The delayed bloodstream clearance of Plasmodium falciparum parasites after M5717 treatment is attributable to the inability to modify their red blood cell hosts

Abstract

M5717 is a promising antimalarial drug under development that acts against multiple stages of the life cycle of Plasmodium parasites by inhibiting the translation elongation factor 2 (PfeEF2), thereby preventing protein synthesis. The parasite clearance profile after drug treatment in preclinical studies in mice, and clinical trials in humans showed a notable delayed clearance phenotype whereby parasite infected red blood cells (iRBCs) persisted in the bloodstream for a significant period before eventual clearance. In a normal P. falciparum infection iRBCs sequester in the deep circulation by cytoadherence, allowing them to avoid surveillance and clearance in the spleen. We found that M5717 blocks parasite modification of their host red blood cells (RBCs) by preventing synthesis of new exported proteins, rather than by directly blocking the export of these proteins into the RBC compartment. Using in vitro models, we demonstrated that M5717 treated ring/trophozoite stage iRBCs became less rigid, and cytoadhered less well compared to untreated iRBCs. This indicates that in vivo persistence of M5717 treated iRBCs in the bloodstream is likely due to reduced cytoadherence and splenic clearance.

Defining the next generation of severe malaria treatment: a target product profile

“…The novel Plasmodium eukaryotic translation elongation factor 2 inhibitor M5717 (formerly DDD107498) blocks parasite modification of host red blood cells (RBCs) by preventing synthesis of new exported proteins [ 104 ]. M5717 presents some interesting perspectives on anti-malarial drug development for severe malaria.…”

“…The drug has a long half-life but demonstrates a distinct delay in parasite clearance in both mouse and human studies [ 88 , 105 , 106 ]. This delay has been recently explained by an M5717-induced decrease in the rigidity of infected red blood cells, reducing splenic clearance while inhibiting sequestration into tissues [ 104 ]. The clinical implications of these findings for severe malaria require further investigation but indicate that for drugs with novel mechanisms of action, it may be necessary to consider attributes beyond the classical measures of PCT 1/2 and PRR.…”

Multiscale effects of perturbed translation dynamics inform antimalarial design

“…To explore how malaria-specific translation inhibitors might perturb the translational landscape, we analyzed our in situ datasets of parasites treated with P. falciparum-specific translation inhibitors across multiple timepoints and determined the ensemble of structures of the Pf80S ribosome in the native cellular context for each timepoint (Table S1). The first, known as cabamiquine 37,38,39 (CBQ), is a leading compound currently in phase II clinical trials that has been shown to target the translation elongation factor PfeEF2. The second, MMV019189, was identified as the top hit in a high-throughput screen for malarial translation inhibitors from the Medicines for Malaria Venture Pandemic and Pathogen Box 40 .…”