Translation of liver stage activity of M5717, a Plasmodium elongation factor 2 inhibitor: from bench to bedside

Abstract

Background Targeting the asymptomatic liver stage of Plasmodium infection through chemoprevention could become a key intervention to reduce malaria-associated incidence and mortality. Methods M5717, a Plasmodium elongation factor 2 inhibitor, was assessed in vitro and in vivo with readily accessible Plasmodium berghei parasites. In an animal refinement, reduction, replacement approach, the in vitro IC99 value was used to feed a Population Pharmacokinetics modelling and simulation approach to determine meaningful effective doses for a subsequent Plasmodium sporozoite-induced volunteer infection study. Results Doses of 100 and 200 mg would provide exposures exceeding IC99 in 96 and 100% of the simulated population, respectively. Conclusions This approach has the potential to accelerate the search for new anti-malarials, to reduce the number of healthy volunteers needed in a clinical study and decrease and refine the animal use in the preclinical phase. Graphical Abstract

Semi-mechanistic population pharmacokinetic/pharmacodynamic modeling of a Plasmodium elongation factor 2 inhibitor cabamiquine for prevention and cure of malaria

“…The PK model was as semi-mechanistic as could be supported by the data; however, absorption, distribution, and recycling are the result of related processes, and once these processes are better understood and more data are available, it may be possible to develop a more physiologically plausible model. Despite these limitations, this PK model was deemed to be suitable and was successfully used in combination with in vitro data to predict the starting dose to be used in the SpzCh study through model-based simulations ( 9 ).…”

“…The molecular target of cabamiquine is the eukaryotic translation elongation factor 2 (eEF2), which is responsible for the guanosine triphosphate-dependent translocation of the ribosome along mRNA and is therefore essential for protein synthesis ( 6 , 7 ). With a long half-life [146 h–193 h at doses ≥200 mg ( 8 )] and activity against the liver stage ( 9 ), cabamiquine has the potential to address several clinical needs in malaria chemotherapy, including single-dose treatment and transmission blocking via inhibition of gametocyte formation, and chemoprevention. It has demonstrated good pharmacokinetic (PK) and pharmacodynamic (PD) properties and an acceptable safety profile in preclinical studies, animal models ( 6 , 7 ), and in a recently completed combined phase Ia and Ib experimental infection study in healthy subjects ( 8 ).…”

Post-Translational Modifications of Proteins of Malaria Parasites during the Life Cycle

“…Interestingly, M5717 as a specific inhibitor of Plasmodium eEF-2, an essential factor for protein synthesis in all parasite stages and the substrate of numerous PTMs, was shown to also be associated with kinases in the mechanism of action [ 311 ]. M5717 is undergoing clinical study as a multi-stage antimalarial [ 311 , 312 , 313 ]. PfAMA-1 and PvAMA-1, involved in serine protease action [ 30 ] and potentially glycosylated, can induce strong cellular and humoral responses, and are proposed and actively studied for vaccine development [ 31 , 111 ].…”