University of Melbourne - High throughput screening to identify selective proteasome inhibitors as new antimalarials with a novel mode of action

Start : May 2017 | Status : Active

The scientist: Dr. Stanley Xie is a postdoctoral researcher at the University of Melbourne, working under the supervision of Dr. Leann Tilley. He has extensive experience studying the P. falciparum proteasome and the mechanisms of action of and resistance to artemisinins. He will focus his research on identification and characterization ofnew hits acting through the P. falciparum proteasome.

The sponsor: University of Melbourne

Foundation funding: The Foundation is providing £198.239 in support.

GSK’s contribution: GSK will support the project with its enzymology and high throughput screening platforms and contribute with its past experience working on the P. falciparum Ubiquitin Proteasome System. Additionally, GSK will also provide access to Biosafety Level 3 facilities and to GSK´s collection of proprietary compounds.

Project Description: Current antimalarial control is highly dependent on Artemisinin-based Combination Therapies (ACTs), which makes the emergence of artemisinin (ART) resistance extremely concerning. This situation highlights the need to identify new drugs targeting different mechanisms in the parasite. The proteasome is a validated target for malaria. Inhibitors of the proteasome show parasiticidal activity against both ART sensitive and resistant parasites, and are active both against sexual and asexual intraerythroctyic stages, as well as liver stages. Moreover, the Leann Tilley lab has demonstrated that inhibitors of the proteasome strongly synergize ART-mediated killing of P. falciparum, being also suitable for combination therapies.

The objective of this Open Lab project is to undertake a screening campaign to identify P. falciparum-specific proteasome inhibitors, thereby avoiding any toxicity associated with inhibition of the human proteasome. An extensive compound characterization will be performed, determining the parasitological profile and the mechanism of action applying tools developed in parallel during the project.