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

Beatriz Baragaña, Barbara Forte, Ryan Choi, Stephen Nakazawa Hewitt, Juan A. Bueren-Calabuig, João Pedro Pisco, Caroline Peet, David M. Dranow, David A. Robinson, Chimed Jansen, Neil R. Norcross, Sumiti Vinayak, Mark Anderson, Carrie F. Brooks, Caitlin A. Cooper, Sebastian Damerow, Michael Delves, Karen Dowers, James Duffy, Thomas E. EdwardsIrene Hallyburton, Benjamin G. Horst, Matthew A. Hulverson, Liam Ferguson, María Belén Jiménez-Díaz, Rajiv S. Jumani, Donald D. Lorimer, Melissa S. Love, Steven Maher, Holly Matthews, Case W. McNamara, Peter Miller, Sandra O'Neill, Kayode K. Ojo, Maria Osuna-Cabello, Erika Pinto, John Post, Jennifer Riley, Matthias Rottmann, Laura M. Sanz, Paul Scullion, Arvind Sharma, Sharon M. Shepherd, Yoko Shishikura, Frederick R. C. Simeons, Erin E. Stebbins, Laste Stojanovski, Ursula Straschil, Fabio K. Tamaki, Jevgenia Tamjar, Leah S. Torrie, Amélie Vantaux, Benoît Witkowski, Sergio Wittlin, Manickam Yogavel, Fabio Zuccotto, Iñigo Angulo-Barturen, Robert Sinden, Jake Baum, Francisco-Javier Gamo, Pascal Mäser, Dennis E. Kyle, Elizabeth A. Winzeler, Peter J. Myler, Paul G. Wyatt, David Floyd, David Matthews, Amit Sharma, Boris Striepen, Christopher D. Huston, David W. Gray, Alan H. Fairlamb, Andrei V. Pisliakov, Chris Walpole, Kevin D. Read, Wesley C. Van Voorhis, Ian H. Gilbert

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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 novel series of selective inhibitors of apicomplexan KRSs. Following a biochemical screen, a small molecule hit was identified and then optimized using a structurebased approach, supported by structures of both PfKRS1 and C. parvum lysyl-tRNA synthetase (CpKRS). In vivo proof of concept was established in a SCID mouse model of malaria, after oral administration (ED90 = 1.5 mg/kg, once a day for 4 days). 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 C. hominis in culture and our optimized lead 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 versus human HsKRS. Our work validates apicomplexan lysyl-tRNA synthetases as promising targets for the development of new drugs for malaria and cryptosporidiosis.
Original languageEnglish
Pages (from-to)7015-7020
Number of pages6
JournalProceedings of the National Academy of Sciences
Volume116
Issue number14
Early online date20 Mar 2019
DOIs
Publication statusPublished - 2 Apr 2019

Keywords

  • Cryptosporidiosis
  • Malaria
  • TRNA synthetase

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    Baragaña, B., Forte, B., Choi, R., Nakazawa Hewitt, S., Bueren-Calabuig, J. A., Pisco, J. P., Peet, C., Dranow, D. M., Robinson, D. A., Jansen, C., Norcross, N. R., Vinayak, S., Anderson, M., Brooks, C. F., Cooper, C. A., Damerow, S., Delves, M., Dowers, K., Duffy, J., ... Gilbert, I. H. (2019). Lysyl-tRNA synthetase as a drug target in malaria and cryptosporidiosis. Proceedings of the National Academy of Sciences, 116(14), 7015-7020. https://doi.org/10.1073/pnas.1814685116