![]() Most notably, the fungal secondary metabolite cladosporin ( Figure 1), a potent inhibitor of parasite growth in blood and liver stages of Plasmodium was confirmed to specifically target cytosolic lysyl tRNA synthetase (KRS (12)). Novel bicyclic azetidines, active in mouse models of malaria, specifically target cytosolic phenylalanyl-tRNA synthetase, (9) while antimalarials borrelidin and halofuginone inhibit threonyl-tRNA synthetase (10) and prolyl-tRNA synthetase, (11) respectively. tRNA synthetases have multiple sites to facilitate binding of ATP, the amino acid, tRNA, and in some cases an editing site to cleave incorrectly charged tRNAs. These enzymes work through a two-step process, initially activating the amino acid through reaction with ATP, with the activated amino acid then transferred to the cognate tRNA. (6)Īminoacyl-tRNA synthetases, which catalyze the aminoacylation of tRNAs with their cognate amino acids, have also shown promise as targets for chemotherapeutic intervention. A further impediment is the dearth of robustly validated drug targets in Plasmodium, thus limiting target-focused screening programs. Control and eradication of malaria will be dependent upon the development of compounds that are active against the majority of parasite lifecycle stages, thus presenting a significant challenge for drug discovery. A small number of blood-stage parasites differentiate into transmissible sexual forms (gametocytes). Intraerythrocytic infection is characterized by repeated rounds of asexual replication (schizogony), resulting in a huge expansion of the parasite population. Parasites replicate and differentiate within hepatocytes prior to entering the bloodstream, where merozoites invade red blood cells. Following initial transmission, sporozoites enter dermal blood vessels and travel through the bloodstream to the liver where they invade hepatocytes. The lifecycle of the Plasmodium parasite is complex. The development of new antimalarials is complicated by a number of factors. (4) In addition, there is a need for new medicines for chemoprotection and prevention of transmission and activity against the hypnozoite stage for the purpose of elimination and eradication. falciparum malaria are extremely high, the consequences could be catastrophic. (3) Should this trend herald the emergence of wide-spread resistance in sub-Saharan Africa where cases and deaths from P. falciparum isolates from Uganda (2) and Rwanda. (1) Even more concerning is the increasing incidence of mutations associated with ACT resistance in P. However, the efficacy of these front-line therapies is now being threatened by emerging resistance, with ACT treatment failure rates in some regions of Southeast Asia reaching 50%. Current antimalarial control is heavily reliant upon a range of artemisinin-based combination therapies (ACTs). The vast majority of malaria deaths are caused by P. The disease results from infection with protozoan parasites from the genus Plasmodium, transmitted through the bite of the Anopheles mosquito. ![]() Malaria is a life-threatening disease that results in more than 600,000 deaths every year, with children under the age of five among the most vulnerable to infection (World Malaria Report 2019, World Health Organization). This combination of tools and methodologies acts as a template for the development of future target-enabling packages. The toolkit includes resistant mutants to probe resistance mechanisms and on-target engagement for specific chemotypes a hybrid KRS protein capable of producing crystals suitable for ligand soaking, thus providing high-resolution structural information to guide compound optimization chemical probes to facilitate pulldown studies aimed at revealing the full range of specifically interacting proteins and thermal proteome profiling (TPP) as well as streamlined isothermal TPP methods to provide unbiased confirmation of on-target engagement within a biologically relevant milieu. Here, we describe the development of a toolkit to support the therapeutic exploitation of a promising target, lysyl tRNA synthetase ( PfKRS). However, with the development of improved target validation strategies, target-focused approaches are now being utilized. Most antimalarial drug discovery is reliant upon phenotypic screening. There is a pressing need for new medicines to prevent and treat malaria.
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