Insights into the development of chemical probes for RNA

Morgan, Brittany S; Forte, Jordan E; Hargrove, Amanda E

The selection of a library and primary screening strategy is also critical for the success of chemical probe discovery. For RNA targets with known structure and/or ligands, the use of focused screening libraries (35, 36) has proven to be an efficient strategy, though this approach generally limits the chemical diversity of the library. Advances such as the identification of more RNA-privileged scaffolds (39) and biologically relevant RNA chemical space (22, 100) will facilitate the discovery of chemical probes for additional RNA targets. These efforts could be expedited by additional fragment-or natural product-based screening to access vast chemical space with fewer ligands (41) and to probe known biologically relevant chemical space, respectively (101) . Additional high-throughput screens could likewise discover novel chemotypes, though the expense may exceed the resources available in academia, where focused approaches are more attainable. Continued progress in the development and refinement of computational tools will also aid in expanding the boundaries of focused screening and structurebased design; (56, 57) although the latter will also depend upon advancements for accurately determining atomic resolution structures (8, 9, 37, 38) . In addition, in vitro or cellular activity-based assays that probe well-studied RNA functions (e.g. splicing, translation, or processing) may be more practical starting points to identify chemical probes. This includes screening strategies described herein as well as others recently developed (102, 103) . Finally, numerous opportunities exist to build upon the established multivalent targeting strategies discussed above, particularly the application of dynamic combinatorial chemistry to RNAs of unknown structure.