Drug Target Strategies
There is a growing appreciation for the many roles that structured RNAs play in disease progression. Accordingly, significant efforts are being devoted to identify low molecular weight compounds that specifically target these RNA molecules. These efforts may expand the number of therapeutic targets for disease intervention. While several groups are developing antisense oligonucleotides or siRNAs to target RNA, we sought to identify low molecular weight compounds that have desired drug-like properties, oral bioavailability, while retaining target specificity and potency. To accomplish this goal we have devised novel biochemical assays that are amenable to ultra-high throughput screening. As a proof of concept, we have used these assays to identify compounds that bind well-characterized structured RNA, such as aptamers and ribozymes. For example, we developed screens that target the theophylline aptamer, which binds theophylline with high affinity and specificity. Through these screens, we identified theophylline, as well as several related molecules that bind the theophylline aptamer with an affinity that matches those reported in the literature. We also identified several compounds that are distinct from the theophylline scaffold, some of which have affinities exceeding that of the cognate ligand. To date we have screened over 3 million compounds in these assays and have begun to understand the power and limitations of running HTS campaigns that target RNA. This presentation will highlight the assay development, screening results, and a view to what is required to carry out high-throughput screening campaigns that purposively target RNA.