2. Academic Validation
  3. Identification of structurally re-engineered rocaglates as inhibitors against hepatitis E virus replication

Identification of structurally re-engineered rocaglates as inhibitors against hepatitis E virus replication

  • Antiviral Res. 2022 Aug:204:105359. doi: 10.1016/j.antiviral.2022.105359.
Dimas F Praditya 1,  Mara Klöhn 2,  Yannick Brüggemann 3,  Lauren E Brown 4,  John A Porco Jr 5,  Wenhan Zhang 6,  Volker Kinast 7,  Andreas Kirschning 8,  Florian W R Vondran 9,  Daniel Todt 10,  Eike Steinmann 11
Affiliations

Affiliations

  • 1 Department of Molecular and Medical Virology, Ruhr-University Bochum, Bochum, Germany; Research Center for Vaccine and Drugs, The National Research and Innovation Agency, Cibinong, Indonesia. Electronic address: [email protected].
  • 2 Department of Molecular and Medical Virology, Ruhr-University Bochum, Bochum, Germany. Electronic address: [email protected].
  • 3 Department of Molecular and Medical Virology, Ruhr-University Bochum, Bochum, Germany. Electronic address: [email protected].
  • 4 Department of Chemistry, Boston University, Boston, MA, 02215, USA; Center for Molecular Discovery (BU-CMD), Boston University, Boston, MA, USA. Electronic address: [email protected].
  • 5 Department of Chemistry, Boston University, Boston, MA, 02215, USA; Center for Molecular Discovery (BU-CMD), Boston University, Boston, MA, USA. Electronic address: [email protected].
  • 6 Department of Chemistry, Boston University, Boston, MA, 02215, USA; Center for Molecular Discovery (BU-CMD), Boston University, Boston, MA, USA. Electronic address: [email protected].
  • 7 Department of Molecular and Medical Virology, Ruhr-University Bochum, Bochum, Germany; Department of Medical Microbiology and Virology, Carl von Ossietzky University Oldenburg, Oldenburg, Germany. Electronic address: [email protected].
  • 8 Institute of Organic Chemistry, Leibniz University Hannover, Schneiderberg 1B, 30167, Hannover, Germany. Electronic address: [email protected].
  • 9 ReMediES, Department of General, Visceral and Transplantation Surgery, Hannover Medical School, Hannover, Germany; German Centre for Infection Research (DZIF), Partner Site Hannover-Braunschweig, Hannover, Germany. Electronic address: [email protected].
  • 10 Department of Molecular and Medical Virology, Ruhr-University Bochum, Bochum, Germany; European Virus Bioinformatics Center (EVBC), 07743, Jena, Germany. Electronic address: [email protected].
  • 11 Department of Molecular and Medical Virology, Ruhr-University Bochum, Bochum, Germany; German Centre for Infection Research (DZIF), External Partner Site, Bochum, Germany. Electronic address: [email protected].
PMID: 35728703 DOI: 10.1016/j.antiviral.2022.105359
Abstract

Hepatitis E virus (HEV) infections are a leading cause of acute viral hepatitis in humans and pose a considerable threat to public health. Current standard of care treatment is limited to the off-label use of nucleoside-analog ribavirin (RBV) and PEGylated interferon-α, both of which are associated with significant side effects and provide limited efficacy. In the past few years, a promising natural product compound class of eukaryotic initiation factor 4A (eIF4A) inhibitors (translation initiation inhibitors), called rocaglates, were identified as Antiviral agents against RNA virus infections. In the present study, we evaluated a total of 205 synthetic rocaglate derivatives from the BU-CMD compound library for their Antiviral properties against HEV. At least eleven compounds showed inhibitory activities against the HEV genotype 3 (HEV-3) subgenomic replicon below 30 nM (EC50 value) as determined by Gaussia luciferase assay. Three amidino-rocaglates (ADRs) (CMLD012073, CMLD012118, and CMLD012612) possessed Antiviral activity against HEV with EC50 values between 1 and 9 nM. In addition, these three selected compounds inhibited subgenomic replicons of different genotypes (HEV-1 [Sar55], wild boar HEV-3 [83-2] and human HEV-3 [p6]) in a dose-dependent manner and at low nanomolar concentrations. Furthermore, tested ADRs tend to be better tolerated in primary hepatocytes than hepatoma Cancer cell lines and combination treatment of CMLD012118 with RBV and interferon-α (IFN-α) showed that CMLD012118 acts additive to RBV and IFN-α treatment. In conclusion, our results indicate that ADRs, especially CMLD012073, CMLD012118, and CMLD012612 may prove to be potential therapeutic candidates for the treatment of HEV infections and may contribute to the discovery of pan-genotypic inhibitors in the future.

Keywords

Amidino-rocaglates; Antiviral treatment; Antivirals; Hepatitis E virus; elF4A inhibitors.

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