Plasmodium Prolyl-tRNA Synthetase: How Metabolism Drives Drug Resistance in Malaria Parasites
Lecture held by Professor Ralph Mazitschek, Harvard Medical School / Massachusetts General Hospital, USA
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 the development of the next-generation of 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 synthetase (PfcPRS) of the malaria parasite Plasmodium falciparum is a biochemical and functional target of febrifugine and its synthetic derivatives such as 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 P. berghei mouse model of malaria that halofuginol, a new halofuginone analog that we developed, is highly 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.
The lecture is organised on behalf of the graduate programme in pharmaceutical sciences, Drug Research Academy, and Center for Biopharmaceuticals by Professor Christian A. Olsen (email@example.com), Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen.
The DRA lecture is free of charge and open for attendance by all interested parties. It is not necessary to pre-register.