Reaction hijacking of tyrosine tRNA synthetase as a new whole-of-life-cycle antimalarial strategy

  • Science. 2022 Jun 3;376(6597):1074-1079. doi: 10.1126/science.abn0611.
Stanley C Xie  #  1 ,  Riley D Metcalfe  #  1 ,  Elyse Dunn  1 ,  Craig J Morton  1 ,  Shih-Chung Huang  2 ,  Tanya Puhalovich  1 ,  Yawei Du  1 ,  Sergio Wittlin  3  4 ,  Shuai Nie  5 ,  Madeline R Luth  6 ,  Liting Ma  2 ,  Mi-Sook Kim  2 ,  Charisse Flerida A Pasaje  7 ,  Krittikorn Kumpornsin  8 ,  Carlo Giannangelo  9 ,  Fiona J Houghton  1 ,  Alisje Churchyard  10 ,  Mufuliat T Famodimu  10 ,  Daniel C Barry  1 ,  David L Gillett  1 ,  Sumanta Dey  7 ,  Clara C Kosasih  1 ,  William Newman  1 ,  Jacquin C Niles  7 ,  Marcus C S Lee  8 ,  Jake Baum  10 ,  Sabine Ottilie  6 ,  Elizabeth A Winzeler  6 ,  Darren J Creek  9 ,  Nicholas Williamson  5 ,  Michael W Parker  1  11 ,  Stephen Brand  12 ,  Steven P Langston  #  2 ,  Lawrence R Dick  #  1  13 ,  Michael D W Griffin  #  1 ,  Alexandra E Gould  #  2 ,  Leann Tilley  #  1
Affiliations
  • 1. Department of Biochemistry and Pharmacology, Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Melbourne, VIC 3010, Australia.
  • 2. Takeda Development Center Americas, Inc., Cambridge, MA 02139, USA.
  • 3. Swiss Tropical and Public Health Institute, 4051 Basel, Switzerland.
  • 4. University of Basel, 4003 Basel, Switzerland.
  • 5. Melbourne Mass Spectrometry and Proteomics Facility, Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Melbourne, VIC 3010, Australia.
  • 6. Department of Pediatrics, School of Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
  • 7. Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
  • 8. Parasites and Microbes Programme, Wellcome Sanger Institute, Hinxton CB10 1SA, UK.
  • 9. Drug Delivery, Disposition, and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC 3052, Australia.
  • 10. Department of Life Sciences, Imperial College London, London SW7 2AZ, UK.
  • 11. St. Vincent's Institute of Medical Research, Fitzroy, VIC 3065, Australia.
  • 12. Medicines for Malaria Venture, P.O. Box 1826, 20, Route de Pré-Bois, 1215 Geneva 15, Switzerland.
  • 13. Seofon Consulting, Natick, MA 01760, USA.
  • # Contributed equally.
PMID: 35653481 DOI: 10.1126/science.abn0611
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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