Characterising a new drug target in the malaria parasite

by Natalie Spillman

Measurement of the Na+ concentration within malaria parasites. Upon treatment with a ‘PfATP4 inhibitor’ (at the red arrow) the parasites rapidly fill with Na+, which leads to death.

Malaria remains a serious global health threat, with up to half of the world’s population living in malaria endemic regions. Although significant advances in malaria control have been made in the past few decades, resistance to our current antimalarial drug repertoire threatens control efforts. Therefore, it is important to identify and characterise new antimalarials.

Whilst screening chemical libraries for compounds that could kill the parasite, multiple screens identified a gene called pfatp4 as being a potential new drug target. However PfATP4 function was a mystery and the mechanism by which the compounds killed the parasites was unclear. In 2013 Prof. Kiaran Kirk’s lab showed that the PfATP4 protein is involved in parasite sodium (Na+) regulation. This research showed that the parasite uses a specialised pump to efflux Na+ out of the cell, thus maintaining low Na+ inside the cell. Upon treatment with the new antimalarials the parasites rapidly fill with Na+, leading to parasite death. Current research involves finding out why the extra Na+ is so lethal. Additionally, researchers are trying to characterise PfATP4 function in greater detail so more potent inhibitors with better pharmacokinetic properties can be discovered.

Three antimalarials in the current Medicines for Malaria Venture drug discovery pipeline are PfATP4 inhibitors. With results of early clinical trials giving promising results, ANU researchers are hopeful that PfATP4 inhibitors will become a novel weapon to treat the worldwide malaria scourge. 

 

In 2017, we celebrate 50 years of Biology at ANU. This article is one of a set featuring the achievements and memorable occasions of ANU biologists those first 50 years.
Read more at Biology at ANU – the first 50 years.

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