Non-protein coding RNA transcripts have been increasingly recognized as potential drug targets owing to their important roles in cellular processes. Since peptide-based and RNA-based therapeutics often exhibit poor <i>in vivo</i> delivery and pharmacokinetics, small molecules offer an excellent alternative tool for targeting RNA. However, due to its unique chemical and structural properties compared to protein targets, RNA has been difficult to target with drug-like small molecules. For example, despite the proven promise of targeting RNA with multivalent ligands, progress in this area has been hampered by current limitations in three-dimensional structure characterization of large RNAs. There is thus a need to develop techniques that do not rely on structure-based design. We are developing an imine-based dynamic combinatorial chemistry (DCC) technique for multivalent ligand discovery for large RNAs. In DCC, a target biomolecule is incubated with a thermodynamically-controlled dynamic library of small molecules, allowing it to select its highest affinity binders. DCC is thus superior to structure-based design since all thermodynamically stable conformations of the target participate in the ligand discovery process. To date, we have identified favorable conditions for imine formation in aqueous media, conducted comparative studies of amine reactivity towards imine formation, and begun validation studies on a known RNA binding scaffold. For validation studies, an aldehyde scaffold will be incubated with a diverse library of primary amines to discover ligands for the HIV-1 Transactivation Response (TAR) RNA. Upon validating the DCC method, we will set out to identify first multivalent ligands for a number of disease-relevant RNA targets. Ultimately, this work will provide a much-needed platform for multivalent ligand discovery for large RNAs, particularly those that have yet to be structurally characterized.

Imine-based dynamic combinatorial chemistry for discovery of multivalent RNA-binding ligands

254th National Meeting (2017)

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