The RNA helicase eIF4A as a target structure for the development of new antiviral agents against

The synthesis of viral proteins depends on the protein synthesis machinery of the infected host cell, as viruses do not have their own translation factors or ribosomes. Viruses often have functional RNA structural elements in their 5´-UTRs (untranslated regions) that are unwound by the RNA helicase eIF4A. Hence, eIF4A is a relevant broad spectrum antiviral target and inhibition of eIF4A, e.g. by rocaglate derivatives like Silvestrol, leads to broad spectrum antiviral effects. From our research we know that rocaglate derivatives can act like a clamp on viral RNAs at the surface of the RNA helicase eIF4A and thus prevent the synthesis of the virus proteins. All coronaviruses have pronounced and conserved RNA structures in their 5 'UTRs. So far we could show that MERS-CoV and HCoV-229E require eIF4A for their protein synthesis. SARS-CoV-2 has comparable RNA structural elements in its 5´-UTR. We therefore expect that the protein synthesis in SARS-CoV-2 is dependent on eIF4A. Effective eIF4A inhibitors could thus be a general treatment option for infections with coronaviruses. Since the mechanism of the Rocaglat effect on the eIF4A-RNA complex is well understood at the molecular level, this information can be used for the synthesis of new inhibitors. Rocaglate derivatives are very effective, but also have a complex structure. Hence the development of easily manufactured eIF4A inhibitors will be required. The goal of our HELIACOR project is to develop alternative eIF4A inhibitors that are easier to synthesize and can be used as a basis for lead optimization.