The past twenty years have seen an explosion of interest in the structure and function of RNA and DNA.  We now know that while some 80% of the human genome is transcribed into RNA, just ~3% of those transcripts code for protein sequences.  Noncoding RNAs and DNAs have been demonstrated to regulate gene expression and other biological regulatory processes. The deregulation of these RNAs is now known to be causative in a variety of human diseases, ranging from cancer to bacterial and viral infection.  However, efforts to target RNA and DNA with small molecules have lagged far behind protein targets.  Here we discuss our group’s efforts to target RNA and DNA with druglike small molecules using a Small Molecule Microarray (SMM) screening platform. We demonstrate that by rapidly screening a variety of diverse folded nucleic acids targets such as G-quadruplexes, it is possible to identify selective small molecule hits suitable for further study. Furthermore, structural approaches including biomolecular NMR and X-Ray crystallography using hits from SMM screens highlight the potential for structure-guided design on RNA and DNA related to cancer and infectious disease. In this talk, I will discuss in detail our efforts aimed toward designing potent and selective druglike compounds that modulate the behavior of RNA tertiary structures such as pseudoknots, including targeting a riboswitch with a novel synthetic ligand.

Targeting structurally and functionally diverse nucleic acids with druglike small molecules

2019 Fall National Meeting

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