{
  "abstract": "Background Hepatitis E virus (HEV) infections remain a global health concern. Immunocompromised patients are at an increased risk of developing chronic HEV infection and thereby severe liver disease. Current off-label regimens are suboptimal with treatment failure being reported. Therefore, there is an urgent need for an effective anti-HEV treatment.Objective In this study, we aimed to identify potent inhibitors of HEV replication.Design We developed a rapid, image-based screening platform based on a full-length HEV fluorescence reporter virus and screened a nucleotide/nucleoside analogue library. The identified lead candidate was validated in authentic hepatocyte culture systems, as well as in a gerbil infection model.Results Bemnifosbuvir (BEM), previously characterised as a nucleotide analogue with activity against other RNA viruses, efficiently suppressed HEV replication in vitro and in vivo in a dose-dependent manner, with minimal cytotoxicity at effective concentrations. Combining BEM with ribavirin, the off-label drug given to patients with chronic HEV, resulted in an additive antiviral effect against HEV. We found that HEV-3 remains susceptible to inhibition by BEM over an extended treatment period, reducing concerns about the rapid development of viral resistance. Importantly, BEM significantly reduced HEV viral loads and liver inflammation in a gerbil infection model.Conclusions Given BEM’s favourable safety profile in preclinical and clinical settings, our results suggest investigating its efficacy in patients with chronic HEV infection.",
  "authors": [
    {
      "affiliations": [
        "Schaller Research Group, Department of Infectious Diseases, Virology, Medical Faculty Heidelberg, Heidelberg University, Heidelberg, Germany",
        "Heidelberg Biosciences International Graduate School (HBIGS), Heidelberg, Germany"
      ],
      "name": "Jungen Hu"
    },
    {
      "affiliations": [
        "Department of Microbiology and Infectious Disease Center, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China"
      ],
      "name": "Tianxu Liu"
    },
    {
      "affiliations": [
        "Department of Molecular and Medical Virology, Ruhr University Bochum, Bochum, Germany",
        "Hepatitis E Virus Research Hub (HepE-Hub), Bochum, Germany"
      ],
      "name": "Mara Klöhn"
    },
    {
      "affiliations": [
        "Schaller Research Group, Department of Infectious Diseases, Virology, Medical Faculty Heidelberg, Heidelberg University, Heidelberg, Germany"
      ],
      "name": "Andrew Freistaedter"
    },
    {
      "affiliations": [
        "Schaller Research Group, Department of Infectious Diseases, Virology, Medical Faculty Heidelberg, Heidelberg University, Heidelberg, Germany",
        "Heidelberg Biosciences International Graduate School (HBIGS), Heidelberg, Germany"
      ],
      "name": "Elif Toprak"
    },
    {
      "affiliations": [
        "Schaller Research Group, Department of Infectious Diseases, Virology, Medical Faculty Heidelberg, Heidelberg University, Heidelberg, Germany"
      ],
      "name": "Huanting Chi"
    },
    {
      "affiliations": [
        "Department of Molecular and Medical Virology, Ruhr University Bochum, Bochum, Germany",
        "Hepatitis E Virus Research Hub (HepE-Hub), Bochum, Germany"
      ],
      "name": "André Gömer"
    },
    {
      "affiliations": [
        "Department of Molecular and Medical Virology, Ruhr University Bochum, Bochum, Germany",
        "Hepatitis E Virus Research Hub (HepE-Hub), Bochum, Germany",
        "Institute of Virology, University of Veterinary Medicine Hannover, Hannover, Germany",
        "Virus detection, pathogenesis and intervention (VIPER), Hannover, Germany"
      ],
      "name": "Lilli Pottkaemper"
    },
    {
      "affiliations": [
        "Schaller Research Group, Department of Infectious Diseases, Virology, Medical Faculty Heidelberg, Heidelberg University, Heidelberg, Germany",
        "Heidelberg Biosciences International Graduate School (HBIGS), Heidelberg, Germany"
      ],
      "name": "Paula Jordan"
    },
    {
      "affiliations": [
        "Department of Microbiology and Infectious Disease Center, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China"
      ],
      "name": "Xinyue Yang"
    },
    {
      "affiliations": [
        "State Key Laboratory for Animal Disease Control and Prevention, Harbin Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Harbin, China"
      ],
      "name": "He Zhang"
    },
    {
      "affiliations": [
        "Department of Infectious Diseases, Molecular Virology, Medical Faculty Heidelberg, Heidelberg University, Heidelberg, Germany"
      ],
      "name": "Johanna Becker"
    },
    {
      "affiliations": [
        "Department of Infectious Diseases, Molecular Virology, Medical Faculty Heidelberg, Heidelberg University, Heidelberg, Germany",
        "Internal Medicine IV (Gastroenterology, Hepatology, Infectious Diseases), University Hospital Heidelberg, Heidelberg, Germany",
        "German Centre for Infection Research (DZIF), Partner Site Heidelberg, Heidelberg, Germany"
      ],
      "name": "Shirin Nkongolo"
    },
    {
      "affiliations": [
        "Department of Infectious Diseases, Molecular Virology, Medical Faculty Heidelberg, Heidelberg University, Heidelberg, Germany",
        "German Centre for Infection Research (DZIF), Partner Site Heidelberg, Heidelberg, Germany"
      ],
      "name": "Volker Lohmann"
    },
    {
      "affiliations": [
        "Department of Molecular and Medical Virology, Ruhr University Bochum, Bochum, Germany",
        "Hepatitis E Virus Research Hub (HepE-Hub), Bochum, Germany",
        "German Centre for Infection Research (DZIF), Partner Site Bochum, Bochum, Germany"
      ],
      "name": "Eike Steinmann"
    },
    {
      "affiliations": [
        "Department of Microbiology and Infectious Disease Center, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China"
      ],
      "name": "Lin Wang"
    },
    {
      "affiliations": [
        "Schaller Research Group, Department of Infectious Diseases, Virology, Medical Faculty Heidelberg, Heidelberg University, Heidelberg, Germany",
        "German Centre for Infection Research (DZIF), Partner Site Heidelberg, Heidelberg, Germany"
      ],
      "name": "Viet Loan Dao Thi"
    }
  ],
  "title": "Nucleotide analogue bemnifosbuvir inhibits hepatitis E virus replication in preclinical models",
  "uid": "8513d51a-7037-539a-b715-2c8c7654e087"
}