Walter and Eliza Hall Institute researchers have uncovered a potential new target in the fight to eliminate malaria, a parasitic disease that kills more than 400,000 people annually.

The research, led by Dr Danushka Marapana and Professor Alan Cowman, discovered a protein complex essential for the function of the malaria protein plasmepsin V, which their earlier research had also identified as a promising target for antimalarial drugs.

The team hopes that targeting this complex, which is critical for the takeover of red blood cells by the malaria parasite, could lead to the development potential new antimalarial treatments.

At a glance

• New drugs are urgently needed to treat malaria, and our researchers recently developed a potential antimalarial drug that targets the parasite protein plasmepsin V.
• The team have now discovered plasmepsin V replies on the newly identified protein complex, improving the understanding of how this protein enables malaria parasites to survive within red blood cells.
• In the future, drugs that target this complex could potentially be combined with inhibitors of plasmepsin V to provide new antimalarial treatments

Protein gatekeeper

There are many separate compartments within cells, like rooms in a house. The movement of proteins and other molecules between these areas is tightly controlled.

When the malaria parasite invades a red blood cell, it ‘remodels’ the red blood cell, living within its own compartment and moving its own proteins into different parts of the cell, Dr Marapana said.

“Our team recently demonstrated that the protein plasmepsin V is critical for this remodelling by the deadliest malaria parasite, Plasmodium falciparum. Plasmepsin V modifies certain parasite proteins – called PEXEL proteins – so they can be sent into other compartments in the red blood cells,” he said.

Plasmepsin V is located in a compartment within the parasite called the endoplasmic reticulum. PEXEL proteins are located outside this compartment, and until now it was a mystery how the PEXEL proteins reached plasmepsin V.

“Our research showed that a cluster of proteins act as ‘gatekeepers’, recruiting PEXEL proteins to the endoplasmic reticulum where they can be processed by plasmepsin V.”

The research, which was published in the journal Nature Microbiology, also showed that without this complex of proteins, PEXEL proteins couldn’t reach plasmepsin V.

“This discovery explains an important step in how plasmepsin V functions. Plasmepsin V is essential for the survival of P. falciparum parasites in red blood cells, so it is valuable to understand how this complex functions,” Dr Marapana said.

Potential new drug target

New drugs for malaria are urgently needed, as parasite strains have emerged that have developed resistance to almost all the leading antimalarials in clinical use. This newly identified complex of proteins, which is critical for parasite survival, may be a new target for antimalarial therapies, Professor Cowman said.

“Teams at our Institute have already developed inhibitors that block the function of P. falciparum plasmepsin V, and this approach shows promise as a new treatment for malaria. We speculate that drugs that prevent PEXEL proteins from engaging plasmepsin V could be another avenue for treating malaria, or could enhance the efficacy of drugs directly targeting plasmepsin V,” he said.

“There are already potential anti-cancer drugs that block a human protein complex similar to the one we have identified in P. falciparum, so we are optimistic that it would be possible to develop a similar drug as a possible antimalarial agent.

“As well as being potential new treatments for malaria on their own, drugs that target the newly identified complex might also be combined with drugs targeting plasmepsin V. A combination of drugs could potentially use less of each drug to kill the malaria parasite, a concept known as synergy. Combining these putative antimalarial drugs could also make it harder for drug resistant parasites to emerge,” Professor Cowman said.

The research was supported by the Australian National Health and Medical Research Council, Howard Hughes Medical Institute, EMBO and the Victorian Government.

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