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

Sci Transl Med
Authors
Keywords
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.

Year of Publication
2015
Journal
Sci Transl Med
Volume
7
Issue
288
Pages
288ra77
Date Published
2015 May 20
ISSN
1946-6242
URL
DOI
10.1126/scitranslmed.aaa3575
PubMed ID
25995223
PubMed Central ID
PMC4675670
Links
Grant list
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