. doi: 10.1016/j.virs.2026.05.010
Citation: Kuan Liu, Yang Wang, Xincheng Li, Yilan Zhao, Luc J.W. van der Laan, Pengfei Li, Qiuwei Pan. The guanosine nucleotide analog bemnifosbuvir inhibits hepatitis E virus infection in cell and organoid models .VIROLOGICA SINICA, 2026, 41(3) : 716-719.  http://dx.doi.org/10.1016/j.virs.2026.05.010

鸟苷核苷酸类似物Bemnifosbuvir在细胞与类器官模型中抑制戊型肝炎病毒感染

  • 戊型肝炎病毒(HEV)是导致急性病毒性肝炎的重要病原体,目前临床治疗选择有限。本研究评估了核苷酸类似物bemnifosbuvir(AT-527)对HEV感染的抗病毒活性。结果显示,AT-527可在Huh7细胞及人源肝类器官模型中有效抑制GT1和GT3 HEV复制,并表现出较低细胞毒性。在GT3复制子模型中,AT-527的抗病毒活性明显强于利巴韦林;在感染性克隆模型中,AT-527进一步显著降低病毒RNA水平及ORF2蛋白表达,并抑制二次感染。长期处理实验表明,AT-527能够持续抑制HEV复制。此外,AT-527对与利巴韦林耐药相关的G1634R突变体仍保持良好抑制作用。外源补充鸟苷可明显逆转AT-527的抗病毒作用,提示其抗病毒活性可能通过干扰HEV RdRp介导的RNA合成发挥作用。联合用药实验显示,AT-527与利巴韦林或干扰素-α联用均产生协同抗病毒效应。综上,本研究表明AT-527具有强效且持久的抗HEV活性,支持其作为HEV感染潜在治疗药物进一步开展研究。

The guanosine nucleotide analog bemnifosbuvir inhibits hepatitis E virus infection in cell and organoid models

  • Highlights
    1 The nucleotide analog bemnifosbuvir (AT-527) inhibits hepatitis E virus (HEV) infection in cell and organoid models.
    2 Supplementation with guanosine largely reversed the anti-HEV activity of AT-527.
    3 Combining AT-527 with ribavirin or interferon-α resulted in synergistic antiviral effects.

  • 加载中
    1. Berliba, E., Bogus, M., Vanhoutte, F., Berghmans, P.J., Good, S.S., Moussa, A., Pietropaolo, K., Murphy, R.L., Zhou, X.J. & Sommadossi, J.P., 2019. Safety, pharmacokinetics and antiviral activity of AT-527, a novel purine nucleotide prodrug, in HCV-infected subjects with and without cirrhosis. Antimicrob Agents Chemother 63, e01201-e01219.

    2. Good, S.S., Moussa, A., Zhou, X.J., Pietropaolo, K. & Sommadossi, J.P., 2020. Preclinical evaluation of AT-527, a novel guanosine nucleotide prodrug with potent, pan-genotypic activity against hepatitis C virus. PLoS One 15, e0227104.

    3. Good, S.S., Westover, J., Jung, K.H., Zhou, X.J., Moussa, A., La Colla, P., Collu, G., Canard, B. & Sommadossi, J.P., 2021. AT-527, a Double Prodrug of a Guanosine Nucleotide Analog, Is a Potent Inhibitor of SARS-CoV-2 In Vitro and a Promising Oral Antiviral for Treatment of COVID-19. Antimicrob Agents Chemother 65.

    4. Hakim, M.S., Wang, W., Bramer, W.M., Geng, J., Huang, F., de Man, R.A., Peppelenbosch, M.P. & Pan, Q., 2017. The global burden of hepatitis E outbreaks: a systematic review. Liver Int 37, 19-31.

    5. Kamar, N., Selves, J., Mansuy, J.M., Ouezzani, L., Peron, J.M., Guitard, J., Cointault, O., Esposito, L., Abravanel, F., Danjoux, M., Durand, D., Vinel, J.P., Izopet, J. & Rostaing, L., 2008. Hepatitis E virus and chronic hepatitis in organ-transplant recipients. N Engl J Med 358, 811-817.

    6. Li, P., Li, Y., Wang, Y., Liu, J., Lavrijsen, M., Li, Y., Zhang, R., Verstegen, M.M.A., Wang, Y., Li, T.C., Ma, Z., Kainov, D.E., Bruno, M.J., de Man, R.A., van der Laan, L.J.W., Peppelenbosch, M.P. & Pan, Q., 2022. Recapitulating hepatitis E virus-host interactions and facilitating antiviral drug discovery in human liver-derived organoids. Sci Adv 8, eabj5908.

    7. Li, P., Liu, J., Li, Y., Su, J., Ma, Z., Bramer, W.M., Cao, W., de Man, R.A., Peppelenbosch, M.P. & Pan, Q., 2020. The global epidemiology of hepatitis E virus infection: A systematic review and meta-analysis. Liver Int 40, 1516-1528.

    8. Liu, K., Wang, Y., Li, J., Zhou, J., da Silva, A.M.G., Suner, C., Dai, Z., Schraauwen, R., Boor, P.P.C., Ober-Vliegen, K., van den Hil, F., Offermans, D.M., Tsikari, T., Ayada, I., Peppelenbosch, M.P., van Royen, M.E., Verstegen, M.M.A., Wang, Y., Orkin, C.M., Janssen, H.L.A., Orlova, V.V., Li, P., Mitja, O., Duarte-Neto, A.N., van der Laan, L.J.W. & Pan, Q., 2025. Macrophage-augmented organoids recapitulate the complex pathophysiology of viral diseases and enable development of multitarget therapeutics. Nat Biomed Eng 9, 1848-1868.

    9. Ma, Z., de Man, R.A., Kamar, N. & Pan, Q., 2022. Chronic hepatitis E: Advancing research and patient care. J Hepatol 77, 1109-1123.

    10. Pan, Q., Li, P., Liu, K., 2024. PubChem Patent Summary for WO-2025014360-A1, Guanosine nucleotide analogs for use in preventing and/or treating hepatitis e virus infection. https://pubchem.ncbi.nlm.nih.gov/patent/WO-2025014360-A1.

    11. Roberts, S.S., Miller, R.K., Jones, J.K., Lindsay, K.L., Greene, M.F., Maddrey, W.C., Williams, I.T., Liu, J. & Spiegel, R.J., 2010. The Ribavirin Pregnancy Registry: Findings after 5 years of enrollment, 2003-2009. Birth Defects Res A Clin Mol Teratol 88, 551-559.

    12. Shannon, A. & Canard, B., 2023. Kill or corrupt: Mechanisms of action and drug-resistance of nucleotide analogues against SARS-CoV-2. Antiviral Res 210, 105501.

    13. Shannon, A., Fattorini, V., Sama, B., Selisko, B., Feracci, M., Falcou, C., Gauffre, P., El Kazzi, P., Delpal, A., Decroly, E., Alvarez, K., Eydoux, C., Guillemot, J.C., Moussa, A., Good, S.S., La Colla, P., Lin, K., Sommadossi, J.P., Zhu, Y., Yan, X., Shi, H., Ferron, F. & Canard, B., 2022. A dual mechanism of action of AT-527 against SARS-CoV-2 polymerase. Nat Commun 13, 621.

    14. Shukla, P., Nguyen, H.T., Faulk, K., Mather, K., Torian, U., Engle, R.E. & Emerson, S.U., 2012. Adaptation of a genotype 3 hepatitis E virus to efficient growth in cell culture depends on an inserted human gene segment acquired by recombination. J Virol 86, 5697-5707.

    15. Todt, D., Gisa, A., Radonic, A., Nitsche, A., Behrendt, P., Suneetha, P.V., Pischke, S., Bremer, B., Brown, R.J., Manns, M.P., Cornberg, M., Bock, C.T., Steinmann, E. & Wedemeyer, H., 2016. In vivo evidence for ribavirin-induced mutagenesis of the hepatitis E virus genome. Gut 65, 1733-1743.

  • 加载中

Figures(1)

Article Metrics

Article views(36) PDF downloads(0) Cited by(0)

Related
Proportional views
    通讯作者: 陈斌, bchen63@163.com
    • 1. 

      沈阳化工大学材料科学与工程学院 沈阳 110142

    1. 本站搜索
    2. 百度学术搜索
    3. 万方数据库搜索
    4. CNKI搜索

    The guanosine nucleotide analog bemnifosbuvir inhibits hepatitis E virus infection in cell and organoid models

      Corresponding author: Pengfei Li, p.li@erasmusmc.nl
      Corresponding author: Qiuwei Pan, q.pan@erasmusmc.nl
    • a. Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center, Rotterdam, 3015 GD, the Netherlands;
    • b. Department of Surgery, Erasmus MC Transplant Institute, University Medical Center, Rotterdam, 3015 GD, the Netherlands

    Abstract: Highlights
    1 The nucleotide analog bemnifosbuvir (AT-527) inhibits hepatitis E virus (HEV) infection in cell and organoid models.
    2 Supplementation with guanosine largely reversed the anti-HEV activity of AT-527.
    3 Combining AT-527 with ribavirin or interferon-α resulted in synergistic antiviral effects.

    Figure (1)  Reference (15) Relative (20)

    目录

    /

    DownLoad:  Full-Size Img  PowerPoint
    Return
    Return