Fragment-basierter Ansatz zur Entwicklung von Inhibitoren des eIF4A-RNA-Komplexes als antiviral wirksame Substanzen
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The global impact of the COVID-19 pandemic underscored the critical need for broad-spectrum antiviral therapeutics to mitigate future viral outbreaks. Prior to vaccine development, no effective antiviral treatments existed to modulate disease progression, emphasizing the urgency of pan-antiviral drug discovery. In this context, the Grünweller group identified Rocaglates as a promising antiviral natural product class and validated eIF4A helicase as a host-target for an antiviral strategy. To overcome limitations of Rocaglates, including poor bioavailability and complex synthesis, the Heine group employed fragment-based drug design (FBDD) identified fragment J83 binding to the RNA-eIF4A complex via in silico screening and thermal shift assays. Guided by the crystal structure of helicase eIF4A in complex with RocA (PDB: 5ZC9), this fragment was optimized through structure-based modifications, yielding the first antiviral hit, Schl-45.102 (EC50 = 1.2 µM against HCoV-229E).
Further refinement of aromatic interactions with the eIF4A complex led to the discovery of two additional antiviral compounds, Schl-45.149 and Schl-45.216. Analysis of the Lipophilic ligand efficiency (LLE) for each antiviral compound revealed that Schl 45.102 is still the most promising candidate for further evaluation. The synthesis and in vitro evaluation of potential metabolites, alongside 1H-NMR-based stability assessments provided further insight into the potential of the compound. Additionally, a second novel structural class of eIF4A inhibitors was designed, culminating in the identification of Schl-55.006 (EC50 = 8.3 µM against HCoV-229E). These findings establish a foundation for the development of next-generation eIF4A-targeted antivirals with broad-spectrum potential, advancing the pursuit of pan-antiviral therapeutics for future pandemic preparedness.
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