The cytoplasmic prolyl-tRNA synthetase of the malaria parasite is a dual-stage target of febrifugine and its analogs

Jonathan D. Herman, Lauren R. Pepper, Joseph F. Cortese, Guillermina Estiu, Kevin Galinsky, Vanessa Zuzarte-Luis, Emily R. Derbyshire, Ulf Ribacke, Amanda K. Lukens, Sofia A. Santos, Vishal Patel, Clary B. Clish, William J. Sullivan, Huihao Zhou, Selina E. Bopp, Paul Schimmel, Susan Lindquist, Jon Clardy, Maria M. Mota, Tracy L. KellerMalcolm Whitman, Olaf Wiest, Dyann F. Wirth, Ralph Mazitschek

Research output: Contribution to journalArticle

31 Scopus citations

Abstract

The emergence of drug resistance is a major limitation of current antimalarials. The discovery of new druggable targets and pathways including those that are critical for multiple life cycle stages of the malaria parasite is a major goal for developing next-generation antimalarial drugs. Using an integrated chemogenomics approach that combined drug resistance selection, whole-genome sequencing, and an orthogonal yeast model, we demonstrate that the cytoplasmic prolyl-tRNA (transfer RNA) synthetase (PfcPRS) of the malaria parasite Plasmodium falciparum is a biochemical and functional target of febrifugine and its synthetic derivative halofuginone. Febrifugine is the active principle of a traditional Chinese herbal remedy for malaria. We show that treatment with febrifugine derivatives activated the amino acid starvation response in both P. falciparum and a transgenic yeast strain expressing PfcPRS. We further demonstrate in the Plasmodium berghei mouse model of malaria that halofuginol, a new halofuginone analog that we developed, is active against both liver and asexual blood stages of the malaria parasite. Halofuginol, unlike halofuginone and febrifugine, is well tolerated at efficacious doses and represents a promising lead for the development of dual-stage next-generation antimalarials.

Original languageEnglish (US)
JournalScience translational medicine
Volume7
Issue number288
DOIs
StatePublished - May 20 2015

ASJC Scopus subject areas

  • Medicine(all)

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    Herman, J. D., Pepper, L. R., Cortese, J. F., Estiu, G., Galinsky, K., Zuzarte-Luis, V., Derbyshire, E. R., Ribacke, U., Lukens, A. K., Santos, S. A., Patel, V., Clish, C. B., Sullivan, W. J., Zhou, H., Bopp, S. E., Schimmel, P., Lindquist, S., Clardy, J., Mota, M. M., ... Mazitschek, R. (2015). The cytoplasmic prolyl-tRNA synthetase of the malaria parasite is a dual-stage target of febrifugine and its analogs. Science translational medicine, 7(288). https://doi.org/10.1126/scitranslmed.aaa3575