Research ArticleMalaria

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

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Science Translational Medicine  20 May 2015:
Vol. 7, Issue 288, pp. 288ra77
DOI: 10.1126/scitranslmed.aaa3575

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An ancient remedy for a modern scourge

Malaria is a devastating disease. It is caused by a unicellular parasite and claims more than 600,000 lives every year—mostly young children and pregnant women. Renewed worldwide efforts to eradicate malaria demand new therapeutic approaches to overcome the emergence and spread of clinical resistance to mainstay drugs.

Now, Herman et al. validate the cytoplasmic prolyl-tRNA synthetase of the Plasmodium malaria parasite as the enigmatic target of the natural plant product febrifugine, the active principle of an ancient herbal malaria remedy that has been used for millennia in China. These authors establish a path forward for the rational development of next-generation antimalarial therapies based on febrifugine and its analogs.

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.

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