The malaria parasite is a mutation expert.

This enables it to become resistant to all known antimalarial treatments. So far, the only option has been controlling the mosquito populations that spread the parasite between humans.

Riding in the salivary glands of pregnant mosquitoes, the Plasmodium falciparum parasite is injected into our skin when we are bitten.

From there the parasite undergoes a series of transformations – adapting to grow in liver tissue where it adjusts to avoid our immune systems by invading and growing in our red blood cells, which eventually burst, spreading even more parasites.

If a victim is bitten by another mosquito, that mosquito will become infectious and the cycle goes on and on.

But researchers have developed small molecule compounds that stop the parasite itself from being spread by mosquitoes.

The malaria parasite only develops male and female forms, the so-called gametocytes, once inside the human body, but these don't fertilise until they are in a mosquito's stomach.

What the new study shows is that compounds can block a key enzyme that the parasite needs to develop into gametocytes. And without gametocytes the parasite will simply be digested in the mosquito's stomach and die there, preventing it from infecting the insect in the first place.

Published today in Cell Reports, researchers at the University of Melbourne and Walter and Eliza Hall Institute (WEHI), in collaboration with Griffith University in Queensland, have developed small molecule compounds that acts as an "inhibitor", knocking out the plasmepsin V enzyme, without which the gametocytes dies.

Associate Professor Justin Boddey from WEHI and the University of Melbourne says the discovery breaks new ground towards helping malaria elimination.

"It's exciting to find that our inhibitors can target plasmepsin V in gametocytes and block transmission to the mosquito from occurring," he says.

"Blocking the parasite from transmitting itself to mosquitoes is important for developing preventative therapies that stop the spread of disease."

More than half a million people die from malaria every year. Plasmodium falciparum – the most lethal of all malaria parasites – is responsible for 90 per cent of infection cases and deaths.

In Africa – which accounts for 94 per cent of malaria deaths – P. falciparum is responsible for 99.7 per cent of malaria infections.

New preventions and treatments are required that act across different stages of the malaria parasite's complicated lifecycle – liver, blood and gametocyte - the final transmission step back to the mosquito.

Arrested development

Using high-containment facilities at WEHI, researchers bred malaria mosquitoes and were able to study how gametocytes transmit from human blood to mosquito.

They used gametocyte-specific fluorescent 'tags' to observe how gametocytes hijack their host cell and develop inside by exporting effector proteins.

It was this technique that enabled them to identify the critical role played by plasmepsin V in gametocytes.

This highlighted the key part that plasmepsin V plays in export of gametocyte proteins and malaria parasite transmission, making this protease an effective drug target for killing the malaria parasite in both the asexual blood stage of its lifecycle, which is when malaria symptoms – fever, chills, muscle pain and nausea – occur, and in gametocytes that spread disease via mosquitoes.

In collaboration with Professor Vicky Avery at Griffith University, the team used plasmepsin V inhibitors developed in 2015 to show that an optimal concentration killed young gametocytes.

However, a lower dose that allowed gametocytes to completely develop still blocked infection of mosquitoes at the WEHI Insectary.

"This shows that plasmepsin V is a target for transmission-blocking drugs," says Associate Professor Boddey.

Double whammy for disease

WEHI and University of Melbourne chemical biologist Dr Brad Sleebs, who was involved in both the current and previous studies, says the enzyme was proving to be an ideal drug target because of its importance for parasite survival at different stages of the malaria lifecycle.

"It's encouraging to observe inhibitors that target plasmepsin V are effective against both the asexual blood and sexual transmission stages of the parasite's lifecycle," he says.

"Our research demonstrates that an antimalarial treatment targeting plasmepsin V has potential, not only in treatment of the disease, but also as a preventative population control measure."

Associate Professor Boddey says the research had been a great example of how basic and translational knowledge was established from new studies building on the last.

"It's been a rewarding journey from identifying the function of plasmepsin V, to developing inhibitors that block it and kill asexual malaria parasites, to now validating this enzyme's dual function as an effective blood stage and transmission-blocking drug target," he says.

Sights set on the final pillar

Researchers are now turning their attention to the role of plasmepsin V in the remaining pillar of the malaria lifecycle: the liver stage.

"Our aim is to assess plasmepsin V as a multi-stage drug target for treating, as well as preventing, the spread of malaria; and to understand the unique biology occurring during liver infection," says Associate Professor Boddey.

Researchers are collaborating with pharmaceutical company Merck and the Wellcome Trust to develop drugs targeting plasmepsin V in multiple parasite species.

This research was supported by the Australian National Health and Medical Research Council of Australia, the CASS Foundation and the Victorian Government.

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