Small molecule inhibition of protein secretion in malaria parasites

Malaria remains a major global health burden causing hundreds of millions of debilitating infections per year that tragically result in nearly half a million deaths. The mosquito-borne Plasmodium parasites which cause malaria, grow inside in human hepatocytes and erythrocytes. 

Although the parasites can be eliminated with drugs, they eventually develop resistance, including to the latest frontline artemisinin therapies. Currently there is no replacement for artemisinin and it is crucial that new drugs be identified soon since it can take many years for these to reach the clinic.

A potential new drug target is the machinery used by parasites to move proteins around its cytoplasm and organelles, and even into the human cells in which they grow. Parasites export hundreds of effector proteins particularly into their erythrocytes, and these effectors aid nutrient acquisition to fuel rapid growth and help the parasite avoid host immunity.

Several years ago, we discovered a transporter complex called PTEX that exports effector proteins into the host cell and have genetically stopped its expression which led to rapid parasite death. This validates PTEX as an important drug target along with the protein trafficking machinery that delivers effectors to PTEX.

We have recently screened a library of parasite-killing compounds and identified several that reduce parasite protein secretion and export. This Honours project will involve trying to find and validate the biological targets of these inhibitors in parasites to further understand how protein export works and inform future development of new drugs that can block protein export.

Laboratory techniques learned will include tissue culturing, parasites growth experiments, assay development, and fluorescence microscopy.