Stopping malaria parasites before they get started: investigating role of PfSTART1 during parasite invasion

With resistance to frontline antimalarial drugs increasing around the world new drugs need to be discovered and developed ready to enter the antimalarial pipeline when they are needed.

New drugs also need to function differently to current drugs so parasites that are resistant to current medicines will not be resistant to the new drugs.

One promising new drug target is the step in the lifecycle where the parasites invade human red blood cells (RBC)in which they grow and reproduce.

To find drugs that inhibit RBC invasion we have screened libraries of drug-like compounds and discovered one compound M833, that blocks parasites from growing after they invade a RBC.

We have discovered the target of M833 is a protein called START1 which normally transports lipids around the cell to help expand the cell’s membranes as it grows. We have engineered M833 into a much more potent form W991, which is as powerful as current antimalarial drugs.

We still do not fully understand how START1 helps parasites grow and therefore how M833/W991 works. This project will therefore attempt to answer important questions about START1’s biology such as where it functions inside the parasite-infected RBCs and how that changes during the cell cycle.

We would also like to know what stages of the parasite’s cell cycle are inhibited by M833/W991 and if START1 functions by itself or works in collaboration with other proteins.

For drug development, we would like to develop a START1 inhibitor that inhibits multiple parasite species and how resistance to START1 could arise.

Skills that will be acquired during this project include parasite cell culture, immunofluorescence microscopy, parasite molecular biology, genetic engineering and protein purification.