The cytoplasmic prolyl-tRNA synthetase of the malaria parasite is a dual-stage target of febrifugine and its analogs.
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.
|Year of Publication||
Sci Transl Med
2015 May 20
|PubMed Central ID||
K99 GM099796 / GM / NIGMS NIH HHS / United States
GM099796 / GM / NIGMS NIH HHS / United States
R01 CA092577 / CA / NCI NIH HHS / United States
F32 AI084440 / AI / NIAID NIH HHS / United States
R21 AI105786 / AI / NIAID NIH HHS / United States
R00 GM099796 / GM / NIGMS NIH HHS / United States
AI105786 / AI / NIAID NIH HHS / United States
Howard Hughes Medical Institute / United States
5F32AI084440-02 / AI / NIAID NIH HHS / United States
CA92577 / CA / NCI NIH HHS / United States