Insights into the development of chemical probes for RNA

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

Recently, we compiled the RNA-targeted BIoactive ligaNd Database (R-BIND), which comprised organic small molecules that target non-ribosomal RNAs and show activity in cell culture or animal models (22) . For this Survey, the compilation was updated to include chemical probe discoveries through May 2017 for a total of 116 chemical probes (see Supplementary Material, R-BIND 1-1.xls). Aminoglycosides are excluded due to established non-specific binding behavior (23) (24) (25) as well as peptides and oligonucleotides due to distinctive medicinal chemistry properties (26, 27) . The chemical probes were divided into two classes: monovalent, traditional drug-like small molecules (SM) and multivalent ligands (MV) with alkyl, aryl, or peptidyl linkers between multiple binding moieties. Previous work compared the physicochemical, structural, and spatial properties of the small molecules to FDAapproved drugs as well as RNA-binding ligands without reported biological activity (22) . This analysis revealed several key differences between these libraries that can in turn be used to bias small molecules toward biological RNA targeting. In addition to that work, the curation of this collection allowed us to gain insights into: (i) the RNA elements targeted; (ii) the design and discovery strategies utilized and (iii) the in cellulo characterization of these chemical probes. Herein, we discuss these insights, highlight unique examples, and consider the need to establish standards for cellbased selectivity. We conclude by proposing future directions that utilize our current and prospective chemical biology toolbox to expedite the discovery of chemical probes for RNA.