The cytoplasmic prolyl-tRNA synthetase of the malaria parasite is a dual-stage target of febrifugine and its analogs
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Author(s)
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.
Date Issued
May 2015
Journal
Science Translational Medicine
Publisher
American Association for the Advancement of Science (AAAS)
Citation
Herman, J. D. et al. “The Cytoplasmic Prolyl-tRNA Synthetase of the Malaria Parasite Is a Dual-Stage Target of Febrifugine and Its Analogs.” Science Translational Medicine 7.288 (2015): 288ra77-288ra77.
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Author's final manuscript
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.
MIT Department
Harvard University--MIT Division of Health Sciences and Technology
Massachusetts Institute of Technology. Department of Biology
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DOI of Published Version
https://doi.org/10.1126/scitranslmed.aaa3575
