhibit the HBV/preS1 internalization. Moreover, SO-145 does not inhibit the bile acid uptake facilitated by NTCP. Further mechanistic analysis suggested that SO-145 interferes with the NTCP oligomerization. Taken together, these results suggest that SO-145 inhibits HBV entry into hepatocytes by interfering with the NTCP oligomerization.

Keywords
Anti-HBV agent; Bile acid derivative; Hepatitis B virus; NTCP; NanoLuc.
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