New drugs targeting malaria
Malaria remains a serious health issue in certain parts of the world. Current treatment is based on a combinatorial administration of antimalarial drugs. This is only partly effective and is unfortunately associated with increased drug-resistance. Novel targeted drugs are urgently required against the causative agent Plasmodium falciparum. The EU-funded MEPHITIS (Targeting protein synthesis in the apicoplast and cytoplasm of Plasmodium) project embarked on antimalarial drug discovery. Their innovative approach targeted the parasite protein synthesis machinery. To achieve this, researchers had to first study protein synthesis in Plasmodium and then identify molecules that could serve as therapeutic targets for malaria. Project activities concentrated on the apicoplast, a Plasmodium-specific cellular compartment that constitutes an excellent target for the development of new drugs. Of particular interest was the analysis of two different enzyme families: the aminoacyl-tRNA synthetases (ARS) and the elongation factors that are implicated in protein synthesis. The consortium followed both a computational and structural approach in the analysis of protein synthesis components. Emphasis was also given to the study of the evolutionary relationships among ARSs, because this is an obligate step to the identification of the best candidates for future drug development. MEMPHITIS successfully characterised the cellular distribution and the biological activity of several components of the protein synthesis apparatus of the parasite. They obtained structural data for various ARS enzymes and unveiled a new transfer RNA (tRNA) binding protein responsible for the transport of exogenous tRNAs into the parasite. This data served as the basis for the design of novel inhibitory scaffolds directed against different ARSs. Furthermore, other factors required for translation initiation, peptide release, and ribosome recycling in apicoplast and mitochondria of the Plasmodium were identified. Efforts at validating the ability of known enzyme inhibitors to specifically inhibit parasite translation unveiled the compound borrelidin with a powerful anti-malarial activity. New inhibitory molecules have also been identified opening up novel paths for therapeutic exploitation in malaria research.
Keywords
Drugs, malaria, Plasmodium falciparum, protein synthesis, aminoacyl-tRNA synthetases, borrelidin
