Crucial malaria discovery validated by international researchers

Crucial malaria discovery validated by international researchers

3 February 2016

Image of Plasmepsin V protein
The Plasmepsin V enzyme has been reinforced as key in
enabling malaria parasites to evade the immune system.

An international research effort has reinforced a Walter and Eliza Hall Institute finding about an enzyme that holds the key to developing a new class of antimalarial drugs.

The finding, originally made by institute scientists in 2010, identified the enzyme Plasmepsin V as being crucial in controlling the transport of critical proteins out of the malaria parasite and into human red blood cells, allowing the parasite to evade the host’s immune system.

It led to the development at the institute in 2014 of WEHI-916 and WEHI-814, compounds that block Plasmepsin V. The compound’s development was the first stage in creating antimalarial drugs that could prevent and cure malaria caused by all species of the parasite – including those resistant to existing antimalarial drugs.

The search for new drug targets is vital – more than 600,000 people worldwide die from malaria each year and more than 200 million people are infected. 

However, the institute’s Plasmepsin V discovery was disputed in 2012 by researchers, publishing in the journal Cell, who claimed that the malaria parasite’s protein export could occur independently of the action of Plasmepsin V.

Professor Alan Cowman and Dr Justin Boddey from the institute’s Infection and Immunity division led the team interrogating the new research. They were joined by scientists from the University of Melbourne; University of Aberdeen, Scotland; Laval University, Québec, Canada; Bernhard Nocht Institute for Tropical Medicine, Hamburg, Germany; and the Philipps University in Marburg, Germany.

The researchers undertook extensive independent studies to test both the institute’s original findings, and the new data. “We established experiments that tried to repeat as closely as possible the published experiments in the Cell paper,” Dr Boddey said.

The new research proposed that a lipid (a fatty acid) involved in general cellular transport was binding to the malaria parasite proteins to transport them from the parasite to the host cell.

A number of different experiments investigating this were unable to reproduce the Cell findings, Dr Boddey said. “These independent laboratories found that although a control that was usually expected to bind to this lipid did so, there was quite strong evidence from these laboratories that malarial proteins were unable to bind to the lipid,” he said.

Professor Cowman said he was delighted the institute’s original finding had been thoroughly vindicated. “We tested their data and our data and concluded that Plasmepsin V was indeed exactly what we said it was – the key to exporting these proteins,” he said. “It showed that the mechanism we proposed in the first place is correct and that Plasmepsin V is a good target for the development of a new class of antimalarial drugs. That’s what we’re pursuing at the moment.”

Dr Boddey said the research also yielded a surprising finding that will aid the institute’s development of an antimalarial drug. “Plasmepsin V is like a bus conductor that selects the proteins that are to be exported into the red blood cell,” he said.

“If you imagine the ticket has a little perforation – that’s where the Plasmepsin V cuts the protein. We moved the position of the ‘perforation’ and it did not export. This means that the specificity of the mechanism is very fine and controlled, very specific – so we can make a drug that is equally specific.”

The research has been published today in Nature Communications.

The research was supported by the National Health and Medical Council of Australia, the Ramaciotti Foundation, the Victorian Government Operational Infrastructure Support Scheme and the Canadian Institutes for Health Research.

Further information

Liz Williams
Media and Publications Manager
M: 0428 034 089
E: williams@wehi.edu.au

 

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