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

Journal Article

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.

Full Text

Duke Authors

Cited Authors

  • Herman, JD; Pepper, LR; Cortese, JF; Estiu, G; Galinsky, K; Zuzarte-Luis, V; Derbyshire, ER; Ribacke, U; Lukens, AK; Santos, SA; Patel, V; Clish, CB; Sullivan, WJ; Zhou, H; Bopp, SE; Schimmel, P; Lindquist, S; Clardy, J; Mota, MM; Keller, TL; Whitman, M; Wiest, O; Wirth, DF; Mazitschek, R

Published Date

  • May 2015

Published In

Volume / Issue

  • 7 / 288

Start / End Page

  • 288ra77 -

PubMed ID

  • 25995223

Electronic International Standard Serial Number (EISSN)

  • 1946-6242

International Standard Serial Number (ISSN)

  • 1946-6234

Digital Object Identifier (DOI)

  • 10.1126/scitranslmed.aaa3575

Language

  • eng