title: Pilot-scale compound screening against RNA editing identifies trypanocidal agents.
abstract: Most mitochondrial messenger RNAs in trypanosomatid pathogens undergo a unique type of posttranscriptional modification involving insertion and/or deletion of uridylates. This process, RNA editing, is catalyzed by a multiprotein complex (~1.6 MDa), the editosome. Knockdown of core editosome proteins compromises mitochondrial function and, ultimately, parasite viability. Hence, because the editosome is restricted to trypanosomatids, it serves as a unique drug target in these pathogens. Currently, there is a lack of editosome inhibitors for antitrypanosomatid drug development or that could serve as unique tools for perturbing and characterizing editosome interactions or RNA editing reaction stages. Here, we screened a library of pharmacologically active compounds (LOPAC1280) using high-throughput screening to identify RNA editing inhibitors. We report that aurintricarboxylic acid, mitoxantrone, PPNDS, and NF449 are potent inhibitors of deletion RNA editing (IC50 range, 1-5 µM). However, none of these compounds could specifically inhibit the catalytic steps of RNA editing. Mitoxantrone blocked editing by inducing RNA-protein aggregates, whereas the other three compounds interfered with editosome-RNA interactions to varying extents. Furthermore, NF449, a suramin analogue, was effective at killing Trypanosoma brucei in vitro. Thus, new tools for editosome characterization and downstream RNA editing inhibitor have been identified.
authors.affiliation: Department of Biochemistry, McGill University, Montreal, Quebec, Canada Institute of Parasitology, McGill University, Montreal, Quebec, Canada.
authors.forename: Houtan
authors.initials: H
authors.lastname: Moshiri
authors.affiliation: Department of Biochemistry, McGill University, Montreal, Quebec, Canada Institute of Parasitology, McGill University, Montreal, Quebec, Canada.
authors.forename: Vaibhav
authors.initials: V
authors.lastname: Mehta
authors.affiliation: Institute of Parasitology, McGill University, Montreal, Quebec, Canada.
authors.forename: Chun Wai
authors.initials: CW
authors.lastname: Yip
authors.affiliation: Department of Biochemistry, McGill University, Montreal, Quebec, Canada Institute of Parasitology, McGill University, Montreal, Quebec, Canada McGill Centre for Bioinformatics, McGill University, Montreal, Quebec, Canada reza.salavati@mcgill.ca.
authors.forename: Reza
authors.initials: R
authors.lastname: Salavati
mesh_terms: D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery / Q000379:methods*; D031541:Fluorescence Resonance Energy Transfer / Q000379:methods; D057166:High-Throughput Screening Assays; D017393:RNA Editing / Q000187:drug effects*; D012333:RNA, Messenger; D000077278:RNA, Mitochondrial; D016601:RNA-Binding Proteins / Q000378:metabolism; D054852:Small Molecule Libraries; D014344:Trypanocidal Agents / Q000494:pharmacology*; D014345:Trypanosoma / Q000187:drug effects* / Q000235:genetics*
chemical_list: D012333:RNA, Messenger; D000077278:RNA, Mitochondrial; D016601:RNA-Binding Proteins; D054852:Small Molecule Libraries; D014344:Trypanocidal Agents; C029305:mitochondrial messenger RNA
keywords: HTS; RNA editing; editosome; trypanosomes