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Discovery of Selective RNA-Binding Small Molecules by Affinity-Selection Mass Spectrometry

Journal Article · · ACS Chemical Biology
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  1. Merck & Co., Inc., Boston, MA (United States)
  2. Merck & Co., Inc., Kenilworth, NJ (United States)
  3. Merck & Co., Inc., West Point, PA (United States)
  4. Biodesy, Inc., South San Francisco, CA (United States)
+ Show Author Affiliations
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. In this paper, 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.
Research Organization:
Argonne National Laboratory (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
Sponsoring Organization:
USDOE
OSTI ID:
1526054
Journal Information:
ACS Chemical Biology, Journal Name: ACS Chemical Biology Journal Issue: 3 Vol. 13; ISSN 1554-8929
Publisher:
American Chemical Society (ACS)Copyright Statement
Country of Publication:
United States
Language:
ENGLISH

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Cited By (7)

Synthetic ligands for PreQ1 riboswitches provide structural and mechanistic insights into targeting RNA tertiary structure journal April 2019
Fluorescent peptide displacement as a general assay for screening small molecule libraries against RNA journal January 2019
Identification of thienopyridine carboxamides as selective binders of HIV-1 trans Activation Response (TAR) and Rev Response Element (RRE) RNAs journal January 2018
Synthetic small-molecule RNA ligands: future prospects as therapeutic agents journal January 2019
Emerging modes-of-action in drug discovery journal January 2019
Identification of G-Quadruplex-Binding Inhibitors of Myc Expression through Affinity Selection–Mass Spectrometry journal September 2018
Targeting RNA with Small Molecules: Identification of Selective, RNA-Binding Small Molecules Occupying Drug-Like Chemical Space journal November 2019

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Related Subjects

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY
59 BASIC BIOLOGICAL SCIENCES
Drug discovery
Genetics
Ligands
Screening assays
Small molecules