The discovery of novel antivirals to treat hepatitis B virus (HBV) infection is urgently needed, as the currently available drugs mainly target viral proteins at replication step, whereas host factors also play significant roles in HBV infection. Although numerous studies have reported candidate drugs for HBV treatment, there remains a need to find a new drug that may target other steps of the HBV life cycle. In this study, by drug screening of a 533 G-protein-coupled receptors (GPCRs)-associated compound library, we identified ponesimod, a selective agonist of sphingosine-1-phosphate receptor 1 (S1P1), as a drug candidate for the suppression of HBV infection. However, the anti-HBV effect of ponesimod is independent of S1P1 and other sphingosine-1-phosphate receptors (S1PRs). Treatment with ponesimod at an early step of infection but not at a post-entry step significantly reduced the HBV relaxed circular DNA (rcDNA) level in a dose-dependent manner. Ponesimod treatment did not inhibit attachment, binding, or internalization of HBV particles via endocytosis through an interaction with sodium taurocholate cotransporting polypeptide (NTCP) or epidermal growth factor receptor (EGFR). Importantly, during the transportation of HBV particles to the nucleus, co-localization of HBV with early endosomes but not with late endosomes and lysosomes was induced by the treatment with ponesimod, suggesting that ponesimod interferes with the conversion of early endosomes to late endosomes without significant damage to cellular growth. Conclusion: Ponesimod is a promising anti-HBV drug targeting the endosome maturation of HBV. This finding can be applied to the development of novel antivirals that target the trafficking pathway of HBV particles.

Yuzy Fauzyah

Chikako Ono

Shiho Torii

Itsuki Anzai

Rigel Suzuki

Takuma Izumi

Yuhei Morioka

Yusuke Maeda

Toru Okamoto

Takasuke Fukuhara

Yoshiharu Matsuura

Antiviral Research

ANTIVIRAL RESEARCH 发表关于控制人类和动物病毒感染的研究报告、简短通讯、评论文章和评论。其范围包括：抗病毒药物、抗体和宿主反应调节剂，包括它们的合成、体外和体内测试以及作用机制；针对人类病毒感染的新的或改进的疫苗；药物和疫苗安全性评估；耐药病毒或疫苗耐药病毒的进化和有效对策的制定；新药靶点的识别和验证；病毒性疾病的实验动物模型；病毒性疾病的发病机制和病毒逃避宿主免疫反应的机制。

The journal "Antiviral Research" publishes research reports, short communications, review articles, and commentaries on the control of human and animal viral infections. Its scope includes: antiviral drugs, antibodies, and host response modulators, including their synthesis, in vitro and in vivo testing, and mechanisms of action; new or improved vaccines for human viral infections; safety assessments of drugs and vaccines; the evolution of drug-resistant viruses or vaccine-resistant viruses and the development of effective countermeasures; identification and validation of new drug targets; experimental animal models of viral diseases; and mechanisms of viral diseases and how viruses evade host immune responses.

《Antiviral Research》期刊发表关于控制人类和动物病毒感染的研究报告、简短通讯、评论文章及综述。其研究范围包括：抗病毒药物、抗体及宿主反应调节剂的合成、体外和体内测试及作用机制；针对人类病毒感染的新型或改进疫苗；药物和疫苗的安全性评估；耐药病毒或疫苗耐药病毒的进化及有效对策的制定；新药靶点的识别与验证；病毒性疾病的实验动物模型；病毒性疾病的发病机制及病毒逃避宿主免疫反应的机制。

Ponesimod suppresses hepatitis B virus infection by inhibiting endosome maturation

Ponesimod is a promising anti-HBV drug targeting the endosome maturation of HBV, and this finding can be applied to the development of novel antivirals that target the trafficking pathway ofHBV particles.

Category	Quartile
医学	2
医学, 药学	2
医学, 病毒学	2

Ponesimod suppresses hepatitis B virus infection by inhibiting endosome maturation

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