Gad Sameh A, Abo Elwafa Doaa A, Hussein Saied A, Fukano Kento, Kato Takanobu, Shoji Ikuo, Chayama Kazuaki, Muramatsu Masamichi, Isogawa Masanori, Wakita Takaji, Merk Daniel, Aly Hussein H
Department of Virology II, National Institute of Infectious Diseases, Japan Institute for Health Security, 1-23-1 Toyama, Shinjuku-ku, Tokyo, 162-8640, Japan; Department of Microbiology and Immunology, Faculty of Pharmacy, Minia University, Minia, 61519, Egypt.
Department of Virology II, National Institute of Infectious Diseases, Japan Institute for Health Security, 1-23-1 Toyama, Shinjuku-ku, Tokyo, 162-8640, Japan; Graduate School of Medical and Pharmaceutical Sciences, Chiba University, Japan; Department of Medical Microbiology and Immunology, Faculty of Medicine, South Valley University, Egypt.
Antiviral Res. 2025 Aug;240:106214. doi: 10.1016/j.antiviral.2025.106214. Epub 2025 Jun 14.
Chronic hepatitis B (HBV) and hepatitis D (HDV) viral infections pose serious global health challenges, and the lack of curative therapies calls for the development of new antiviral approaches. Recently, we have identified the Kinesin Family Member 4 (KIF4) as a crucial regulator of the surface transport for NTCP (HBV/HDV entry receptor). Our research has shown that the pan-RXR agonist, Bexarotene, suppresses KIF4 expression and inhibits HBV/HDV infections. However, the clinical use of Bexarotene is limited by poor physicochemical and pharmacokinetic (PK) properties and significant side effects. Here we investigated chemically diverse RXR modulators with tuned activity, and identified the RXR agonist S169 as a novel HBV/HDV entry inhibitor. S169 effectively blocks HBV and HDV infections in primary human hepatocyte (PXB) cultures without evident cytotoxicity. S169's suppressive effect on HBV infection was confirmed by reduction of secreted HBsAg and HBeAg, as well as inhibition of HBV cccDNA, pregenomic RNA, and intracellular HBV DNA. Mechanistically, S169 suppressed FOXM1-mediated KIF4 expression, leading to decreased NTCP surface levels and a marked decrease in HBV preS1 peptide binding to the hepatocyte cell surface. S169 is reported to exhibit enhanced oral bioavailability, favorable PK parameters, lower toxicity compared to Bexarotene. Interestingly, S169 induced a modest inhibition of NTCP-mediated bile acid transport up to 10 μM, which remained unchanged at higher concentrations. Furthermore, S169 significantly impeded HBV spread in HBV infected long-time cultured PHHs (PXB). We speculate that S169 can be a promising seed for the development of novel oral HBV and HDV antiviral therapeutics.
慢性乙型肝炎（HBV）和丁型肝炎（HDV）病毒感染给全球健康带来了严峻挑战，而缺乏治愈性疗法促使人们开发新的抗病毒方法。最近，我们已确定驱动蛋白家族成员4（KIF4）是钠-牛磺胆酸共转运多肽（NTCP，HBV/HDV进入受体）表面转运的关键调节因子。我们的研究表明，全反式维甲酸受体（RXR）激动剂贝沙罗汀可抑制KIF4表达并抑制HBV/HDV感染。然而，贝沙罗汀的临床应用受到其不良的理化和药代动力学（PK）特性以及显著副作用的限制。在此，我们研究了具有不同活性的化学结构多样的RXR调节剂，并确定RXR激动剂S169为一种新型的HBV/HDV进入抑制剂。S169可有效阻断原代人肝细胞（PXB）培养物中的HBV和HDV感染，且无明显细胞毒性。通过降低分泌的乙肝表面抗原（HBsAg）和乙肝e抗原（HBeAg），以及抑制HBV共价闭合环状DNA（cccDNA）、前基因组RNA和细胞内HBV DNA，证实了S169对HBV感染的抑制作用。从机制上讲，S169抑制了叉头框蛋白M1（FOXM1）介导的KIF4表达，导致NTCP表面水平降低，以及HBV前S1肽与肝细胞表面的结合显著减少。据报道，与贝沙罗汀相比，S169具有更高的口服生物利用度、良好的PK参数和更低的毒性。有趣的是，S169在高达10μM的浓度下对NTCP介导的胆汁酸转运有适度抑制作用，而在更高浓度下该作用保持不变。此外，S169显著阻碍了HBV在长期培养的HBV感染的原代人肝细胞（PHH，PXB）中的传播。我们推测S169可能是开发新型口服HBV和HDV抗病毒疗法的一个有前景的先导化合物。
