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

Genetic diversity of next generation antimalarial targets: A baseline for drug resistance surveillance programmes

“…These SNPs were localized in the Pfatp4 , Pfcarl , Pfpi4k and the Pfcprs genes. The Pfcprs i s a cytoplasmic prolyl-tRNA synthetase and a functional target of febrifugine and its synthetic derivatives with activity at erythrocytic and liver stages (Herman et al., 2015).

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“…Here we consider eleven gene-targets of key investigated compounds that due to their efficiency might become the next antimalarial drugs, and for which mutations conferring resistance have been identified in in vitro studies (Baragaña et al., 2015, Dong et al., 2011, Flannery et al., 2015, Herman et al., 2015, Kato et al., 2016, LaMonte et al., 2016, Lim et al., 2016, McNamara et al., 2013, Ross et al., 2014). These 11 genes were also selected because they are gene-targets for a range of new antimalarial compounds already under evaluation in clinical trials.…”

Biochemical and Structural Characterization of Selective Allosteric Inhibitors of the Plasmodium falciparum Drug Target, Prolyl-tRNA-synthetase

“…This also suggests that the parasite could become more resistant to the effects of such an inhibitor by increasing its intracellular concentration of proline, which would be a potential liability. Indeed, this mechanism of resistance to halofuginone analogues, accomplished by the parasite increasing its intracellular proline levels, was described by Hermann et al 9 …”

A potent prolyl tRNA synthetase inhibitor antagonizes Chikungunya and Dengue viruses

“…Although inhibiting host translation may lead to toxic effects, halofuginone and similar derivatives have been shown in murine models to inhibit malaria (Herman et al, 2015), reduce cardiac stress (Qin et al, 2017), suppress viral myocarditis (Sun et al, 2016), and improve hepatitis B virus-induced liver inflammation (Zhan et al, 2017). Furthermore, commercial preparations of halofuginone (Stenorol and Halocur) are used in livestock to inhibit parasite growth (Pines and Spector, 2015), and a clinical trial for a slow-release form of halofuginone has been approved by the FDA to treat Duchenne muscular dystrophy (Pines and Spector, 2015).…”