title: Selective inhibitors of trypanosomal uridylyl transferase RET1 establish druggability of RNA post-transcriptional modifications.
abstract: Non-coding RNAs are crucial regulators for a vast array of cellular processes and have been implicated in human disease. These biological processes represent a hitherto untapped resource in our fight against disease. In this work we identify small molecule inhibitors of a non-coding RNA uridylylation pathway. The TUTase family of enzymes is important for modulating non-coding RNA pathways in both human cancer and pathogen systems. We demonstrate that this new class of drug target can be accessed with traditional drug discovery techniques. Using the Trypanosoma brucei TUTase, RET1, we identify TUTase inhibitors and lay the groundwork for the use of this new target class as a therapeutic opportunity for the under-served disease area of African Trypanosomiasis. In a broader sense this work demonstrates the therapeutic potential for targeting RNA post-transcriptional modifications with small molecules in human disease.
authors.affiliation: a The Gurdon Institute, University of Cambridge , Cambridge , UK.
authors.forename: Amy
authors.initials: A
authors.lastname: Cording
authors.affiliation: b Department of Chemistry , University of Cambridge , Cambridge , UK.|c Cancer Research UK Cambridge Institute, Li Ka Shing Center , Cambridge , UK.|d National Center for Advancing Translational Sciences , National Institutes of Health , Bethesda , MD , USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Gormally
authors.affiliation: e Bioinformatics Institute (A*STAR) , Singapore.|f Department of Biological Sciences , National University of Singapore , Singapore.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Bond
authors.affiliation: g Department of Biochemistry , Cambridge , UK.
authors.forename: Mark
authors.initials: M
authors.lastname: Carrington
authors.affiliation: b Department of Chemistry , University of Cambridge , Cambridge , UK.|c Cancer Research UK Cambridge Institute, Li Ka Shing Center , Cambridge , UK.
authors.forename: Shankar
authors.initials: S
authors.lastname: Balasubramanian
authors.affiliation: a The Gurdon Institute, University of Cambridge , Cambridge , UK.
authors.forename: Eric A
authors.initials: EA
authors.lastname: Miska
authors.affiliation: b Department of Chemistry , University of Cambridge , Cambridge , UK.
authors.forename: Beth
authors.initials: B
authors.lastname: Thomas
mesh_terms: D055808:Drug Discovery; D006801:Humans; D019384:Nucleic Acid Synthesis Inhibitors / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D015800:Protozoan Proteins / Q000037:antagonists & inhibitors*; D017393:RNA Editing / Q000187:drug effects*; D012316:RNA Nucleotidyltransferases / Q000037:antagonists & inhibitors*; D022661:RNA, Untranslated / Q000096:biosynthesis*; D014344:Trypanocidal Agents / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D014346:Trypanosoma brucei brucei / Q000201:enzymology* / Q000235:genetics; D014353:Trypanosomiasis, African / Q000188:drug therapy; D014544:Uridine Triphosphate / Q000378:metabolism
chemical_list: D019384:Nucleic Acid Synthesis Inhibitors; D015800:Protozoan Proteins; D022661:RNA, Untranslated; D014344:Trypanocidal Agents; D012316:RNA Nucleotidyltransferases; C031687:UTP-RNA uridylyltransferase; D014544:Uridine Triphosphate
keywords: African trypanosomiasis; RET1; RNA modifications; TUTase; drug-discovery; non-coding RNA; post-transcriptional modification; trypanosome; uridylylation