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

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.

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    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.

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    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.

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