1 research outputs found
Discovery of Selective RNA-Binding Small Molecules by Affinity-Selection Mass Spectrometry
Recent
advances in understanding the relevance of noncoding RNA
(ncRNA) to disease have increased interest in drugging ncRNA with
small molecules. The recent discovery of ribocil, a structurally distinct
synthetic mimic of the natural ligand of the flavin mononucleotide
(FMN) riboswitch, has revealed the potential chemical diversity of
small molecules that target ncRNA. Affinity-selection mass spectrometry
(AS-MS) is theoretically applicable to high-throughput screening (HTS)
of small molecules binding to ncRNA. Here, we report the first application
of the Automated Ligand Detection System (ALIS), an indirect AS-MS
technique, for the selective detection of small molecule–ncRNA
interactions, high-throughput screening against large unbiased small-molecule
libraries, and identification and characterization of novel compounds
(structurally distinct from both FMN and ribocil) that target the
FMN riboswitch. Crystal structures reveal that different compounds
induce various conformations of the FMN riboswitch, leading to different
activity profiles. Our findings validate the ALIS platform for HTS
screening for RNA-binding small molecules and further demonstrate
that ncRNA can be broadly targeted by chemically diverse yet selective
small molecules as therapeutics