Emerging and re-emerging mosquito-borne flaviviruses cause widespread mortality, morbidity, and economic burden. Options for prevention and treatment of mosquito-borne flaviviruses are limited: Flavivirus vaccines face unique development challenges, no antiviral therapies are available, and the mosquito vectors have proven difficult to eradicate. Despite vaccines against Yellow Fever and Japanese encephalitis viruses, these two flaviviruses together cause more than 75,000 deaths each year. Half of the world?s population is at risk of Dengue virus (DENV) infection, and emerging flaviviruses, including the Zika virus, pose significant public health challenges. RNA is a compelling target for small-molecule drug discovery, and the genomes of RNA viruses, such as flaviviruses, contain highly conserved targetable structures. Multiple natural products target ribosomal RNA, establishing proof of concept for RNA as a drug target; however, RNA-targeted drug discovery remains a nascent field. Specific tertiary structures in the DENV RNA genome have recently been shown to be essential for viral replication. These structures are highly conserved across mosquito-borne flaviviruses and interfering with their formation inhibits packaging and replication, suggesting that small molecules that disrupt these RNA motifs will have broad-spectrum antiflaviviral activity. At Ribometrix, our lead discovery platform combines a very rapid and high-throughput initial screen with a secondary assay based on SHAPE technology, the gold standard for RNA structure analyses. We plan to apply our platform to identify small molecules with favorable medicinal chemistry properties that bind to and disrupt the structure of essential DENV RNA motifs. These lead compounds will serve as the foundation for the development of anti-DENV and broad-spectrum antiflaviviral therapies in a Phase 2 project. RNAs share broadly similar overall properties, so a strategy that allows RNA to be targeted efficiently in a single case will likely allow targeting of diverse therapeutically important RNAs. The long-term vision of Ribometrix is to apply this platform technology to discover small-molecule therapeutics that target functional RNA structures involved in indications for which there are no approved therapies. With this study, we will establish proof-of-principle for an efficient and generic approach for RNA-targeted ligand discovery.
Mosquito-borne flaviviruses pose a significant threat to human health, but flavivirus vaccines face unique development challenges, no therapies are available, and the mosquito vectors have proven difficult to eradicate. We propose to identify small molecules that bind to highly conserved structures in the Dengue virus genomic RNA using the Ribometrix lead discovery platform, which combines a high-throughput initial screen of fragment-based libraries with innovative SHAPE-MaP technology. Disruption of the targeted RNA structures should prevent viral replication, and future work will advance the compounds identified in this project into a lead optimization program.
| Dethoff, Elizabeth A; Boerneke, Mark A; Gokhale, Nandan S et al. (2018) Pervasive tertiary structure in the dengue virus RNA genome. Proc Natl Acad Sci U S A 115:11513-11518 |
