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

Baragaña, Beatriz; Forte, Barbara; Choi, Ryan; Nakazawa Hewitt, Stephen; Bueren-Calabuig, Juan A.; Pisco, João Pedro; Peet, Caroline; Dranow, David M.; Robinson, David A.; Jansen, Chimed; Norcross, Neil R.; Vinayak, Sumiti; Anderson, Mark; Brooks, Carrie F.; Cooper, Caitlin A.; Damerow, Sebastian; Delves, Michael; Dowers, Karen; Duffy, James; Edwards, Thomas E.; Hallyburton, Irene; Horst, Benjamin G.; Hulverson, Matthew A.; Ferguson, Liam; Jiménez-Díaz, María Belén; Jumani, Rajiv S.; Lorimer, Donald D.; Love, Melissa S.; Maher, Steven; Matthews, Holly; McNamara, Case W.; Miller, Peter; O’Neill, Sandra; Ojo, Kayode K.; Osuna-Cabello, Maria; Pinto, Erika; Post, John; Riley, Jennifer; Rottmann, Matthias; Sanz, Laura M.; Scullion, Paul; Sharma, Arvind; Shepherd, Sharon M.; Shishikura, Yoko; Simeons, Frederick R. C.; Stebbins, Erin E.; Stojanovski, Laste; Straschil, Ursula; Tamaki, Fabio K.; Tamjar, Jevgenia; Torrie, Leah S.; Vantaux, Amélie; Witkowski, Benoît; Wittlin, Sergio; Yogavel, Man...

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 clado-
sporin 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). Further-
more, 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 Cryptosporid-
ium hominis in culture, and our lead compound shows oral efficacy in
two cryptosporidiosis mouse models. X-ray crystallography and molec-
ular 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.

• Journal Article Type: Article
• Online Publication Date: Mar 20, 2019
• Publication Date: Apr 2, 2019
• Deposit Date: May 23, 2025
• Publicly Available Date: May 29, 2025
• Print ISSN: 0027-8424
• Publisher: National Academy of Sciences
• Peer Reviewed: Peer Reviewed
• Volume: 116
• Issue: 14
• Pages: 7015-7020
• DOI: https://doi.org/10.1073/pnas.1814685116
• Additional Information: Published: 2019-03-20