Every year, an estimated 20 million people become infected with HEV, resulting in 3.3 million acute cases and approximately 70,000 deaths annually, making HEV the leading cause for acute viral hepatitis worldwide. As current standard-of-care treatment against HEV infections is limited to the use of ribavirin and interferon-α – drugs associated with poor tolerability and treatment failure – novel drugs are urgently needed. Targeting the translation machinery of the host has been extensively studied and proposed as a therapeutic strategy for the treatment of viral infections. In particular, a compound class of DEAD-box RNA helicase (elF4A) activity inhibitors, so called rocaglates, were identified as antiviral agents for the treatment of viral infections.
A recent study led by Prof. Eike Steinmann from Ruhr-University Bochum, Germany explored novel synthetic rocaglates as potential antiviral agents against HEV. They assessed the antiviral activity of 205 racemic rocaglate-derivatives from the BU-CMD collection by Gaussia luciferase assay. Most importantly, the team identified three amidino-rocaglates (ADRs; CMLD012073, CMLD012118, and CMLD012612) that exhibit pan-genotypic inhibitory properties against HEV replication of 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, treatment of tested ADRs also resulted in improved tolerability in primary porcine hepatocytes compared to hepatoma cells. To assess putative combinatory effects of CMLD012118 treatment with RBV and IFN-α, the team performed combination treatment experiments and found that CMLD012118 acts additive during combination treatment with RBV and IFN-α.
These findings demonstrate, that synthetic ADRs are putative candidates for the treatment of HEV infections and that host-targeting antiviral (HTAs) drugs that target the host cell machinery might have great potential as broad-spectrum pan-antivirals. Yet, determining potential toxicity in vivo and further development of large-scale synthesis procedures are still necessary to establish ADRs as a potential antiviral HEV treatment option.
Read the full article (Antiviral Res. 2022 Jun 18;105359.) DOI: 10.1016/j.antiviral.2022.105359
