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Reaction hijacking of tyrosine tRNA synthetase as a new whole-of-life-cycle antimalarial strategy.
Xie, Stanley C; Metcalfe, Riley D; Dunn, Elyse; Morton, Craig J; Huang, Shih-Chung; Puhalovich, Tanya; Du, Yawei; Wittlin, Sergio; Nie, Shuai; Luth, Madeline R; Ma, Liting; Kim, Mi-Sook; Pasaje, Charisse Flerida A; Kumpornsin, Krittikorn; Giannangelo, Carlo; Houghton, Fiona J; Churchyard, Alisje; Famodimu, Mufuliat T; Barry, Daniel C; Gillett, David L; Dey, Sumanta; Kosasih, Clara C; Newman, William; Niles, Jacquin C; Lee, Marcus C S; Baum, Jake; Ottilie, Sabine; Winzeler, Elizabeth A; Creek, Darren J; Williamson, Nicholas; Parker, Michael W; Brand, Stephen; Langston, Steven P; Dick, Lawrence R; Griffin, Michael D W; Gould, Alexandra E; Tilley, Leann.
  • Xie SC; Department of Biochemistry and Pharmacology, Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Melbourne, VIC 3010, Australia.
  • Metcalfe RD; Department of Biochemistry and Pharmacology, Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Melbourne, VIC 3010, Australia.
  • Dunn E; Department of Biochemistry and Pharmacology, Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Melbourne, VIC 3010, Australia.
  • Morton CJ; Department of Biochemistry and Pharmacology, Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Melbourne, VIC 3010, Australia.
  • Huang SC; Takeda Development Center Americas, Inc., Cambridge, MA 02139, USA.
  • Puhalovich T; Department of Biochemistry and Pharmacology, Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Melbourne, VIC 3010, Australia.
  • Du Y; Department of Biochemistry and Pharmacology, Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Melbourne, VIC 3010, Australia.
  • Wittlin S; Swiss Tropical and Public Health Institute, 4051 Basel, Switzerland.
  • Nie S; University of Basel, 4003 Basel, Switzerland.
  • Luth MR; Melbourne Mass Spectrometry and Proteomics Facility, Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Melbourne, VIC 3010, Australia.
  • Ma L; Department of Pediatrics, School of Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
  • Kim MS; Takeda Development Center Americas, Inc., Cambridge, MA 02139, USA.
  • Pasaje CFA; Takeda Development Center Americas, Inc., Cambridge, MA 02139, USA.
  • Kumpornsin K; Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
  • Giannangelo C; Parasites and Microbes Programme, Wellcome Sanger Institute, Hinxton CB10 1SA, UK.
  • Houghton FJ; Drug Delivery, Disposition, and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC 3052, Australia.
  • Churchyard A; Department of Biochemistry and Pharmacology, Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Melbourne, VIC 3010, Australia.
  • Famodimu MT; Department of Life Sciences, Imperial College London, London SW7 2AZ, UK.
  • Barry DC; Department of Life Sciences, Imperial College London, London SW7 2AZ, UK.
  • Gillett DL; Department of Biochemistry and Pharmacology, Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Melbourne, VIC 3010, Australia.
  • Dey S; Department of Biochemistry and Pharmacology, Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Melbourne, VIC 3010, Australia.
  • Kosasih CC; Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
  • Newman W; Department of Biochemistry and Pharmacology, Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Melbourne, VIC 3010, Australia.
  • Niles JC; Department of Biochemistry and Pharmacology, Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Melbourne, VIC 3010, Australia.
  • Lee MCS; Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
  • Baum J; Parasites and Microbes Programme, Wellcome Sanger Institute, Hinxton CB10 1SA, UK.
  • Ottilie S; Department of Life Sciences, Imperial College London, London SW7 2AZ, UK.
  • Winzeler EA; Department of Pediatrics, School of Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
  • Creek DJ; Department of Pediatrics, School of Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
  • Williamson N; Drug Delivery, Disposition, and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC 3052, Australia.
  • Parker MW; Melbourne Mass Spectrometry and Proteomics Facility, Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Melbourne, VIC 3010, Australia.
  • Brand S; Department of Biochemistry and Pharmacology, Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Melbourne, VIC 3010, Australia.
  • Langston SP; St. Vincent's Institute of Medical Research, Fitzroy, VIC 3065, Australia.
  • Dick LR; Medicines for Malaria Venture, P.O. Box 1826, 20, Route de Pré-Bois, 1215 Geneva 15, Switzerland.
  • Griffin MDW; Takeda Development Center Americas, Inc., Cambridge, MA 02139, USA.
  • Gould AE; Department of Biochemistry and Pharmacology, Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Melbourne, VIC 3010, Australia.
  • Tilley L; Seofon Consulting, Natick, MA 01760, USA.
Science ; 376(6597): 1074-1079, 2022 06 03.
Article en En | MEDLINE | ID: mdl-35653481
ABSTRACT
Aminoacyl transfer RNA (tRNA) synthetases (aaRSs) are attractive drug targets, and we present class I and II aaRSs as previously unrecognized targets for adenosine 5'-monophosphate-mimicking nucleoside sulfamates. The target enzyme catalyzes the formation of an inhibitory amino acid-sulfamate conjugate through a reaction-hijacking mechanism. We identified adenosine 5'-sulfamate as a broad-specificity compound that hijacks a range of aaRSs and ML901 as a specific reagent a specific reagent that hijacks a single aaRS in the malaria parasite Plasmodium falciparum, namely tyrosine RS (PfYRS). ML901 exerts whole-life-cycle-killing activity with low nanomolar potency and single-dose efficacy in a mouse model of malaria. X-ray crystallographic studies of plasmodium and human YRSs reveal differential flexibility of a loop over the catalytic site that underpins differential susceptibility to reaction hijacking by ML901.
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Texto completo: 1 Banco de datos: MEDLINE Asunto principal: Plasmodium falciparum / Biosíntesis de Proteínas / Tirosina-ARNt Ligasa / Proteínas Protozoarias / Malaria Falciparum / Terapia Molecular Dirigida / Antimaláricos Límite: Animals / Humans Idioma: En Año: 2022 Tipo del documento: Article
Texto completo
Imprimir
XML
PubMed Links
Search on Google

Texto completo: 1 Banco de datos: MEDLINE Asunto principal: Plasmodium falciparum / Biosíntesis de Proteínas / Tirosina-ARNt Ligasa / Proteínas Protozoarias / Malaria Falciparum / Terapia Molecular Dirigida / Antimaláricos Límite: Animals / Humans Idioma: En Año: 2022 Tipo del documento: Article