title: A druggable target for rescuing microRNA defects.
abstract: Despite immense promise, development of microRNA (miRNA) therapeutics remains limited by pharmacodynamic challenges that have hindered progress of related oligonucleotide-based technologies. Recent discovery of enzymes that mediate miRNA metabolism represent potential pharmacological targets for directing miRNA function, circumventing barriers associated with oligonucleotides. We previously identified the Translin/Trax (TN/TX) ribonuclease complex as a pre-miRNA degrading enzyme that competes with pre-miRNA processing by Dicer. Here, we establish a high-throughput TN/TX assay and screened 2320 drug and natural product compounds for inhibitors of TN/TX. Secondary analyses demonstrate small molecule mediated inhibition of pre-miRNA degradation by TN/TX and enhanced miRNA processing by Dicer. This application of traditional enzyme-inhibitor pharmacology to the miRNA pathway establishes a druggable target for rescuing global miRNA defects, providing an important complement to current approaches towards miRNA therapeutics. More broadly, demonstrating feasibility of pharmacological targeting of the 'ribonucleome' is particularly important given emerging classes of regulatory RNA and growing understanding of their importance in health and disease.
authors.affiliation: Center for Pharmaceutical Biotechnology, University of Illinois at Chicago, Chicago, IL 60612, USA.
authors.forename: Ken
authors.initials: K
authors.lastname: Asada
authors.affiliation: Center for Pharmaceutical Biotechnology, University of Illinois at Chicago, Chicago, IL 60612, USA.
authors.forename: Emanuele
authors.initials: E
authors.lastname: Canestrari
authors.affiliation: Center for Pharmaceutical Biotechnology, University of Illinois at Chicago, Chicago, IL 60612, USA; Department of Pharmacology, University of Illinois at Chicago, Chicago, IL 60612, USA. Electronic address: zain.paroo@gmail.com.
authors.forename: Zain
authors.initials: Z
authors.lastname: Paroo
mesh_terms: D000818:Animals; D004268:DNA-Binding Proteins / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D012322:RNA Precursors / Q000235:genetics / Q000378:metabolism*; D012323:RNA Processing, Post-Transcriptional; D016601:RNA-Binding Proteins / Q000235:genetics
chemical_list: D004268:DNA-Binding Proteins; D035683:MicroRNAs; D012322:RNA Precursors; D016601:RNA-Binding Proteins; C498303:Tsn protein, mouse
keywords: Dicer; High-throughput screen; Small molecule; Translin; Trax; miRNA therapeutics