title: Sequence-based design of bioactive small molecules that target precursor microRNAs.
abstract: Oligonucleotides are designed to target RNA using base pairing rules, but they can be hampered by poor cellular delivery and nonspecific stimulation of the immune system. Small molecules are preferred as lead drugs or probes but cannot be designed from sequence. Herein, we describe an approach termed Inforna that designs lead small molecules for RNA from solely sequence. Inforna was applied to all human microRNA hairpin precursors, and it identified bioactive small molecules that inhibit biogenesis by binding nuclease-processing sites (44% hit rate). Among 27 lead interactions, the most avid interaction is between a benzimidazole (1) and precursor microRNA-96. Compound 1 selectively inhibits biogenesis of microRNA-96, upregulating a protein target (FOXO1) and inducing apoptosis in cancer cells. Apoptosis is ablated when FOXO1 mRNA expression is knocked down by an siRNA, validating compound selectivity. Markedly, microRNA profiling shows that 1 only affects microRNA-96 biogenesis and is at least as selective as an oligonucleotide.
authors: 1] Department of Chemistry, The Scripps Research Institute, Scripps Florida, Jupiter, Florida, USA. [2] The Department of Chemistry, The University at Buffalo, Buffalo, New York, USA.
authors: Sai Pradeep
authors: SP
authors: Velagapudi
authors: The New York State Center of Excellence in Bioinformatics and Life Sciences, The University at Buffalo, Buffalo, New York, USA.
authors: Steven M
authors: SM
authors: Gallo
authors: Department of Chemistry, The Scripps Research Institute, Scripps Florida, Jupiter, Florida, USA.
authors: Matthew D
authors: MD
authors: Disney
mesh_terms: D017304:Annexin A5 / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects; D001483:Base Sequence; D015153:Blotting, Western; D045744:Cell Line, Tumor; D002626:Chemistry, Pharmaceutical; D016172:DNA Fingerprinting; D004273:DNA, Neoplasm / Q000235:genetics; D015195:Drug Design; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000187:drug effects; D057809:HEK293 Cells; D057166:High-Throughput Screening Assays; D006801:Humans; D020287:In Situ Nick-End Labeling; D035683:MicroRNAs / Q000096:biosynthesis / Q000187:drug effects*; D023282:Nuclease Protection Assays; D009841:Oligonucleotides / Q000138:chemical synthesis / Q000494:pharmacology; D016133:Polymerase Chain Reaction; D043244:Ribonuclease III / Q000187:drug effects; D054852:Small Molecule Libraries; D014158:Transcription, Genetic / Q000187:drug effects
chemical_list: D017304:Annexin A5; D004273:DNA, Neoplasm; C085126:FOXO1 protein, human; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; D035683:MicroRNAs; D009841:Oligonucleotides; D054852:Small Molecule Libraries; C517918:DROSHA protein, human; D043244:Ribonuclease III