Promising anti-malaria target found

An international collaboration, including scientists from the Queensland Institute of Medical Research (QIMR), University of Western Sydney, University of Technology Sydney, Monash and Griffith Universities, has detailed the structure and function of an enzyme crucial to the malaria parasite which could prove to be a highly effective drug target.

According to Associate Professor Don Gardiner of the QIMR, the enzyme, M17 leucine aminopeptidase (M17LAP), enables the parasite to obtain nutrients from the blood.

“If we can make a drug that will stop this enzyme from working properly, we can essentially starve the parasites to death,” said Gardiner.

The hunt for the enzyme began several years ago in order to better understand the mechanism that underpinned the function of the aminopeptidase inhibitor, Bestatin.

"We had some ideas based on the fact aminopeptidase inhibitors appeared to kill the malaria parasite, but the targets weren't obvious," said Gardiner.

Bestatin is a natural analog of the dipeptide Phe-Leu derived from the fungus Streptomyces olivoretticuli, and is a potent inhibitor of neutral aminopeptidase activity (Ki 50.7 nM) in malaria cell extracts. It was found to block the growth of P. falciparum parasites in vitro.

However, Bestatin is not an ideal anti-malaria drug in itself due to its short half-life.

The international team used x-ray crystallography to see the structure and function of the enzyme and also produced compounds that could block its action.

The team has already screen quarter of a million compounds looking for inhibitors that block this enzyme, with the top performing 128 being investigated in greater depth.

The hope is to develop a drug that can effectively halt malaria without significant side-effects. It is known that Bestatin is very well tolerated in humans, so it's hoped another compound will be similarly tolerated.

This study was done in collaboration with McGill University, Monash University, University of Western Sydney, University of Edinburgh, Wroclaw University of Technology, University of Virginia, and University of Technology Sydney. The paper was published in Proceedings of the National Academy of Sciences on 29 January.