Lysyl-tRNA synthetase as a drug target in malaria and cryptosporidiosis

  • Proc Natl Acad Sci U S A. 2019 Apr 2;116(14):7015-7020. doi: 10.1073/pnas.1814685116.
Beatriz Baragaña  1 ,  Barbara Forte  1 ,  Ryan Choi  2  3  4 ,  Stephen Nakazawa Hewitt  2  3  4 ,  Juan A Bueren-Calabuig  1 ,  João Pedro Pisco  1 ,  Caroline Peet  1 ,  David M Dranow  2  5 ,  David A Robinson  1 ,  Chimed Jansen  1 ,  Neil R Norcross  1 ,  Sumiti Vinayak  6 ,  Mark Anderson  1 ,  Carrie F Brooks  6 ,  Caitlin A Cooper  6 ,  Sebastian Damerow  1 ,  Michael Delves  7 ,  Karen Dowers  1 ,  James Duffy  8 ,  Thomas E Edwards  2  5 ,  Irene Hallyburton  1 ,  Benjamin G Horst  2  3  4 ,  Matthew A Hulverson  3  4 ,  Liam Ferguson  1 ,  María Belén Jiménez-Díaz  9 ,  Rajiv S Jumani  10 ,  Donald D Lorimer  2  5 ,  Melissa S Love  11 ,  Steven Maher  6 ,  Holly Matthews  7 ,  Case W McNamara  11 ,  Peter Miller  10 ,  Sandra O'Neill  1 ,  Kayode K Ojo  3  4 ,  Maria Osuna-Cabello  1 ,  Erika Pinto  1 ,  John Post  1 ,  Jennifer Riley  1 ,  Matthias Rottmann  12  13 ,  Laura M Sanz  14 ,  Paul Scullion  1 ,  Arvind Sharma  15 ,  Sharon M Shepherd  1 ,  Yoko Shishikura  1 ,  Frederick R C Simeons  1 ,  Erin E Stebbins  10 ,  Laste Stojanovski  1 ,  Ursula Straschil  7 ,  Fabio K Tamaki  1 ,  Jevgenia Tamjar  1 ,  Leah S Torrie  1 ,  Amélie Vantaux  16 ,  Benoît Witkowski  16 ,  Sergio Wittlin  12  13 ,  Manickam Yogavel  15 ,  Fabio Zuccotto  1 ,  Iñigo Angulo-Barturen  9 ,  Robert Sinden  7 ,  Jake Baum  7 ,  Francisco-Javier Gamo  14 ,  Pascal Mäser  12  13 ,  Dennis E Kyle  6 ,  Elizabeth A Winzeler  17  18 ,  Peter J Myler  2  19  20  21 ,  Paul G Wyatt  1 ,  David Floyd  22 ,  David Matthews  22 ,  Amit Sharma  15 ,  Boris Striepen  6  23 ,  Christopher D Huston  10 ,  David W Gray  1 ,  Alan H Fairlamb  1 ,  Andrei V Pisliakov  24  25 ,  Chris Walpole  26 ,  Kevin D Read  1 ,  Wesley C Van Voorhis  2  3  4 ,  Ian H Gilbert  27
Affiliations
  • 1. Wellcome Centre for Anti-Infectives Research, Drug Discovery Unit, Division of Biological Chemistry and Drug Discovery, University of Dundee, DD1 5EH Dundee, United Kingdom.
  • 2. Seattle Structural Genomics Center for Infectious Disease, Seattle, WA 98109.
  • 3. Division of Allergy and Infectious Diseases, University of Washington, Seattle, WA 98109.
  • 4. Center for Emerging and Re-emerging Infectious Diseases, University of Washington, Seattle, WA 98109.
  • 5. Beryllium Discovery Corp., Bainbridge Island, WA 98110.
  • 6. Center for Tropical and Emerging Global Diseases, University of Georgia, Athens, GA 30602.
  • 7. Department of Life Sciences, Imperial College, South Kensington, SW7 2AZ London, United Kingdom.
  • 8. Medicines for Malaria Venture, 1215 Geneva 15, Switzerland.
  • 9. The Art of Discovery, 48160 Derio, Bizkaia, Basque Country, Spain.
  • 10. Department of Medicine, University of Vermont, Burlington, VT 05405.
  • 11. Biology Department, Calibr at Scripps Research, La Jolla, CA 92037.
  • 12. Department of Medical Parasitology and Infection Biology, Swiss Tropical and Public Health Institute, CH-4002 Basel, Switzerland.
  • 13. Universität Basel, CH-4003 Basel, Switzerland.
  • 14. Diseases of the Developing World, Global Health, GlaxoSmithKline, 28760 Tres Cantos, Madrid, Spain.
  • 15. Structural Parasitology Group, International Centre for Genetic Engineering and Biotechnology, 110067 New Delhi, India.
  • 16. Malaria Molecular Epidemiology Unit, Institut Pasteur du Cambodge, 12 201 Phnom Penh, Cambodia.
  • 17. Skaggs School of Pharmaceutical Sciences, University of California, San Diego, La Jolla, CA 92093.
  • 18. Department of Pediatrics, School of Medicine, University of California, San Diego, La Jolla, CA 92093.
  • 19. Center for Global Infectious Disease Research, Seattle Children's Research Institute, Seattle, WA 98109.
  • 20. Department of Global Health, University of Washington, Seattle, WA 98195.
  • 21. Department of Biomedical Informatics and Medical Education, University of Washington, Seattle, WA 98195.
  • 22. Structural Genomics Consortium, University of Toronto, Toronto, ON M5G 1L7, Canada.
  • 23. Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104.
  • 24. Computational Biology, School of Life Sciences, University of Dundee, DD1 5EH Dundee, United Kingdom.
  • 25. Physics, School of Science and Engineering, University of Dundee, Dundee DD1 4HN, United Kingdom.
  • 26. Structural Genomics Consortium, Research Institute of the McGill University Health Centre, Montreal, QC H4A 3J1, Canada.
  • 27. Wellcome Centre for Anti-Infectives Research, Drug Discovery Unit, Division of Biological Chemistry and Drug Discovery, University of Dundee, DD1 5EH Dundee, United Kingdom; [email protected].
PMID: 30894487 DOI: 10.1073/pnas.1814685116
Abstract

Malaria and cryptosporidiosis, caused by apicomplexan parasites, remain major drivers of global child mortality. New drugs for the treatment of malaria and cryptosporidiosis, in particular, are of high priority; however, there are few chemically validated targets. The natural product cladosporin is active against blood- and liver-stage Plasmodium falciparum and Cryptosporidium parvum in cell-culture studies. Target deconvolution in P. falciparum has shown that cladosporin inhibits lysyl-tRNA synthetase (PfKRS1). Here, we report the identification of a series of selective inhibitors of apicomplexan KRSs. Following a biochemical screen, a small-molecule hit was identified and then optimized by using a structure-based approach, supported by structures of both PfKRS1 and C. parvum KRS (CpKRS). In vivo proof of concept was established in an SCID mouse model of malaria, after oral administration (ED90 = 1.5 mg/kg, once a day for 4 d). Furthermore, we successfully identified an opportunity for pathogen hopping based on the structural homology between PfKRS1 and CpKRS. This series of compounds inhibit CpKRS and C. parvum and Cryptosporidium hominis in culture, and our lead compound shows oral efficacy in two cryptosporidiosis mouse models. X-ray crystallography and molecular dynamics simulations have provided a model to rationalize the selectivity of our compounds for PfKRS1 and CpKRS vs. (human) HsKRS. Our work validates apicomplexan KRSs as promising targets for the development of drugs for malaria and cryptosporidiosis.

Keywords
cryptosporidiosis; malaria; tRNA synthetase.
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