Aaron Frank, Director and Head of Computational Chemistry at Arrakis Therapeutics, presented his research on using computational methods to identify small molecules that target RNA. His work, conducted at the University of Michigan in collaboration with Yale University, focused on RNA structure-based drug discovery. Frank's presentation highlighted the growing evidence supporting RNA as a viable drug target, with Arrakis Therapeutics building platforms to identify RNA-binding molecules deliberately rather than accidentally.
Frank explained that Arrakis Therapeutics had developed an end-to-end platform for RNA-targeting drug discovery, which included target identification using chemical probing data, screening with mass spectrometry, and target engagement assays. The research centred on the group II intron RNA, a self-splicing ribozyme absent in mammals but essential for yeast respiration. This RNA presented solvent-accessible pockets suitable for small molecule binding, making it an attractive target for antifungal agents.
Using available crystal structures of domain 5 of the group II intron, Frank's team conducted virtual docking of molecules from the ZINC library. They identified three scaffolds with inhibitory activity, confirmed through splicing assays and structure-activity relationship (SAR) studies. The active compounds inhibited splicing in different group II intron variants sharing a conserved active site, and inhibition was not reduced by excess tRNA, indicating selectivity.
Frank also discussed the functional impact of the active compound on fungal growth. The compound inhibited fungal growth under respiration-dependent conditions in intron-containing yeast but not in intron-less strains, providing indirect evidence of target engagement. Computational insights into binding predicted stabilising interactions of active compounds within the RNA active site, supporting their mechanism of action despite challenges in obtaining crystal structures.
In summary, Frank's research demonstrated the potential of RNA-targeting small molecules in antifungal therapy. The study provided a proof of concept that combining structure-based virtual screening with robust biochemical assays could identify compounds that inhibit RNA splicing and fungal growth. This approach highlighted the importance of understanding RNA structure-function relationships and the potential for deliberate RNA-targeting drug discovery.
