title: The first small-molecule inhibitors of members of the ribonuclease E family.
abstract: The Escherichia coli endoribonuclease RNase E is central to the processing and degradation of all types of RNA and as such is a pleotropic regulator of gene expression. It is essential for growth and was one of the first examples of an endonuclease that can recognise the 5'-monophosphorylated ends of RNA thereby increasing the efficiency of many cleavages. Homologues of RNase E can be found in many bacterial families including important pathogens, but no homologues have been identified in humans or animals. RNase E represents a potential target for the development of new antibiotics to combat the growing number of bacteria that are resistant to antibiotics in use currently. Potent small molecule inhibitors that bind the active site of essential enzymes are proving to be a source of potential drug leads and tools to dissect function through chemical genetics. Here we report the use of virtual high-throughput screening to obtain small molecules predicted to bind at sites in the N-terminal catalytic half of RNase E. We show that these compounds are able to bind with specificity and inhibit catalysis of Escherichia coli and Mycobacterium tuberculosis RNase E and also inhibit the activity of RNase G, a paralogue of RNase E.
authors.affiliation: Astbury Centre for Structural Molecular Biology, University of Leeds, Leeds, LS2 9JT, UK.
authors.forename: Louise
authors.initials: L
authors.lastname: Kime
authors.affiliation: School of Biological Sciences and Institute of Biomedical and Biomolecular Sciences, University of Portsmouth, Portsmouth, PO1 2DY, UK.
authors.forename: Helen A
authors.initials: HA
authors.lastname: Vincent
authors.affiliation: Astbury Centre for Structural Molecular Biology, University of Leeds, Leeds, LS2 9JT, UK.
authors.forename: Deena M A
authors.initials: DM
authors.lastname: Gendoo
authors.affiliation: Astbury Centre for Structural Molecular Biology, University of Leeds, Leeds, LS2 9JT, UK.
authors.forename: Stefanie S
authors.initials: SS
authors.lastname: Jourdan
authors.affiliation: 1] Astbury Centre for Structural Molecular Biology, University of Leeds, Leeds, LS2 9JT, UK [2] School of Chemistry, University of Leeds, Leeds, LS2 9JT, UK.
authors.forename: Colin W G
authors.initials: CW
authors.lastname: Fishwick
authors.affiliation: School of Biological Sciences and Institute of Biomedical and Biomolecular Sciences, University of Portsmouth, Portsmouth, PO1 2DY, UK.
authors.forename: Anastasia J
authors.initials: AJ
authors.lastname: Callaghan
authors.affiliation: Astbury Centre for Structural Molecular Biology, University of Leeds, Leeds, LS2 9JT, UK.
authors.forename: Kenneth J
authors.initials: KJ
authors.lastname: McDowall
mesh_terms: D001665:Binding Sites; D002384:Catalysis; D020134:Catalytic Domain; D004722:Endoribonucleases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D004926:Escherichia coli / Q000201:enzymology*; D029968:Escherichia coli Proteins / Q000037:antagonists & inhibitors; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D057166:High-Throughput Screening Assays; D009169:Mycobacterium tuberculosis / Q000201:enzymology*; D054852:Small Molecule Libraries / Q000737:chemistry* / Q000494:pharmacology
chemical_list: D029968:Escherichia coli Proteins; D054852:Small Molecule Libraries; D004722:Endoribonucleases; C081905:rng protein, E coli; C022537:ribonuclease E