Portal de Periódicos da CAPES

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

2019; National Academy of Sciences; Volume: 116; Issue: 14 Linguagem: Inglês

10.1073/pnas.1814685116

1091-6490

Beatriz Baragaña, Barbara Forte, Ryan Choi, Stephen N. 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 Cooper, Sebastian Damerow, Michael J. Delves, Karen Dowers, James Duffy, Thomas E. Edwards, Irene Hallyburton, Benjamin G. Horst, Matthew A. Hulverson, Liam Ferguson, Marı́a Belén Jiménez-Dı́az, Rajiv S. Jumani, Donald D. Lorimer, Melissa S. Love, Steven P. Maher, Holly Matthews, Case W. McNamara, Peter G. Miller, Sandra M. O’Neill, Kayode K. Ojo, Maria Osuna‐Cabello, Érika G. 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, Fábio K. Tamaki, J. Tamjar, Leah S. Torrie, Amélie Vantaux, Benoît Witkowski, Sergio Wittlin, M. Yogavel, Fabio Zuccotto, Íñigo Angulo‐Barturen, Robert E. Sinden, Jake Baum, Francisco‐Javier Gamo, Pascal Mäser, Dennis E. Kyle, Elizabeth A. Winzeler, Peter J. Myler, Paul G. Wyatt, David Floyd, David J. 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,

Antibiotic Resistance in Bacteria

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 ( Pf KRS1). 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 Pf KRS1 and C. parvum KRS ( Cp KRS). In vivo proof of concept was established in an SCID mouse model of malaria, after oral administration (ED 90 = 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 Pf KRS1 and Cp KRS. This series of compounds inhibit Cp KRS 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 Pf KRS1 and Cp KRS vs. (human) Hs KRS. Our work validates apicomplexan KRSs as promising targets for the development of drugs for malaria and cryptosporidiosis.