Structure-based development of novel broad-spectrum antiviral inhibitors through inhibition of the human eIF4A-RNA complex

• Applicants: Professor Dr. Arnold Grünweller; Professor Dr. Martin Schlitzer
• Subject Area: Pharmacy ; Biochemistry ; Parasitology and Biology of Tropical Infectious Disease Pathogens ; Virology
• Term: since 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 533973968

The cellular RNA helicase eIF4A unwinds stable RNA structures in mRNA 5' UTRs during protein synthesis. Inhibiting the RNA helicase prevents translation of specific mRNAs encoding proto-oncogenes and viral proteins. eIF4A inhibition has low toxicity in healthy cells as only a limited number of cellular mRNAs require the helicase for translation. In recent years, small-molecule compounds have been developed that target translation factors since viruses rely on the translation machinery of infected host cells for their own protein synthesis. In particular, rocaglates as specific eIF4A inhibitors have great potential for further development as new broad-spectrum antiviral drugs. Many RNA viruses require eIF4A for replication due to stable RNA structures in viral 5' UTRs. Pathogenic microorganisms also express eIF4A isoforms. Inhibitors of eIF4A thus have anti-infective potential beyond the treatment of viral infections. Rocaglates clamp RNA substrates onto the surface of eIF4A, thereby blocking the enzyme in its active RNA-bound form. One drawback of rocaglates lies in their complex structure and the associated time-consuming synthesis. In 2019, co-crystallization revealed the molecular interactions of rocaglates with the eIF4A-RNA complex using a polypurine RNA and RocA. This information serves as the basis for a structure-based drug development approach to identify novel eIF4A inhibitors that are more accessible for synthesis. In this process, the corresponding binding pockets on the surface of eIF4A are targeted with small molecules which are subsequently optimized in an iterative process consisting of docking, synthesis and testing. In general, targeting a protein-RNA complex using small molecules represents an innovative strategy in drug development approaches. Developing an efficient lead compound inhibiting eIF4A enables further steps towards a broad-spectrum antiviral, enhancing preparedness for future outbreaks involving unknown viruses.

• DFG Programme: Research Grants