title: Inhibition of isoleucyl-tRNA synthetase as a potential treatment for human African Trypanosomiasis.
abstract: Trypanosoma brucei sp. causes human African trypanosomiasis (HAT; African sleeping sickness). The parasites initially proliferate in the hemolymphatic system and then invade the central nervous system, which is lethal if not treated. New drugs are needed for HAT because the approved drugs are few, toxic, and difficult to administer, and drug resistance is spreading. We showed by RNAi knockdown that T. brucei isoleucyl-tRNA synthetase is essential for the parasites in vitro and in vivo in a mouse model of infection. By structure prediction and experimental analysis, we also identified small molecules that inhibit recombinant isoleucyl-tRNA synthetase and that are lethal to the parasites in vitro and highly selective compared with mammalian cells. One of these molecules acts as a competitive inhibitor of the enzyme and cures mice of the infection. Because members of this class of molecules are known to cross the blood-brain barrier in humans and to be tolerated, they may be attractive as leading candidates for drug development for HAT.
authors.affiliation: Seattle Biomedical Research Institute, Seattle, Washington 98109.
authors.forename: Igor
authors.initials: I
authors.lastname: Cestari
authors.affiliation: Seattle Biomedical Research Institute, Seattle, Washington 98109; Department of Global Health, University of Washington, Seattle, Washington 98195. Electronic address: ken.stuart@seattlebiomed.org.
authors.forename: Kenneth
authors.initials: K
authors.lastname: Stuart
mesh_terms: D000818:Animals; D001812:Blood-Brain Barrier; D004195:Disease Models, Animal; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D007533:Isoleucine-tRNA Ligase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D062105:Molecular Docking Simulation; D034622:RNA Interference; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D014162:Transfection; D014344:Trypanocidal Agents / Q000494:pharmacology* / Q000627:therapeutic use; D014346:Trypanosoma brucei brucei / Q000201:enzymology*; D014353:Trypanosomiasis, African / Q000188:drug therapy*
chemical_list: D004791:Enzyme Inhibitors; D011994:Recombinant Proteins; D014344:Trypanocidal Agents; D007533:Isoleucine-tRNA Ligase
keywords: Aminoacyl-tRNA Synthetase; Chemical Biology; Drug Development; Enzyme Inhibitors; Molecular Biology; Parasitology; Trypanosoma brucei
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