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

authored by: Dimas F. Praditya, Mara Klöhn, Yannick Brüggemann, Lauren E. Brown, John A. Porco, Wenhan Zhang, Volker Kinast, Andreas Kirschning, Florian W.R. Vondran, Daniel Todt, Eike Steinmann
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.
Organisation(s): Institute of Organic Chemistry
External Organisation(s): Ruhr-Universität Bochum
Boston University (BU)
Hannover Medical School (MHH)
Type: Article
Journal: Antiviral Research
Volume: 204
ISSN: 0166-3542
Publication date: 08.2022
Publication status: Published
Peer reviewed: Yes
ASJC Scopus subject areas: Pharmacology, Virology
Sustainable Development Goals: SDG 3 - Good Health and Well-being
Electronic version(s): https://doi.org/10.1016/j.antiviral.2022.105359 (Access: Open)
https://doi.org/10.15488/12832 (Access: Open)