Researchers develop a drug-like compound that blocks a key malaria enzyme, killing the parasite.

Institute researchers advance on a new target for malaria treatment after developing a drug-like compound that blocks the action of a key ‘gatekeeper’ enzyme essential for malaria parasite survival.

The compound, called WEHI-916, is the first step toward a new class of antimalarial drugs that could cure and prevent malaria infections caused by all species of the parasite, including those resistant to existing drugs.

Blocking the gatekeeper

Dr Justin Boddey, Dr Brad Sleebs and colleagues developed WEHI-916 to block the critical malaria enzyme plasmepsin V. The research team previously identified plasmepsin V as a ‘gatekeeper’ enzyme responsible for controlling the delivery of critical malaria proteins out of the parasite into human red blood cells.

Boddey says the research team used WEHI-916 to prove the importance of plasmepsin V to malaria parasite survival. “We’ve developed a novel compound to target plasmepsin V and show for the first time that the enzyme is essential for survival of the malaria parasite,” he says. “WEHI-916 is really exciting because if you block plasmepsin V, the malaria parasite dies.”

Plasmepsin V is an ideal drug target because its inhibition halts the transport of hundreds of malaria proteins. “The Plasmodium parasite needs to produce and deliver more than 400 different proteins into its red blood cell home to survive in the body and hide from the host’s immune system,” Boddey says. “Instead of targeting individual proteins, we can block plasmepsin V and prevent all of them from leaving the parasite.”

New class of antimalarials

Sleebs says WEHI-916 could lead to drugs that are effective in curing malaria caused by all five species of Plasmodium parasite that infect humansa. “Of the five malaria species, Plasmodium falciparum is responsible for the most deaths and is highly prevalent in Africa, while Plasmodium vivax presents major health issues for the Asia-Pacific region,” he says.

“We’ve shown that plasmepsin V is a key enzyme in these two important species of the parasite and WEHI-916 can inhibit plasmepsin V isolated from both of them. Not only does this compound enable us to prove that plasmepsin V is an excellent drug target, it is also an important starting point for our research program that could lead to a new class of antimalarial drugs.”

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