Aminoacyl-tRNA synthetases enzymes as drug targets
Projects on offer are aimed at characterising aminoacyl-tRNA synthetase (aaRS) enzymes as drug targets in Plasmodium. These enzymes catalyse the attachment of amino acids to their relevant tRNA molecules and are essential for protein synthesis. They have recently been recognised as promising drug targets across a broad range of microbes, and we have recently identified Plasmodium aaRSs that are potential targets for new drugs to treat malaria. Plasmodium aaRS enzymes are very different to the forms found in humans, so we hope to develop drugs that inhibit Plasmodium without affecting their human host cells. We are developing assays to measure specific inhibition of Plasmodium aaRS enzymes, and will also test inhibitors for their ability to kill Plasmodium grown in culture.
Figure 1: A structural model of a P. falciparum aminoacyl-tRNA synthetase. aaRS enzymes have several deep substrate-binding pockets that appear to be suitable for targeting with small molecule inhibitors. Such inhibition has already been demonstrated for many bacteria, including Staphylococcus aureus (golden staph).
The Ralph laboratory is a member of a European Union FP7-funded consortium (Mephitis) of eight laboratories studying protein translation in the apicoplast and cystosol of Plasmodium in the search for potential targets for anti-malarial drugs.
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