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

Baragaña, Beatriz and Forte, Barbara and Choi, Ryan and Nakazawa Hewitt, Stephen and Bueren-Calabuig, Juan A. and Pisco, João Pedro and Peet, Caroline and Dranow, David M. and Robinson, David A. and Jansen, Chimed and Norcross, Neil R. and Vinayak, Sumiti and Anderson, Mark and Brooks, Carrie F. and Cooper, Caitlin A. and Damerow, Sebastian and Delves, Michael and Dowers, Karen and Duffy, James and Edwards, Thomas E. and Hallyburton, Irene and Horst, Benjamin G. and Hulverson, Matthew A. and Ferguson, Liam and Jiménez-Díaz, María Belén and Jumani, Rajiv S. and Lorimer, Donald D. and Love, Melissa S. and Maher, Steven and Matthews, Holly and McNamara, Case W. and Miller, Peter and O'Neill, Sandra and Ojo, Kayode K. and Osuna-Cabello, Maria and Pinto, Erika and Post, John and Riley, Jennifer and Rottmann, Matthias and Sanz, Laura M. and Scullion, Paul and Sharma, Arvind and Shepherd, Sharon M. and Shishikura, Yoko and Simeons, Frederick R. C. and Stebbins, Erin E. and Stojanovski, Laste and Straschil, Ursula and Tamaki, Fabio K. and Tamjar, Jevgenia and Torrie, Leah S. and Vantaux, Amélie and Witkowski, Benoît and Wittlin, Sergio and Yogavel, Manickam and Zuccotto, Fabio and Angulo-Barturen, Iñigo and Sinden, Robert and Baum, Jake and Gamo, Francisco-Javier and Mäser, Pascal and Kyle, Dennis E. and Winzeler, Elizabeth A. and Myler, Peter J. and Wyatt, Paul G. and Floyd, David and Matthews, David and Sharma, Amit and Striepen, Boris and Huston, Christopher D. and Gray, David W. and Fairlamb, Alan H. and Pisliakov, Andrei V. and Walpole, Chris and Read, Kevin D. and Van Voorhis, Wesley C. and Gilbert, Ian H.. (2019) Lysyl-tRNA synthetase as a drug target in malaria and cryptosporidiosis. Proceedings of the National Academy of Sciences of the United States of America, 116 (14). pp. 7015-7020.

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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 (; 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.

Faculties and Departments:	09 Associated Institutions > Swiss Tropical and Public Health Institute (Swiss TPH) 09 Associated Institutions > Swiss Tropical and Public Health Institute (Swiss TPH) > Department of Medical Parasitology and Infection Biology (MPI) > Parasite Chemotherapy (Mäser)
UniBasel Contributors:	Rottmann, Matthias and Wittlin, Sergio and Mäser, Pascal
Item Type:	Article, refereed
Article Subtype:	Research Article
Publisher:	National Academy of Sciences
ISSN:	0027-8424
Note:	Publication type according to Uni Basel Research Database: Journal article
Language:	English
Identification Number:	doi: 10.1073/pnas.1814685116 pmid: 30894487
edoc DOI:	10.5451/unibas-ep70292
Last Modified:	25 Apr 2019 08:40
Deposited On:	25 Apr 2019 08:40

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