MEPHITIS

Targeting Protein Synthesis in the Apicoplast and Cytoplasm of Plasmodium

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 Obiettivo del progetto (Objective)

'The protein synthesis machinery represents one of the most useful targets for the development of new anti-infectives. Several families of broadly used antibiotics (tetracyclines, macrolides, and novel glycopeptides like vancomycin, among others) exert their function by blocking the protein synthesis machinery. Doxicycline, a tetracycline antibiotic, remains a useful tool for the prevention of paludism among travellers, despite its numerous secondary effects. And yet, very little is known about the specifics of the protein synthesis machinery in Plasmodium. A search of articles in the PubMed library with the words Plasmodium and ribosome/ribosomal in their titles will yield 6 publications since the year 2000. Only one article contains the words tRNA (or transfer RNA) and Plasmodium in its title, in the same period. And only one article in PubMed (Snewin et al., 1996) contains the words Plasmodium and ‘tRNA synthetase’ (or ligase) in its title. This lack of information about this central metabolic pathway in Plasmodium clearly blocks the possibility of transferring the knowledge in protein synthesis to the development of new anti-malarial drugs directed against the translational machinery of the parasite. Thus, the study of components of the genetic code in Plasmodium has the potential for providing new and important information on the biology of the parasite and, more importantly, open new leads for the development of novel anti-malarials. This proposal coordinates an effort to study tRNA biology in Plasmodium falciparum. It contains specific schemes for the development of new pharmacological screens, several initiatives for the selection of new potential anti-malarial drugs, and projects designed to answer fundamental questions regarding protein synthesis in Plasmodium. The laboratories in MEPHITIS accumulate a large body of experience in the biology of this parasite, and in different aspects of tRNA biology in model species.'

Introduzione (Teaser)

A European study pursued a new avenue in the design of drugs against malaria: it explored gene translation in the parasite Plasmodium falciparum as the target.

Descrizione progetto (Article)

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 http://www.mephitis.eu/ (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.